Effects of Varenicline on Ethanol-Induced Conditioned Place Preference, Locomotor Stimulation, and Sensitization

PubMed Central

Gubner, Noah R.; McKinnon, Carrie S.; Phillips, Tamara J.

2014-01-01

Background Varenicline, a partial nicotinic acetylcholine receptor (nAChR) agonist, is a promising new drug for the treatment of alcohol (ethanol) dependence. Varenicline has been approved by the Food and Drug Administration as a smoking cessation therapeutic and has also been found to reduce ethanol consumption in humans and animal models of alcohol use. The current studies examined the hypotheses that varenicline attenuates the stimulant and sensitizing effects of ethanol, and reduces the motivational effects of ethanol-associated cues. The goal was to determine if these effects of varenicline contribute to its pharmacotherapeutic effects for alcohol dependence. In addition, effects of varenicline on acute stimulation and/or on the acquisition of sensitization would suggest a role for nAChR involvement in these effects of ethanol. Methods Dose-dependent effects of varenicline on the expression of ethanol-induced conditioned place preference (CPP), locomotor activation, and behavioral sensitization were examined. These measures model motivational effects of ethanol-associated cues, euphoric or stimulatory effects of ethanol, and ethanol-induced neuroadaptation. All studies used DBA/2J mice, an inbred strain with high sensitivity to these ethanol-related effects. Results Varenicline did not significantly attenuate the expression of ethanol-induced CPP. Varenicline reduced locomotor activity and had the most pronounced effect in the presence of ethanol, with the largest effect on acute ethanol-induced locomotor stimulation and a trend for varenicline to attenuate the expression of ethanol-induced sensitization. Conclusions Because varenicline did not attenuate the expression of ethanol-induced CPP, it may not be effective at reducing the motivational effects of ethanol-associated cues. This outcome suggests that reductions in the motivational effects of ethanol-associated cues may not be involved in how varenicline reduces ethanol consumption. However, varenicline did have effects on locomotor behavior and significantly attenuated acute ethanol-induced locomotor stimulation. In humans who drink while taking varenicline, it might similarly reduce stimulant responses and have an impact on continued drinking. General sedative effects in such individuals should be carefully considered. PMID:25581658

Long-term effects of chronic intermittent ethanol exposure in adolescent and adult rats: radial-arm maze performance and operant food reinforced responding.

PubMed

Risher, Mary-Louise; Fleming, Rebekah L; Boutros, Nathalie; Semenova, Svetlana; Wilson, Wilkie A; Levin, Edward D; Markou, Athina; Swartzwelder, H Scott; Acheson, Shawn K

2013-01-01

Adolescence is not only a critical period of late-stage neurological development in humans, but is also a period in which ethanol consumption is often at its highest. Given the prevalence of ethanol use during this vulnerable developmental period we assessed the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence, compared to adulthood, on performance in the radial-arm maze (RAM) and operant food-reinforced responding in male rats. Male Sprague Dawley rats were exposed to CIE (or saline) and then allowed to recover. Animals were then trained in either the RAM task or an operant task using fixed- and progressive- ratio schedules. After baseline testing was completed all animals received an acute ethanol challenge while blood ethanol levels (BECs) were monitored in a subset of animals. CIE exposure during adolescence, but not adulthood decreased the amount of time that animals spent in the open portions of the RAM arms (reminiscent of deficits in risk-reward integration) and rendered animals more susceptible to the acute effects of an ethanol challenge on working memory tasks. The operant food reinforced task showed that these effects were not due to altered food motivation or to differential sensitivity to the nonspecific performance-disrupting effects of ethanol. However, CIE pre-treated animals had lower BEC levels than controls during the acute ethanol challenges indicating persistent pharmacokinetic tolerance to ethanol after the CIE treatment. There was little evidence of enduring effects of CIE alone on traditional measures of spatial and working memory. These effects indicate that adolescence is a time of selective vulnerability to the long-term effects of repeated ethanol exposure on neurobehavioral function and acute ethanol sensitivity. The positive and negative findings reported here help to further define the nature and extent of the impairments observed after adolescent CIE and provide direction for future research.

Acute Ethanol Withdrawal Impairs Contextual Learning and Enhances Cued Learning

PubMed Central

Tipps, Megan E.; Raybuck, Jonathan D.; Buck, Kari J.; Lattal, K. Matthew

2014-01-01

Background Alcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure. Methods We assess the effects of acute ethanol withdrawal (6 h post-injection with 4 g/kg ethanol) on two forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post-training withdrawal exposure; foreground/background processing; training strength; non-associative effects) is also investigated. Results Acute ethanol withdrawal during training had a bidirectional effect on fear conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses. Conclusions Our results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes. PMID:25684050

Physicochemical properties, antioxidant activities and protective effect against acute ethanol-induced hepatic injury in mice of foxtail millet (Setaria italica) bran oil.

PubMed

Pang, Min; He, Shujian; Wang, Lu; Cao, Xinmin; Cao, Lili; Jiang, Shaotong

2014-08-01

This study was designed to investigate physicochemical characterization of the oil extracted from foxtail millet bran (FMBO), and the antioxidant and hepatoprotective effects against acute ethanol-induced hepatic injury in mice. GC-MS analysis revealed that unsaturated fatty acids (UFAs) account for 83.76% of the total fatty acids; in particular, the linoleic acid (C18:2) is the predominant polyunsaturated fatty acid (PUFA), and the compounds of squalene and six phytosterols (or phytostanols) were identified in unsaponifiable matter of FMBO. The antioxidant activity examination of FMBO in vitro showed highly ferric-reducing antioxidant power and scavenging effects against DPPH· and HO· radicals. Furthermore, the protective effect of FMBO against acute hepatic injuries induced by ethanol was verified in mice. In this, intragastric administration with different dosages of FMBO in mice ahead of acute ethanol administration could observably antagonize the ethanol-induced increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), and the hepatic malondialdehyde (MDA) levels, respectively, along with enhanced hepatic superoxide dismutase (SOD) levels relative to the control. Hepatic histological changes were also observed and confirmed that FMBO is capable of attenuating ethanol-induced hepatic injury.

Increases in anxiety-like behavior induced by acute stress are reversed by ethanol in adolescent but not adult rats.

PubMed

Varlinskaya, Elena I; Spear, Linda P

2012-01-01

Repeated exposure to stressors has been found to increase anxiety-like behavior in laboratory rodents, with the social anxiety induced by repeated restraint being extremely sensitive to anxiolytic effects of ethanol in both adolescent and adult rats. No studies, however, have compared social anxiogenic effects of acute stress or the capacity of ethanol to reverse this anxiety in adolescent and adult animals. Therefore, the present study was designed to investigate whether adolescent [postnatal day (P35)] Sprague-Dawley rats differ from their adult counterparts (P70) in the impact of acute restraint stress on social anxiety and in their sensitivity to the social anxiolytic effects of ethanol. Animals were restrained for 90 min, followed by examination of stress- and ethanol-induced (0, 0.25, 0.5, 0.75, and 1 g/kg) alterations in social behavior using a modified social interaction test in a familiar environment. Acute restraint stress increased anxiety, as indexed by reduced levels of social investigation at both ages, and decreased social preference among adolescents. These increases in anxiety were dramatically reversed among adolescents by acute ethanol. No anxiolytic-like effects of ethanol emerged following restraint stress in adults. The social suppression seen in response to higher doses of ethanol was reversed by restraint stress in animals of both ages. To the extent that these data are applicable to humans, the results of the present study provide some experimental evidence that stressful life events may increase the attractiveness of alcohol as an anxiolytic agent for adolescents. Copyright © 2011 Elsevier Inc. All rights reserved.

HINDBRAIN AND CRANIAL NERVE DYSMORPHOGENESIS RESULT FROM ACUTE MATERNAL ETHANOL ADMINISTRATION

EPA Science Inventory

Acute exposure of mouse embryos to ethanol during stages of hindbrain segmentation results in excessive cell death in specific cell populations. This study details the ethanol-induced cell loss and defines the subsequent effects of this early insult on rhombomere and cranial ner...

Effects of topiramate and other anti-glutamatergic drugs on the acute intoxicating actions of ethanol in mice: modulation by genetic strain and stress

PubMed Central

Chen, Yi-Chyan; Holmes, Andrew

2008-01-01

Compounds with anti-glutamatergic properties currently in clinical use for various indications (e.g., Alzheimer's disease, epilepsy, psychosis, mood disorders) have potential utility as novel treatments for alcoholism. Enhanced sensitivity to certain acute intoxicating effects (ataxia, sedative) of alcohol may be one mechanism by which anti-glutamatergic drugs modulate alcohol use. We examined the effects of six compounds (memantine, dextromethorphan, haloperidol, lamotrigine, oxcarbazepine, topiramate) on sensitivity to acute intoxicating effects of ethanol (ataxia, hypothermia, sedation/hypnosis) in C57BL/6J mice. Analysis of topiramate was extended to determine the influence of genetic background (via comparison of the 129S1, BALB/cJ, C57BL/6J, DBA/2J inbred strains) and prior stress history (via chronic exposure of C57BL/6J to swim stress) on topiramate's effects on ethanol-induced sedation/hypnosis. Results showed that one N-methyl-D-aspartate receptor (NMDAR) antagonist, memantine, but not another, dextromethorphan, potentiated the ataxic but not hypothermic or sedative/hypnotic effects of ethanol. Haloperidol increased ethanol-induced ataxia and sedation/hypnosis to a similar extent as the prototypical NMDAR antagonist MK-801. Of the anticonvulsants tested, lamotrigine accentuated ethanol-induced sedation/hypnosis, while oxcarbazepine was without effect. Topiramate was without effect per se under baseline conditions in C57BL/6J, but had a synergistic effect with MK-801 on ethanol-induced sedation/hypnosis. Comparing inbred strains, topiramate was found to significantly potentiated ethanol's sedative/hypnotic effects in BALB/cJ, but not 129S1, C57BL/6J or DBA/2J strains. Topiramate also increased ethanol-induced sedation/hypnosis in C57BL/6J after exposure to chronic stress exposure. Current data demonstrate that, with the exception of MK-801 and haloperidol, the compounds tested had either no significant or assay-selective effects on sensitivity to acute ethanol under baseline conditions in C57BL/6J. However, significant effects of topiramate were revealed as a function of co-treatment with a NMDAR blocker, genetic background or prior stress history. These findings raise the possibility that topiramate and possibly other anti-glutamatergic drugs could promote the acute intoxicating effects of ethanol in specific subpopulations defined by genetics or life history. PMID:18843265

Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity

PubMed Central

Greenberg, Gian D.; Phillips, Tamara J.; Crabbe, John C.

2017-01-01

Nest building has been used to assess thermoregulatory behavior and positive motivational states in mice. There are known genetic influences on ethanol withdrawal severity as well as individual/thermoregulatory nest building. Withdrawal Seizure-Prone (WSP-1, WSP-2) and Withdrawal Seizure-Resistant (WSR-1, WSR-2) mice were selectively bred for high vs low handling-induced convulsion (HIC) severity, respectively, during withdrawal from chronic ethanol vapor inhalation. They also differ in HIC severity during withdrawal from an acute, 4 g/kg ethanol injection. In our initial study, withdrawal from an acute dose of ethanol dose-dependently impaired nest building over the initial 24 h of withdrawal in genetically segregating Withdrawal Seizure Control (WSC) mice. In two further studies, acute ethanol withdrawal suppressed nest building for up to two days in WSP-1 females. Deficits in nest building from ethanol were limited to the initial 10 h of withdrawal in WSR-1 females and to the initial 24 h of withdrawal in WSP-1 and WSR-1 males. Effects of ethanol on nest building for up to two days were found in WSP-2 and WSR-2 mice of both sexes. Nest building deficits in female mice from the first replicate could not be explained by a general decrease in locomotor behavior. These results suggest that nest building is a novel behavioral phenotype for indexing the severity of acute ethanol withdrawal, and that genes contributing to this trait differ from those affecting acute withdrawal HIC severity. PMID:27503811

The evolution of Drosophila melanogaster as a model for alcohol research.

PubMed

Devineni, Anita V; Heberlein, Ulrike

2013-07-08

Animal models have been widely used to gain insight into the mechanisms underlying the acute and long-term effects of alcohol exposure. The fruit fly Drosophila melanogaster encounters ethanol in its natural habitat and possesses many adaptations that allow it to survive and thrive in ethanol-rich environments. Several assays to study ethanol-related behaviors in flies, ranging from acute intoxication to self-administration and reward, have been developed in the past 20 years. These assays have provided the basis for studying the physiological and behavioral effects of ethanol and for identifying genes mediating these effects. In this review we describe the ecological relationship between flies and ethanol, the effects of ethanol on fly development and behavior, the use of flies as a model for alcohol addiction, and the interaction between ethanol and social behavior. We discuss these advances in the context of their utility to help decipher the mechanisms underlying the diverse effects of ethanol, including those that mediate ethanol dependence and addiction in humans.

Possible mechanism of acute effect of ethanol on intestinal IgA expression in rat.

PubMed

Budec, Mirela; Koko, Vesna; Todorović, Vera; Marković, Dragana; Postić, Marija; Drndarević, Neda; Spasić, Andelka; Mitrović, Olivera

2007-06-01

The purpose of this study was to investigate the possible mechanism of acute effect of ethanol on IgA expression in rat intestine. To this end, adult female Wistar rats showing diestrus day 1 were treated with (a) ethanol (2 or 4 g/kg, i.p.); (b) N omega-nitro-L-arginine-methyl ester (L-NAME), which inhibits the activity of all isoforms of nitric oxide synthase, (30 mg/kg, s.c.) followed by ethanol 3 h later; and (c) L-NAME (30 mg/kg, s.c.) followed by saline 3 h later. Saline-injected and untreated rats were used as controls. The animals were sacrificed 0.5 h after ethanol administration. Intestinal expression of IgA was evaluated by both immunohistochemistry and Western immunoblotting. Morphometric analysis showed that acute ethanol treatment increased the number of IgA-immunoreactive cells in a dose-dependent manner. Pretreatment with L-NAME abolished this action of alcohol. Injection of L-NAME followed by saline had no influence on the number of IgA+cells. The results, obtained by Western immunoblotting, paralleled our immunohistochemical findings. Taken together, these data suggest that acute effect of ethanol on intestinal IgA might be mediated by endogenous nitric oxide.

Intoxication- and withdrawal-dependent expression of central and peripheral cytokines following initial ethanol exposure

PubMed Central

Doremus-Fitzwater, Tamara L.; Buck, Hollin M.; Bordner, Kelly A.; Richey, Laura; Jones, Megan E.; Deak, Terrence

2016-01-01

Background Evidence has emerged demonstrating that ethanol influences cytokine expression within the CNS, although most studies have examined long-term exposure. Thus, the cytokine response to an acute ethanol challenge was investigated, in order to characterize profiles of cytokine changes following acute exposure. Methods Rats pups were injected intraperitoneally (i.p.) with 2-g/kg ethanol and IL-1 mRNA and protein assessed 0, 60, 120, 180, and 240 min post-injection (Exp. 1). In Exps. 2-5, the expression of several cytokines was examined in adult male rats during acute intoxication (3 hr after 4-g/kg ethanol), as well as withdrawal (18 hr post-injection), after i.p. and intragastric (i.g.) ethanol administration. Results Early in ontogeny, acute ethanol significantly decreased brain IL-1 mRNA and protein. Subsequently, when adult rats were examined, significant and temporally dynamic alterations in central and peripheral cytokines were observed following acute i.p. ethanol exposure (4-g/kg). Although cytokine- and region-dependent, central IL-6 expression was generally increased and TNFα decreased during intoxication, whereas IL-1 expression exhibited increases during withdrawal. In the periphery, acute i.p. ethanol elevated expression of all cytokines, with the response growing in magnitude as the time post-injection increased. Following acute i.g. ethanol (4-g/kg), intoxication-related increases in IL-6 expression were again observed in the PVN, although to a lesser extent. Long-term, voluntary, intermittent ethanol consumption resulted in tolerance to the effects of an i.g. ethanol challenge (4-g/kg) on PVN IL-6 expression, whereas these same elevations in IL-6 expression were still seen in the amygdala in rats with a history of moderate ethanol intake. Treatment with minocycline did not significantly attenuate i.p. or i.g. ethanol-induced changes in central cytokine expression. Conclusions Together, these studies provide a foundation for understanding fluctuations in central and peripheral cytokines following acute ethanol as potential contributors to the constellation of neural and behavioral alterations observed during ethanol intoxication and withdrawal. PMID:25156612

Acute and Chronic Ethanol Exposure Differentially Regulate CB1 Receptor Function at Glutamatergic Synapses in the Rat Basolateral Amygdala

PubMed Central

Robinson, Stacey L.; Alexander, Nancy J.; Bluett, Rebecca J.; Patel, Sachin; McCool, Brian A.

2016-01-01

The endogenous cannabinoid (eCB) system has been suggested to play a key role in ethanol preference and intake, the acute effects of ethanol, and in the development of withdrawal symptoms following ethanol dependence. Ethanol-dependent alterations in glutamatergic signaling within the lateral/basolateral nucleus of the amygdala (BLA) are critical for the development and expression of withdrawal-induced anxiety. Notably, the eCB system significantly regulates both glutamatergic and GABAergic synaptic activity within the BLA. Chronic ethanol exposure significantly alters eCB system expression within regions critical to the expression of emotionality and anxiety-related behavior, including the BLA. Here, we investigated specific interactions between the BLA eCB system and its functional regulation of synaptic activity during acute and chronic ethanol exposure. In tissue from ethanol naïve-rats, a prolonged acute ethanol exposure caused a dose dependent inhibition of glutamatergic synaptic activity via a presynaptic mechanism that was occluded by CB1 antagonist/inverse agonists SR141716a and AM251. Importantly, this acute ethanol inhibition was attenuated following 10 day chronic intermittent ethanol vapor exposure (CIE). CIE exposure also significantly down-regulated CB1-mediated presynaptic inhibition at glutamatergic afferent terminals but spared CB1-inhibition of GABAergic synapses arising from local inhibitory-interneurons. CIE also significantly elevated BLA N-arachidonoylethanolamine (AEA or anandamide) levels and decreased CB1 receptor protein levels. Collectively, these data suggest a dynamic regulation of the BLA eCB system by acute and chronic ethanol. PMID:26707595

Role of Interleukin-1 Receptor Signaling in the Behavioral Effects of Ethanol and Benzodiazepines

PubMed Central

Blednov, Yuri A.; Benavidez, Jillian M.; Black, Mendy; Mayfield, Jody; Harris, R. Adron

2015-01-01

Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway. PMID:25839897

Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines.

PubMed

Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy; Mayfield, Jody; Harris, R Adron

2015-08-01

Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chronic intermittent ethanol exposure during adolescence: effects on social behavior and ethanol sensitivity in adulthood.

PubMed

Varlinskaya, Elena I; Truxell, Eric; Spear, Linda P

2014-08-01

This study assessed long-lasting consequences of repeated ethanol exposure during two different periods of adolescence on 1) baseline levels of social investigation, play fighting, and social preference and 2) sensitivity to the social consequences of acute ethanol challenge. Adult male and female Sprague-Dawley rats were tested 25 days after repeated exposure to ethanol (3.5 g/kg intragastrically [i.g.], every other day for a total of 11 exposures) in a modified social interaction test. Early-mid adolescent intermittent exposure (e-AIE) occurred between postnatal days (P) 25 and 45, whereas late adolescent intermittent exposure (l-AIE) was conducted between P45 and P65. Significant decreases in social investigation and social preference were evident in adult male rats, but not their female counterparts following e-AIE, whereas neither males nor females demonstrated these alterations following l-AIE. In contrast, both e-AIE and l-AIE produced alterations in sensitivity to acute ethanol challenge in males tested 25 days after adolescent exposure. Ethanol-induced facilitation of social investigation and play fighting, reminiscent of that normally seen during adolescence, was evident in adult males after e-AIE, whereas control males showed an age-typical inhibition of social behavior. Males after l-AIE were found to be insensitive to the socially suppressing effects of acute ethanol challenge, suggesting the development of chronic tolerance in these animals. In contrast, females showed little evidence for alterations in sensitivity to acute ethanol challenge following either early or late AIE. The results of the present study demonstrate a particular vulnerability of young adolescent males to long-lasting detrimental effects of repeated ethanol. Retention of adolescent-typical sensitivity to the socially facilitating effects of ethanol could potentially make ethanol especially appealing to these males, therefore promoting relatively high levels of ethanol intake later in life. Copyright © 2014 Elsevier Inc. All rights reserved.

The acute effect of ethanol on adrenal cortex in female rats--possible role of nitric oxide.

PubMed

Dikić, Dragoslava; Budeč, Mirela; Vranješ-Durić, Sanja; Koko, Vesna; Vignjević, Sanja; Mitrović, Olivera

2011-01-01

The present study was designed to investigate a possible role of endogenous nitric oxide (NO) in the adrenal response to an acute alcohol administration in female rats. To this end, N(ω)-nitro-L-arginine-methyl ester (L-NAME), a competitive inhibitor of all isoforms of NO synthase, was used. Adult female Wistar rats showing diestrus Day 1 were treated with: (a) ethanol (2 or 4 g/kg, intraperitoneally); (b) L-NAME (30 or 50 mg/kg, subcutaneously) followed by either ethanol or saline 3 h later. Untreated and saline-injected rats were used as controls. The animals were killed 30 min after last injection. Adrenal cortex was analyzed morphometrically, and plasma levels of adrenocorticotropic hormone (ACTH) and serum concentrations of corticosterone were determined. Acute ethanol treatment enhanced the levels of ACTH and corticosterone in a dose-dependent manner. Stereological analysis revealed that acute alcohol administration induced a significant increase in absolute volume of the cortex and the zona fasciculata (ZF). In addition, ethanol at a dose of 4 g/kg increased volume density and length of the capillaries in the ZF. However, other stereological parameters were unaffected by alcohol exposure. Pretreatment with both doses of L-NAME had no effect on ethanol-induced changes. Obtained findings indicate that acute ethanol treatment stimulates the activity of the adrenal cortex and that this effect is not mediated by endogenous NO in female rats under these experimental conditions.

Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity.

PubMed

Greenberg, Gian D; Phillips, Tamara J; Crabbe, John C

2016-10-15

Nest building has been used to assess thermoregulatory behavior and positive motivational states in mice. There are known genetic influences on ethanol withdrawal severity as well as individual/thermoregulatory nest building. Withdrawal Seizure-Prone (WSP-1, WSP-2) and Withdrawal Seizure-Resistant (WSR-1, WSR-2) mice were selectively bred for high vs low handling-induced convulsion (HIC) severity, respectively, during withdrawal from chronic ethanol vapor inhalation. They also differ in HIC severity during withdrawal from an acute, 4g/kg ethanol injection. In our initial study, withdrawal from an acute dose of ethanol dose-dependently impaired nest building over the initial 24h of withdrawal in genetically segregating Withdrawal Seizure Control (WSC) mice. In two further studies, acute ethanol withdrawal suppressed nest building for up to two days in WSP-1 females. Deficits in nest building from ethanol were limited to the initial 10h of withdrawal in WSR-1 females and to the initial 24h of withdrawal in WSP-1 and WSR-1 males. Effects of ethanol on nest building for up to two days were found in WSP-2 and WSR-2 mice of both sexes. Nest building deficits in female mice from the first replicate could not be explained by a general decrease in locomotor behavior. These results suggest that nest building is a novel behavioral phenotype for indexing the severity of acute ethanol withdrawal, and that genes contributing to this trait differ from those affecting acute withdrawal HIC severity. Published by Elsevier Inc.

Acute ethanol ingestion impairs appetitive olfactory learning and odor discrimination in the honey bee

PubMed Central

Mustard, Julie A; Wright, Geraldine A; Edgar, Elaina A; Mazade, Reece E.; Wu, Chen; Lillvis, Joshua L

2008-01-01

Invertebrates are valuable models for increasing our understanding of the effects of ethanol on the nervous system, but most studies on invertebrates and ethanol have focused on the effects of ethanol on locomotor behavior. In this work we investigate the influence of an acute dose of ethanol on appetitive olfactory learning in the honey bee (Apis mellifera), a model system for learning and memory. Adult worker honey bees were fed a range of doses (2.5, 5, 10 or 25%) of ethanol and then conditioned to associate an odor with a sucrose reward using either a simple or differential conditioning paradigm. Consumption of ethanol before conditioning significantly reduced both the rate of acquisition and the asymptotic strength of the association. Honey bees also exhibited a dose dependent reduction in arousal/attention during conditioning. Consumption of ethanol after conditioning did not affect recall 24 h later. The observed deficits in acquisition were not due to the affect of ethanol on gustatory sensitivity or motor function. However, honey bees given higher doses of ethanol had difficulty discriminating amongst different odors suggesting that ethanol consumption influences olfactory processing. Taken together, these results demonstrate that an acute dose of ethanol affects appetitive learning and olfactory perception in the honey bee. PMID:18723103

ACUTE EFFECT OF ETHANOL ON HEPATIC RETICULAR G6Pase AND Ca2+ POOL

PubMed Central

Jacobs-Harper, Amy; Crumbly, Ashlee; Romani, Andrea

2012-01-01

Background Hydrolysis of glucose 6-phosphate via glucose 6-phosphatase enlarges the reticular Ca2+ pool of the hepatocyte. Exposure of liver cells to ethanol impairs reticular Ca2+ homeostasis. The present study investigated the effect of acute ethanol administration on glucose 6-phosphate supported Ca2+ accumulation in liver cells. Methods Total microsomes were isolated from rat livers acutely perfused with varying doses of ethanol (0.01%, 0.1%, or 1% v/v) for 8 minutes. Calcium uptake was assessed by 45Ca redistribution. Inorganic phosphate (Pi) formation was measured as an indicator of glucose 6-phosphatase hydrolytic activity. Results Glucose 6-phosphate-supported Ca2+ uptake decreased in a manner directly proportional to the dose of ethanol infused in the liver whereas Ca2+ uptake via SERCA pumps was decreased by ~25% only at the highest dose of alcohol administered. The reduced accumulation of Ca2+ within the microsomes resulted in a smaller IP3-induced Ca2+ release. Kinetic assessment of IP3 and passive Ca2+ release indicated a faster mobilization in microsomes from ethanol-treated livers, suggesting alcohol-induced alteration of Ca2+ releasing mechanisms. Pre-treatment of livers with chloromethiazole or dithio-threitol, but not 4-methyl-pyrazole prevented the inhibitory effect of ethanol on glucose 6-phosphatase activity and Ca2+ homeostasis. Conclusions Liver glucose 6-phosphatase activity and IP3-mediated Ca2+ release are rapidly inhibited following acute (8 min) exposure to ethanol, thus compromising the ability of the endoplasmic reticulum to dynamically modulate Ca2+ homeostasis in the hepatocyte. The protective effect of chloromethiazole and di-thio-threitol suggests that the inhibitory effect of ethanol is mediated through its metabolism via reticular cyP4502E1 and consequent free radicals formation. PMID:22958133

Effect of acute ethanol administration on zebrafish tail-beat motion.

PubMed

Bartolini, Tiziana; Mwaffo, Violet; Butail, Sachit; Porfiri, Maurizio

2015-11-01

Zebrafish is becoming a species of choice in neurobiological and behavioral studies of alcohol-related disorders. In these efforts, the activity of adult zebrafish is typically quantified using indirect activity measures that are either scored manually or identified automatically from the fish trajectory. The analysis of such activity measures has produced important insight into the effect of acute ethanol exposure on individual and social behavior of this vertebrate species. Here, we leverage a recently developed tracking algorithm that reconstructs fish body shape to investigate the effect of acute ethanol administration on zebrafish tail-beat motion in terms of amplitude and frequency. Our results demonstrate a significant effect of ethanol on the tail-beat amplitude as well as the tail-beat frequency, both of which were found to robustly decrease for high ethanol concentrations. Such a direct measurement of zebrafish motor functions is in agreement with evidence based on indirect activity measures, offering a complementary perspective in behavioral screening. Copyright © 2015 Elsevier Inc. All rights reserved.

Actions of Acute and Chronic Ethanol on Presynaptic Terminals

PubMed Central

Roberto, Marisa; Treistman, Steven N.; Pietrzykowski, Andrzej Z.; Weiner, Jeff; Galindo, Rafael; Mameli, Manuel; Valenzuela, Fernando; Zhu, Ping Jun; Lovinger, David; Zhang, Tao A.; Hendricson, Adam H.; Morrisett, Richard; Siggins, George Robert

2014-01-01

This article presents the proceedings of a symposium entitled “The Tipsy Terminal: Presynaptic Effects of Ethanol” (held at the annual meeting of the Research Society on Alcoholism, in Santa Barbara, CA, June 27, 2005). The objective of this symposium was to focus on a cellular site of ethanol action underrepresented in the alcohol literature, but quickly becoming a “hot” topic. The chairs of the session were Marisa Roberto and George Robert Siggins. Our speakers were chosen on the basis of the diverse electrophysiological and other methods used to discern the effects of acute and chronic ethanol on presynaptic terminals and on the basis of significant insights that their data provide for understanding ethanol actions on neurons in general, as mechanisms underlying problematic behavioral effects of alcohol. The 5 presenters drew from their recent studies examining the effects of acute and chronic ethanol using a range of sophisticated methods from electrophysiological analysis of paired-pulse facilitation and spontaneous and miniature synaptic currents (Drs. Weiner, Valenzuela, Zhu, and Morrisett), to direct recording of ion channel activity and peptide release from acutely isolated synaptic terminals (Dr. Treistman), to direct microscopic observation of vesicular release (Dr. Morrisett). They showed that ethanol administration could both increase and decrease the probability of release of different transmitters from synaptic terminals. The effects of ethanol on synaptic terminals could often be correlated with important behavioral or developmental actions of alcohol. These and other novel findings suggest that future analyses of synaptic effects of ethanol should attempt to ascertain, in multiple brain regions, the role of presynaptic terminals, relevant presynaptic receptors and signal transduction linkages, exocytotic mechanisms, and their involvement in alcohol’s behavioral actions. Such studies could lead to new treatment strategies for alcohol intoxication, alcohol abuse, and alcoholism. PMID:16441271

Acute Ethanol Administration Rapidly Increases Phosphorylation of Conventional Protein Kinase C in Specific Mammalian Brain Regions in Vivo

PubMed Central

Wilkie, Mary Beth; Besheer, Joyce; Kelley, Stephen P.; Kumar, Sandeep; O’Buckley, Todd K.; Morrow, A. Leslie; Hodge, Clyde W.

2010-01-01

Background Protein kinase C (PKC) is a family of isoenzymes that regulate a variety of functions in the central nervous system including neurotransmitter release, ion channel activity, and cell differentiation. Growing evidence suggests that specific isoforms of PKC influence a variety of behavioral, biochemical, and physiological effects of ethanol in mammals. The purpose of this study was to determine whether acute ethanol exposure alters phosphorylation of conventional PKC isoforms at a threonine 674 (p-cPKC) site in the hydrophobic domain of the kinase, which is required for its catalytic activity. Methods Male rats were administered a dose range of ethanol (0, 0.5, 1, or 2 g/kg, intragastric) and brain tissue was removed 10 minutes later for evaluation of changes in p-cPKC expression using immunohistochemistry and Western blot methods. Results Immunohistochemical data show that the highest dose of ethanol (2 g/kg) rapidly increases p-cPKC immunoreactivity specifically in the nucleus accumbens (core and shell), lateral septum, and hippocampus (CA3 and dentate gyrus). Western blot analysis further showed that ethanol (2 g/kg) increased p-cPKC expression in the P2 membrane fraction of tissue from the nucleus accumbens and hippocampus. Although p-cPKC was expressed in numerous other brain regions, including the caudate nucleus, amygdala, and cortex, no changes were observed in response to acute ethanol. Total PKCγ immunoreactivity was surveyed throughout the brain and showed no change following acute ethanol injection. Conclusions These results suggest that ethanol rapidly promotes phosphorylation of cPKC in limbic brain regions, which may underlie effects of acute ethanol on the nervous system and behavior. PMID:17511744

Acute illness-induced behavioral alterations are similar to those observed during withdrawal from acute alcohol exposure

PubMed Central

Richey, Laura; Doremus-Fitzwater, Tamara L.; Buck, Hollin M.; Deak, Terrence

2012-01-01

Exposure to an immunogen results in a constellation of behavioral changes collectively referred to as “sickness behaviors,” with alterations in cytokine expression previously shown to contribute to this sickness response. Since behaviors observed during ethanol withdrawal are strikingly similar to sickness behaviors, we hypothesized that behavioral manifestations of ethanol withdrawal might be an expression of sickness behaviors induced by ethanol-related changes in peripheral and/or central cytokine expression. Accordingly, behaviors exhibited during a modified social investigation test were first characterized in male rats following an acute injection of lipopolysaccharide (LPS; 100 μg/kg). Subsequently, behavioral changes after either a high (4-g/kg; Experiment 2) or low dose (0.5 g/kg; Experiment 3) of ethanol were also examined in the same social investigation test, as well as in the forced-swim test (FST; Experiment 4). Results from these experiments demonstrated similar reductions in both exploration and social investigatory behavior during acute illness and ethanol withdrawal, while a seemingly paradoxical decrease in immobility was observed in the FST during acute ethanol withdrawal. In follow-up studies, neither indomethacin (Experiment 5) nor interleukin-1 receptor antagonist (Experiment 6) pre-exposure reversed the ethanol withdrawal-induced behavioral changes observed in this social investigation test. Taken together, these studies demonstrate that the behavioral sequelae of acute illness and ethanol withdrawal are similar in nature, while antagonist studies suggest that these behavioral alterations are not reversed by blockade of IL-1 receptors or inhibition of prostaglandin synthesis. Though a direct mechanistic link between cytokines and the expression of acute ethanol withdrawal-related behaviors has yet to be found, future studies examining the involvement of brain cytokines as potential mediators of ethanol effects are greatly needed. PMID:22921768

ACUTE ETHANOL MODULATES GLUTAMATERGIC AND SEROTONERGIC PHASE SHIFTS OF THE MOUSE CIRCADIAN LOCK IN VITRO

PubMed Central

Prosser, Rebecca A.; Mangrum, Charles A.; Glass, J. David

2008-01-01

Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. However, there is no information on the direct effects of ethanol on the mammalian circadian clock. Acute ethanol inhibits glutamate signaling, which is the primary mechanism through which light resets the mammalian clock in the suprachiasmatic nucleus (SCN). Glutamate and light also inhibit circadian clock resetting induced by non-photic signals, including serotonin. Thus, we investigated the effects of acute ethanol on both glutamatergic and serotoninergic resetting of the SCN clock in vitro. We show that ethanol dose-dependently inhibits glutamate-induced phase shifts and enhances serotonergic phase shifts. The inhibition of glutamate-induced phase shifts is not affected by excess glutamate, glycine or D-serine, but is prevented by excess brain-derived neurotrophic factor (BDNF). BDNF is known to augment glutamate signaling in the SCN and to be necessary for glutamate/light-induced phase shifts. Thus, ethanol may inhibit glutamate-induced clock resetting at least in part by blocking BDNF enhancement of glutamate signaling. Ethanol enhancement of serotonergic phase shifts is mimicked by treatments that suppress glutamate signaling in the SCN, including antagonists of glutamate receptors, BDNF signaling and nitric oxide synthase. The combined effect of ethanol with these treatments is not additive, suggesting they act through a common pathway. Our data indicate further that the interaction between serotonin and glutamate in the SCN may occur downstream from nitric oxide synthase activation. Thus, acute ethanol disrupts normal circadian clock phase regulation, which could contribute to the physiological and psychological problems associated with alcohol abuse. PMID:18313227

Frontline Science: ATF3 is responsible for the inhibition of TNF-α release and the impaired migration of acute ethanol-exposed monocytes and macrophages.

PubMed

Hu, Chaojie; Meng, Xiaoming; Huang, Cheng; Shen, Chenlin; Li, Jun

2017-03-01

Binge drinking represses host innate immunity and leads to a high risk of infection. Acute EtOH-pretreated macrophages exhibit a decreased production of proinflammatory mediators in response to LPS. ATF3 is induced and counter-regulates the LPS/TLR4 inflammatory cascade. Here, we investigated the potential role of ATF3 in LPS tolerance in acute ethanol-pretreated macrophages. We found that there was an inverse correlation between ATF3 and LPS-induced TNF-α production in acute ethanol-pretreated murine monocytes and macrophages. The knockdown of ATF3 attenuated the inhibitory effects of acute ethanol treatment on LPS-induced TNF-α production. Furthermore, ChIP assays and co-IP demonstrated that ATF3, together with HDAC1, negatively modulated the transcription of TNF-α. In binge-drinking mice challenged with LPS, an up-regulation of ATF3 and HDAC1 and a concomitant decrease in TNF-α were observed. Given that HDAC1 was concomitantly induced in acute ethanol-exposed monocytes and macrophages, we used the HDACi TSA or silenced HDAC1 to explore the role of HDAC1 in acute ethanol-treated macrophages. Our results revealed that TSA treatment and HDAC1 knockdown prevented acute ethanol-induced ATF3 expression and the inhibition of TNF-α transcription. These data indicated a dual role for HDAC1 in acute ethanol-induced LPS tolerance. Furthermore, we showed that the induction of ATF3 led to the impaired migration of BM monocytes and macrophages. Overall, we present a novel role for ATF3 in the inhibition of LPS-induced TNF-α and in the impairment of monocyte and macrophage migration. © Society for Leukocyte Biology.

Effect of zinc intake on hepatic autophagy during acute alcohol intoxication.

PubMed

Liuzzi, Juan P; Narayanan, Vijaya; Doan, Huong; Yoo, Changwon

2018-04-01

Autophagy is a conserved mechanism that plays a housekeeping role by eliminating protein aggregates and damaged organelles. Recent studies have demonstrated that acute ethanol intoxication induces hepatic autophagy in mice. The effect of dietary zinc intake on hepatic autophagic flux during ethanol intoxication has not been evaluated using animal models. Herein, we investigated whether zinc deficiency and excess can affect autophagic flux in the liver in mice and in human hepatoma cells acutely exposed to ethanol. A mouse model of binge ethanol feeding was utilized to analyze the effect of low, adequate, and high zinc intake on hepatic autophagic flux during ethanol intoxication. Autophagic flux was inferred by analyzing LC3II/LC3I ratio, protein levels of p62/SQSTM1, Beclin1 and Atg7, and phosphorylation of 4EBP1. In addition, the degradation of the fusion protein LC3-GFP and the formation of autophagosomes and autolysosomes were evaluated in cells. Ethanol treatment stimulated autophagy in mice and cells. High zinc intake resulted in enhanced autophagy in mice exposed to ethanol. Conversely, zinc deficiency was consistently associated with impaired ethanol-induced autophagy in mice and cells. Zinc-deficient mice exhibited a high degree of ethanol-driven steatosis. Furthermore, zinc depletion increased apoptosis in cells exposed to ethanol. The results of this study suggest that adequate zinc intake is necessary for proper stimulation of autophagy by ethanol. Poor zinc status is commonly found among alcoholics and could likely contribute to faulty autophagy.

Acute ethanol does not always affect delay discounting in rats selected to prefer or avoid ethanol.

PubMed

Wilhelm, Clare J; Mitchell, Suzanne H

2012-01-01

The purpose of this study was to determine whether animals predisposed to prefer alcohol possess an altered acute response to alcohol on a delay discounting task relative to animals predisposed to avoid alcohol. We used rats selected to prefer or avoid alcohol to assess whether genotype moderates changes in delay discounting induced by acute ethanol exposure. Selectively bred rat lines of Sardinian alcohol-preferring (sP; n = 8) and non-preferring (sNP; n = 8) rats, and alko alcohol (AA, n = 8) and alko non-alcohol (ANA, n = 8) rats were trained in an adjusting amount task to assess delay discounting. There were no significant effects of line on baseline discounting; however, both lines of alcohol-preferring rats exhibit slowed reaction times. Acute ethanol (0, 0.25, 0.5 g/kg) treatment also had no effect on delay discounting in any of the selectively bred rat lines. Our data indicate that in these lines of animals, alcohol preference or avoidance has no impact on delay discounting following acute ethanol exposure. It is possible that other genetic models or lines may be differentially affected by alcohol and exhibit qualitatively and quantitatively different responses in delay discounting tasks.

PKCε plays a causal role in acute ethanol-induced steatosis

PubMed Central

Kaiser, J. Phillip; Beier, Juliane I.; Zhang, Jun; Hoetker, J. David; von Montfort, Claudia; Guo, Luping; Zheng, Yuting; Monia, Brett P.; Bhatnagar, Aruni; Arteel, Gavin E.

2009-01-01

Steatosis is a critical stage in the pathology of alcoholic liver disease (ALD), and preventing steatosis could protect against later stages of ALD. PKCε has been shown to contribute to hepatic steatosis in experimental non-alcoholic fatty liver disease (NAFLD); however, the role of PKCε in ethanol-induced steatosis has not been determined. The purpose of this study was to therefore test the hypothesis that PKCε contributes to ethanol-induced steatosis. Accordingly, the effect of acute ethanol on indices of hepatic steatosis and insulin signaling were determined in PKCε knockout mice and in wild-type mice that received an antisense oligonucleotide (ASO) to knockdown PKCε expression. Acute ethanol (6 g/kg i.g.) caused a robust increase in hepatic non-esterified free fatty acids (NEFA), which peaked 1 h after ethanol exposure. This increase in NEFA was followed by elevated diacylglycerols (DAG), as well as by the concomitant activation of PKCε. Acute ethanol also changed the expression of insulin-responsive genes (i.e. increased G6Pase, downregulated GK), in a pattern indicative of impaired insulin signaling. Acute ethanol exposure subsequently caused a robust increase in hepatic triglycerides. The accumulation of triglycerides caused by ethanol was blunted in ASO-treated or in PKCε−/− mice. Taken together, these data suggest that the increase in NEFA caused by hepatic ethanol metabolism leads to an increase in DAG production via the triacylglycerol pathway. DAG then subsequently activates PKCε, which then exacerbates hepatic lipid accumulation by inducing insulin resistance. These data also suggest that PKCε plays a causal role in at least the early phases of ethanol-induced liver injury. PMID:19022218

Acute Cor Pulmonale and Right Heat Failure Complicating Ethanol Ablative Therapy: Anesthetic and Radiologic Considerations and Management

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naik, Bhiken, E-mail: bin4n@virginia.edu; Matsumoto, Alan H.

2013-10-15

Ethanol is an effective ablative agent used for the treatment of certain solid organ tumors and vascular malformations (VMs). The egress of ethanol beyond the target tissue can be associated with significant changes to the cardiopulmonary system that can lead to cardiac arrest. This article reviews the contemporary role of ethanol in tumor and VM treatment and discusses the physiological mechanisms of acute pulmonary hypertension and cardiovascular collapse. The importance of periprocedural recognition of the hemodynamic changes that can occur with the use of ethanol and the treatment of this condition are discussed.

gamma-Aminobutyric acid-activated chloride channels: relationship to genetic differences in ethanol sensitivity.

PubMed

Allan, A M; Spuhler, K P; Harris, R A

1988-03-01

We demonstrated recently that low concentrations of ethanol enhanced the muscimol-stimulated chloride influx in cerebellar membranes from long sleep (LS-ethanol sensitive) mice, but had no effect on membranes from short sleep (SS-ethanol resistant) mice. The LS and SS were selected from a heterogeneous stock (HS) of mice for differential sensitivity to the hypnotic effects of ethanol as measured by the duration of the loss of the righting reflex (sleep time). In the present study, we tested 100 HS for ethanol sleep time. The mice with the shortest sleep time (HS-SS) and the mice with the longest sleep time (HS-LS) were selected and tested for the effect of ethanol and muscimol on chloride flux in cerebellum. The effects of ethanol and muscimol on both cerebellar and cortical chloride flux were also examined in rats from the 7th generation selected for differential sensitivity to the hypnotic effects of ethanol (high acute ethanol sensitive rats-HAS and low acute ethanol sensitive rats-LAS). Low concentrations of ethanol (10-30 mM) potentiated muscimol stimulation of 36Cl- uptake in both cortical and cerebellar membranes prepared from ethanol-sensitive animals (HS-LS and HAS). None of the ethanol concentrations tested altered stimulated chloride uptake in ethanol-resistant animals (HS-SS and LAS). No differences in muscimol stimulation of chloride uptake were observed between the pairs of selected lines. These findings strongly suggest that genetic differences in ethanol hypnosis are related to differences in the sensitivity of gamma-aminobutyric acid-operated chloride channels to ethanol.

Effects of acute ethanol administration on nocturnal pineal serotonin N-acetyltransferase activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Creighton, J.A.; Rudeen, P.K.

The effect of acute ethanol administration on pineal serotonin N-acetyltransferase (NAT) activity, norepinephrine and indoleamine content was examined in male rats. When ethanol was administered in two equal doses (2 g/kg body weight) over a 4 hour period during the light phase, the nocturnal rise in NAT activity was delayed by seven hours. The nocturnal pineal norepinephrine content was not altered by ethanol except for a delay in the reduction of NE with the onset of the following light phase. Although ethanol treatment led to a significant reduction in nocturnal levels of pineal serotonin content, there was no significant effectmore » upon pineal content of 5-hydroxyindoleacetic acid (5-HIAA). The data indicate that ethanol delays the onset of the rise of nocturnal pineal NAT activity.« less

The new kisspeptin derivative - kissorphin (KSO) - attenuates acute hyperlocomotion and sensitization induced by ethanol and morphine in mice.

PubMed

Gibula-Bruzda, Ewa; Marszalek-Grabska, Marta; Gawel, Kinga; Trzcinska, Roza; Silberring, Jerzy; Kotlinska, Jolanta H

2017-11-01

Kissorphin (KSO) is a new peptide derived from kisspeptin-10. This peptide possesses neuropeptide FF (NPFF)-like biological activity in vitro; NPFF, in many cases, inhibits opioid and ethanol effects in rodents. Therefore, the current study explored the influence of KSO on acute ethanol- and morphine-induced hyperactivity, and on the development and expression of locomotor sensitization induced by these drugs. In the present study, sensitization to locomotor effects was induced by repeated exposure to ethanol (2.4 g/kg, intraperitoneally [i.p.], 1 × 4 days) or morphine (10 mg/kg, subcutaneously [s.c.], 1 × 7 days). We found that KSO (1-10 nmol/300 μL, intravenously [i.v.]) did not have an impact on locomotor activity of naïve mice. However, it reduced both acute ethanol- (10 nmol/300 μL) and morphine-induced hyperactivity (3 and 10 nmol/300 μL). Pretreatment of animals with KSO (10 nmol/300 μL), before every ethanol or morphine injection during development of sensitization or before the ethanol or morphine challenge, attenuated the development, as well as the expression of locomotor sensitization to both substances. Moreover, prior administration of the NPFF receptor antagonist RF9 (10 nmol/300 μL, i.v.) inhibited the ability of KSO (10 nmol/300 μL) to reduce the expression of ethanol and morphine sensitization. KSO given alone, at all used doses, did not influence the motor coordination measured via the rotarod test. The results from this study show that KSO effectively attenuated acute and repeated effects of ethanol and morphine. Thus, KSO possesses NPFF-like anti-opioid activity in these behavioral studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute ethanol intoxication suppresses pentraxin 3 expression in a mouse sepsis model involving cecal ligation and puncture.

PubMed

Kasuda, Shogo; Kudo, Risa; Yuui, Katsuya; Sakurai, Yoshihiko; Hatake, Katsuhiko

2017-11-01

Acute ethanol intoxication impairs immunological reactions and increases the risk of sepsis; however, the underlying mechanism remains unclear. Pentraxin (PTX) 3 is a humoral pattern recognition receptor whose levels rapidly increase in response to inflammation. PTX3 production is triggered by tumor necrosis factor (TNF)-α and is mediated by c-Jun N-terminal kinase (JNK). As PTX3 exerts protective effects against sepsis as well as acute lung injury, we investigated whether acute ethanol exposure exacerbates sepsis by altering PTX3 expression. Sepsis was induced in C57/BL6 mice by cecal ligation and puncture (CLP) after ethanol/saline administration. Survival rates were significantly lower in ethanol-treated than in saline-treated mice. Increased vascular permeability and attenuation of PTX3 expression were observed in the lungs of ethanol-treated mice 4 h after CLP. Concomitant with a delayed increase of plasma TNF-α in ethanol-treated mice, plasma PTX3 was also suppressed in the early phase of sepsis. Although TNF-α level in ethanol-treated mice exceeded that in saline-treated mice 16 h after CLP, PTX3 levels were still suppressed in the former group. JNK phosphorylation in lung tissue was suppressed in both groups 4 and 16 h after CLP. Furthermore, JNK phosphorylation in ethanol-treated human umbilical vein endothelial cells was suppressed even in the presence of exogenous TNF-α, resulting in inhibition of PTX3 mRNA and protein expression. Our results suggest that ethanol suppresses de novo PTX3 synthesis via two mechanisms - i.e., suppression of TNF-α production and inhibition of JNK phosphorylation. PTX3 suppression may therefore contribute to exacerbation of sepsis in acute ethanol intoxication. Copyright © 2017 Elsevier Inc. All rights reserved.

Paternal preconception ethanol exposure blunts hypothalamic-pituitary-adrenal axis responsivity and stress-induced excessive fluid intake in male mice.

PubMed

Rompala, Gregory R; Finegersh, Andrey; Homanics, Gregg E

2016-06-01

A growing number of environmental insults have been shown to induce epigenetic effects that persist across generations. For instance, paternal preconception exposures to ethanol or stress have independently been shown to exert such intergenerational effects. Since ethanol exposure is a physiological stressor that activates the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that paternal ethanol exposure would impact stress responsivity of offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. Adult male and female offspring were tested for plasma corticosterone (CORT) levels following acute restraint stress and the male offspring were further examined for stress-evoked 2-bottle choice ethanol-drinking. Paternal ethanol exposure blunted plasma CORT levels following acute restraint stress selectively in male offspring; females were unaffected. In a stress-evoked ethanol-drinking assay, there was no effect of stress on ethanol consumption. However, C-sired males exhibited increased total fluid intake (polydipsia) in response to stress while E-sired males were resistant to this stress-induced phenotype. Taken together, these data suggest that paternal ethanol exposure imparts stress hyporesponsivity to male offspring. Copyright © 2016 Elsevier Inc. All rights reserved.

Paternal preconception ethanol exposure blunts hypothalamic-pituitary-adrenal axis responsivity and stress-induced excessive fluid intake in male mice

PubMed Central

Rompala, Gregory R.; Finegersh, Andrey; Homanics, Gregg E.

2016-01-01

A growing number of environmental insults have been shown to induce epigenetic effects that persist across generations. For instance, paternal preconception exposures to ethanol or stress have independently been shown to exert such intergenerational effects. Since ethanol exposure is a physiological stressor that activates the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that paternal ethanol exposure would impact stress responsivity of offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. Adult male and female offspring were tested for plasma corticosterone (CORT) levels following acute restraint stress and the male offspring were further examined for stress-evoked 2-bottle choice ethanol drinking. Paternal ethanol exposure blunted plasma CORT levels following acute restraint stress selectively in male offspring; females were unaffected. In a stress-evoked ethanol-drinking assay, there was no effect of stress on ethanol consumption. However, C-sired males exhibited increased total fluid intake (polydipsia) in response to stress while E-sired males were resistant to this stress-induced phenotype. Taken together, these data suggest that paternal ethanol exposure imparts stress hyporesponsivity to male offspring. PMID:27286933

Ethanol Tolerance Affects Endogenous Adenosine Signaling in Mouse Hippocampus

PubMed Central

Zhang, Dali; Xiong, Wei; Jackson, Michael F.

2016-01-01

Ethanol has many pharmacological effects, including increases in endogenous adenosine levels and adenosine receptor activity in brain. Ethanol consumption is associated with both positive and negative health outcomes, but tolerance to the behavioral effects of ethanol can lead to increased consumption, which increases the risk of negative health outcomes. The present study was performed to test whether a 7-day treatment with ethanol is linked to reduced adenosine signaling and whether this is a consequence of reduced ecto-5′-nucleotidase activity. Wild-type (CD73+/+) and ecto-5′-nucleotidase-deficient (CD73−/−) mice were treated with ethanol (2 g/kg) or saline for 7 days. In CD73+/+ mice, repeated ethanol treatment reduced the hypothermic and ataxic effects of acute ethanol, indicating the development of tolerance to the acute effects of ethanol. In CD73+/+ mice, this 7-day ethanol treatment led to increased hippocampal synaptic activity and reduced adenosine A1 receptor activity under both basal and low Mg2+ conditions. These effects of ethanol tolerance were associated with an 18% decrease in activity of ecto-5′-nucleotidase activity in hippocampal cell membranes. In contrast, ethanol treatment was not associated with changes in synaptic activity or adenosine signaling in hippocampus from CD73−/− mice. These data indicate that ethanol treatment is associated with a reduction in adenosine signaling through adenosine A1 receptors in hippocampus, mediated, at least in part, via reduced ecto-5′-nucleotidase activity. PMID:27189965

Ethanol Tolerance Affects Endogenous Adenosine Signaling in Mouse Hippocampus.

PubMed

Zhang, Dali; Xiong, Wei; Jackson, Michael F; Parkinson, Fiona E

2016-07-01

Ethanol has many pharmacological effects, including increases in endogenous adenosine levels and adenosine receptor activity in brain. Ethanol consumption is associated with both positive and negative health outcomes, but tolerance to the behavioral effects of ethanol can lead to increased consumption, which increases the risk of negative health outcomes. The present study was performed to test whether a 7-day treatment with ethanol is linked to reduced adenosine signaling and whether this is a consequence of reduced ecto-5'-nucleotidase activity. Wild-type (CD73(+/+)) and ecto-5'-nucleotidase-deficient (CD73(-/-)) mice were treated with ethanol (2 g/kg) or saline for 7 days. In CD73(+/+) mice, repeated ethanol treatment reduced the hypothermic and ataxic effects of acute ethanol, indicating the development of tolerance to the acute effects of ethanol. In CD73(+/+) mice, this 7-day ethanol treatment led to increased hippocampal synaptic activity and reduced adenosine A1 receptor activity under both basal and low Mg(2+) conditions. These effects of ethanol tolerance were associated with an 18% decrease in activity of ecto-5'-nucleotidase activity in hippocampal cell membranes. In contrast, ethanol treatment was not associated with changes in synaptic activity or adenosine signaling in hippocampus from CD73(-/-) mice. These data indicate that ethanol treatment is associated with a reduction in adenosine signaling through adenosine A1 receptors in hippocampus, mediated, at least in part, via reduced ecto-5'-nucleotidase activity. Copyright © 2016 The Author(s).

Further characterization of the effect of ethanol on voltage-gated Ca(2+) channel function in developing CA3 hippocampal pyramidal neurons.

PubMed

Morton, Russell A; Valenzuela, C Fernando

2016-02-15

Developmental ethanol exposure damages the hippocampus, a brain region involved in learning and memory. Alterations in synaptic transmission and plasticity may play a role in this effect of ethanol. We previously reported that acute and repeated exposure to ethanol during the third trimester-equivalent inhibits long-term potentiation of GABAA receptor-dependent synaptic currents in CA3 pyramidal neurons through a mechanism that depends on retrograde release of brain-derived neurotrophic factor driven by activation of voltage-gated Ca(2+) channels (Zucca and Valenzuela, 2010). We found evidence indicating that voltage-gated Ca(2+) channels are inhibited in the presence of ethanol, an effect that may play a role in its mechanism of action. Here, we further investigated the acute effect of ethanol on the function of voltage-gated Ca(2+) channels in CA3 pyramidal neurons using Ca(2+) imaging techniques. These experiments revealed that acute ethanol exposure inhibits voltage-gated Ca(2+) channels both in somatic and proximal dendritic compartments. To investigate the long-term consequences of ethanol on voltage-gated Ca(2+) channels, we used patch-clamp electrophysiological techniques to assess the function of L-type voltage-gated Ca(2+) channels during and following ten days of vapor ethanol exposure. During ethanol withdrawal periods, the function of these channels was not significantly affected by vapor chamber exposure. Taken together with our previous findings, our results suggest that 3(rd) trimester-equivalent ethanol exposure transiently inhibits L-type voltage-gated Ca(2+) channel function in CA3 pyramidal neurons and that compensatory mechanisms restore their function during ethanol withdrawal. Transient inhibition of these channels by ethanol may be, in part, responsible for the hippocampal abnormalities associated with developmental exposure to this agent. Copyright © 2015 Elsevier B.V. All rights reserved.

Acute effects of ethanol on the transfer of nicotine and two dietary carcinogens in human placental perfusion.

PubMed

Veid, Jenni; Karttunen, Vesa; Myöhänen, Kirsi; Myllynen, Päivi; Auriola, Seppo; Halonen, Toivo; Vähäkangas, Kirsi

2011-09-10

Many mothers use, against instructions, alcohol during pregnancy. Simultaneously mothers are exposed to a wide range of other environmental chemicals. These chemicals may also harm the developing fetus, because almost all toxic compounds can go through human placenta. Toxicokinetic effects of ethanol on the transfer of other environmental compounds through human placenta have not been studied before. It is known that ethanol has lytic properties and increases the permeability and fluidity of cell membranes. We studied the effects of ethanol on the transfer of three different environmental toxins: nicotine, PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine) and NDMA (N-nitrosodimethylamine) in placental perfusion. We tested in human breast cancer adenocarcinoma cell line MCF-7 whether ethanol affects ABCG2/BCRP, which is also the major transporter in human placenta. We found that the transfer of ethanol is comparable to that of antipyrine, which points to passive diffusion as the transfer mechanism. Unexpectedly, ethanol had no statistically significant effect on the transfer of the other studied compounds. Neither did ethanol inhibit the function of ABCG2/BCRP. These experiments represent only the effects of acute exposure to ethanol and chronic exposure remains to be studied. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Neuronal nitric oxide synthase mediates the effect of ethanol on IgA.

PubMed

Budec, Mirela; Markovic, Dragana; Vignjevic, Sanja; Mitrovic, Olivera; Dikic, Dragoslava; Koko, Vesna; Cokic, Vladan P

2013-01-01

We showed previously that the acute effect of ethanol on intestinal immunoglobulin A (IgA) expression might be mediated by endogenous nitric oxide (NO). To extend these findings, this study was designed to investigate a possible role of neuronal NO synthase (nNOS) in the observed phenomenon, using 7-nitroindazole (7-NI), a selective inhibitor of its activity. Adult male Wistar rats were treated with: (a) ethanol (4 g/kg, intraperitoneally, i.p.), (b) 7-NI (25 mg/kg, i.p.) followed by ethanol (4 g/kg, i.p.) 30 min later and (c) 7-NI (25 mg/kg, i.p.) followed by saline 30 min later. Untreated rats were used as controls. The concentrations of serum and intestinal IgA were measured by enzyme-linked immunosorbent assay, while the expression of nNOS was determined using western blot and immunohistochemistry. Acute ethanol treatment significantly increased the concentration of IgA in the ileal extracts, whereas it decreased its serum level. Inhibition of nNOS activity by 7-NI abolished this action of alcohol on IgA. Additionally, western blot analysis revealed that the acute alcohol administration induced an increase in the expression of intestinal nNOS. Furthermore, nNOS-immunoreactive cells, observed within the lamina propria of small intestine, were numerous in ethanol-treated rats. Taken together, these results extended our previous findings suggesting that nNOS mediates the acute effect of ethanol on IgA and supported an immunomodulatory role of this enzyme isoform.

Effect of acute beer ingestion on the liver: studies in female mice.

PubMed

Kanuri, Giridhar; Wagnerberger, Sabine; Landmann, Marianne; Prigl, Eva; Hellerbrand, Claus; Bischoff, Stephan C; Bergheim, Ina

2015-04-01

The aim of the present study was to assess whether the effects of acute consumption of stout or pilsner beer on the liver differ from those of plain ethanol in a mouse model. Seven-week-old female C57BL/6J mice received either ethanol, stout or pilsner beer (ethanol content: 6 g/kg body weight) or isocaloric maltodextrin solution. Plasma alanine transaminase, markers of steatosis, lipogenesis, activation of the toll-like receptor-4 signaling cascade as well as lipid peroxidation and fibrogenesis in the liver were measured 12 h after acute ethanol or beer intake. Acute alcohol ingestion caused a marked ~11-fold increase in hepatic triglyceride accumulation in comparison to controls, whereas in mice exposed to stout and pilsner beer, hepatic triglyceride levels were increased only by ~6.5- and ~4-fold, respectively. mRNA expression of sterol regulatory element-binding protein 1c and fatty acid synthase in the liver did not differ between alcohol and beer groups. In contrast, expression of myeloid differentiation primary response gene 88, inducible nitric oxide synthases, but also the concentrations of 4-hydroxynonenal protein adducts, nuclear factor κB and plasminogen activator inhibitor-1 were induced in livers of ethanol treated mice but not in those exposed to the two beers. Taken together, our results suggest that acute ingestion of beer and herein especially of pilsner beer is less harmful to the liver than the ingestion of plain ethanol.

The relation of age to the acute effects of ethanol on acetanilide disposition.

PubMed

Wynne, H A; Mutch, E; Williams, F M; James, O F; Rawlins, M D; Woodhouse, K W

1989-03-01

The activity of the major drug-metabolizing enzymes, the mono-oxygenases, can be inhibited by an acute dose of ethanol. We set out to determine whether age has any relation to the degree of inhibition produced by ethanol, using acetanilide as a model substrate. Eight healthy young subjects (mean age 26 years) and eight healthy elderly subjects (mean age 72 years) were studied on two occasions, once receiving acetanilide alone and once acetanilide with 75 ml vodka (30 g ethanol). The clearance of acetanilide was significantly lower (p less than 0.05) in the elderly subjects at 27 +/- 3 l/h compared to 38 +/- 2 l/h in young subjects. No age-related differences in peak blood ethanol concentrations or ethanol elimination rates were noted. After ethanol, acetanilide clearance fell 18% to 31 +/- 3 l/h in young subjects (p = 0.05) and by 15% to 23 +/- 2 l/h in elderly subjects (p = 0.08). This suggests that the elderly do not suffer greater impairment of drug oxidation after acute ethanol ingestion than do the young.

Acute and Chronic Effects of Ethanol on Learning-Related Synaptic Plasticity

PubMed Central

Zorumski, Charles F.; Mennerick, Steven; Izumi, Yukitoshi

2014-01-01

Alcoholism is associated with acute and long-term cognitive dysfunction including memory impairment, resulting in substantial disability and cost to society. Thus, understanding how ethanol impairs cognition is essential for developing treatment strategies to dampen its adverse impact. Memory processing is thought to involve persistent, use-dependent changes in synaptic transmission, and ethanol alters the activity of multiple signaling molecules involved in synaptic processing, including modulation of the glutamate and gamma-aminobutyric acid (GABA) transmitter systems that mediate most fast excitatory and inhibitory transmission in the brain. Effects on glutamate and GABA receptors contribute to ethanol-induced changes in long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie memory acquisition. In this paper, we review the effects of ethanol on learning-related forms of synaptic plasticity with emphasis on changes observed in the hippocampus, a brain region that is critical for encoding contextual and episodic memories. We also include studies in other brain regions as they pertain to altered cognitive and mental function. Comparison of effects in the hippocampus to other brain regions is instructive for understanding the complexities of ethanol’s acute and long-term pharmacological consequences. PMID:24447472

Role of Adrenal Glucocorticoid Signaling in Prefrontal Cortex Gene Expression and Acute Behavioral Responses to Ethanol

PubMed Central

Costin, Blair N.; Wolen, Aaron R.; Fitting, Sylvia; Shelton, Keith L.; Miles, Michael F.

2012-01-01

Background Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. There is growing evidence that glucocorticoids might also modulate behavioral responses to ethanol. Acute ethanol activates the HPA axis, causing release of adrenal glucocorticoid hormones. Our prior genomic studies suggest glucocorticoids play a role in regulating gene expression in the prefrontal cortex (PFC) of DBA2/J (D2) mice following acute ethanol administration. However, few studies have analyzed the role of glucocorticoid signaling in behavioral responses to acute ethanol. Such work could be significant, given the predictive value for level of response to acute ethanol in the risk for alcoholism. Methods We studied whether the glucocorticoid receptor (GR) antagonist, RU-486, or adrenalectomy (ADX) altered male D2 mouse behavioral responses to acute (locomotor activation, anxiolysis or loss-of-righting reflex (LORR)) or repeated (sensitization) ethanol treatment. Whole genome microarray analysis and bioinformatics approaches were used to identify PFC candidate genes possibly responsible for altered behavioral responses to ethanol following ADX. Results ADX and RU-486 both impaired acute ethanol (2 g/kg) induced locomotor activation in D2 mice without affecting basal locomotor activity. However, neither ADX nor RU-486 altered initiation of ethanol sensitization (locomotor activation or jump counts), ethanol-induced anxiolysis or LORR. ADX mice showed microarray gene expression changes in PFC that significantly overlapped with acute ethanol-responsive gene sets derived by our prior microarray studies. Q-rtPCR analysis verified that ADX decreased PFC expression of Fkbp5 while significantly increasing Gpr6 expression. In addition, high dose RU-486 pre-treatment blunted ethanol-induced Fkbp5 expression. Conclusions Our studies suggest that ethanol’s activation of adrenal glucocorticoid release and subsequent GR activation may partially modulate ethanol’s acute locomotor activation in male D2 mice. Furthermore, since adrenal glucocorticoid basal tone regulated PFC gene expression, including a significant set of acute ethanol-responsive genes, this suggests that glucocorticoid regulated PFC gene expression may be an important factor modulating acute behavioral responses to ethanol. PMID:22671426

Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons

PubMed Central

Llorente, Javier; Withey, Sarah; Rivero, Guadalupe; Cunningham, Margaret; Cooke, Alex; Saxena, Kunal; McPherson, Jamie; Oldfield, Sue; Dewey, William L.; Bailey, Chris P.; Kelly, Eamonn; Henderson, Graeme

2013-01-01

Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala2,N-MePhe4,Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in μ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5′-O-(3-[35S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance. PMID:23716621

Nociceptin/orphanin FQ decreases glutamate transmission and blocks ethanol-induced effects in the central amygdala of naive and ethanol-dependent rats.

PubMed

Kallupi, Marsida; Varodayan, Florence P; Oleata, Christopher S; Correia, Diego; Luu, George; Roberto, Marisa

2014-04-01

The central nucleus of the amygdala (CeA) mediates several addiction-related processes and nociceptin/orphanin FQ (nociceptin) regulates ethanol intake and anxiety-like behaviors. Glutamatergic synapses, in the CeA and throughout the brain, are very sensitive to ethanol and contribute to alcohol reinforcement, tolerance, and dependence. Previously, we reported that in the rat CeA, acute and chronic ethanol exposures significantly decrease glutamate transmission by both pre- and postsynaptic actions. In this study, using electrophysiological techniques in an in vitro CeA slice preparation, we investigated the effects of nociceptin on glutamatergic transmission and its interaction with acute ethanol in naive and ethanol-dependent rats. We found that nociceptin (100-1000 nM) diminished basal-evoked compound glutamatergic receptor-mediated excitatory postsynaptic potentials (EPSPs) and spontaneous and miniature EPSCs (s/mEPSCs) by mainly decreasing glutamate release in the CeA of naive rats. Notably, nociceptin blocked the inhibition induced by acute ethanol (44 mM) and ethanol blocked the nociceptin-induced inhibition of evoked EPSPs in CeA neurons of naive rats. In neurons from chronic ethanol-treated (ethanol-dependent) rats, the nociceptin-induced inhibition of evoked EPSP amplitude was not significantly different from that in naive rats. Application of [Nphe1]Nociceptin(1-13)NH2, a nociceptin receptor (NOP) antagonist, revealed tonic inhibitory activity of NOP on evoked CeA glutamatergic transmission only in ethanol-dependent rats. The antagonist also blocked nociceptin-induced decreases in glutamatergic responses, but did not affect ethanol-induced decreases in evoked EPSP amplitude. Taken together, these studies implicate a potential role for the nociceptin system in regulating glutamatergic transmission and a complex interaction with ethanol at CeA glutamatergic synapses.

Ethanol induced antidepressant-like effect in the mouse forced swimming test: modulation by serotonergic system.

PubMed

Jain, Nishant S; Kannamwar, Uday; Verma, Lokesh

2017-02-01

The present investigation explored the modulatory role of serotonergic transmission in the acute ethanol-induced effects on immobility time in the mouse forced swim test (FST). Acute i.p. administration of ethanol (20% w/v, 2 or 2.5 g/kg, i.p.) decreased the immobility time in FST of mice, indicating its antidepressant-like effect while lower doses of ethanol (1, 1.5 g/kg, i.p.) were devoid of any effect in the FST. The mice pre-treated with a sub-effective dose of 5-HT 2A agonist, DOI (10 μg/mouse, i.c.v.) or 5-HT 1A receptor antagonist, WAY 100635 (0.1 μg/mouse, i.c.v.) but not with the 5-HT 2A/2C antagonist, ketanserin (1.5 μg/mouse, i.c.v.) exhibited a synergistic reduction in the immobility time induced by sub-effective dose of ethanol (1.5 g/kg, i.p.). On the other hand, ethanol (2.5 g/kg, i.p.) failed to decrease the immobility time in mice, pre-treated with 5-HT 1A agonist, 8-OH-DPAT (0.1 μg/mouse, i.c.v.) or ketanserin (1.5 μg/mouse, i.c.v.). In addition, pre-treatment with a 5-HT neuronal synthesis inhibitor, p-CPA (300 mg/kg, i.p. × 3 days) attenuated the anti-immobility effect ethanol (2.5 g/kg, i.p.) in mouse FST. Thus, the results of the present study points towards the essentiality of the central 5-HT transmission at the synapse for the ethanol-induced antidepressant-like effect in the FST wherein the regulatory role of the 5-HT 1A receptor or contributory role of the 5-HT 2A/2C receptor-mediated mechanism is proposed in the anti-immobility effect of acute ethanol in mouse FST.

Short Communication: Is Ethanol-Based Hand Sanitizer Involved in Acute Pancreatitis after Excessive Disinfection?-An Evaluation with the Use of PBPK Model.

PubMed

Huynh-Delerme, Céline; Artigou, Catherine; Bodin, Laurent; Tardif, Robert; Charest-Tardif, Ginette; Verdier, Cécile; Sater, Nessryne; Ould-Elhkim, Mostafa; Desmares, Catherine

2012-01-01

An occupational physician reported to the French Health Products Safety Agency (Afssaps) a case of adverse effect of acute pancreatitis (AP) in a teaching nurse, after multiple demonstrations with ethanol-based hand sanitizers (EBHSs) used in a classroom with defective mechanical ventilation. It was suggested by the occupational physician that the exposure to ethanol may have produced a significant blood ethanol concentration and subsequently the AP. In order to verify if the confinement situation due to defective mechanical ventilation could increase the systemic exposure to ethanol via inhalation route, a physiologically based pharmacokinetic (PBPK) modeling was used to predict ethanol blood levels. Under the worst case scenario, the simulation by PBPK modeling showed that the maximum blood ethanol concentration which can be predicted of 5.9 mg/l is of the same order of magnitude to endogenous ethanol concentration (mean = 1.1 mg/L; median = 0.4 mg/L; range = 0-35 mg/L) in nondrinker humans (Al-Awadhi et al., 2004). The present study does not support the likelihood that EBHS leads to an increase in systemic ethanol concentration high enough to provoke an acute pancreatitis.

Adenylyl cylases 1 and 8 mediate select striatal-dependent behaviors and sensitivity to ethanol stimulation in the adolescent period following acute neonatal ethanol exposure.

PubMed

Susick, Laura L; Lowing, Jennifer L; Bosse, Kelly E; Hildebrandt, Clara C; Chrumka, Alexandria C; Conti, Alana C

2014-08-01

Neonatal alcohol exposure in rodents causes dramatic neurodegenerative effects throughout the developing nervous system, particularly in the striatum, acutely after exposure. These acute neurodegenerative effects are augmented in mice lacking adenylyl cyclases 1 and 8 (AC1/8) as neonatal mice with a genetic deletion of both AC isoforms (DKO) have increased vulnerability to ethanol-induced striatal neurotoxicity compared to wild type (WT) controls. While neonatal ethanol exposure is known to negatively impact cognitive behaviors, such as executive functioning and working memory in adolescent and adult animals, the threshold of ethanol exposure required to impinge upon developmental behaviors in mice has not been extensively examined. Therefore, the purpose of this study was to determine the behavioral effects of neonatal ethanol exposure using various striatal-dependent developmental benchmarks and to assess the impact of AC1/8 deletion on this developmental progression. WT and DKO mice were treated with 2.5 g/kg ethanol or saline on postnatal day (P)6 and later subjected to the wire suspension, negative geotaxis, postural reflex, grid hang, tail suspension and accelerating rotarod tests at various time points. At P30, mice were evaluated for their hypnotic responses to 4.0 g/kg ethanol by using the loss of righting reflex assay and ethanol-induced stimulation of locomotor activity after 2.0 g/kg ethanol. Ethanol exposure significantly impaired DKO performance in the negative geotaxis test while genetic deletion of AC1/8 alone increased grid hang time and decreased immobility time in the tail suspension test with a concomitant increase in hindlimb clasping behavior. Locomotor stimulation was significantly increased in animals that received ethanol as neonates, peaking significantly in ethanol-treated DKO mice compared to ethanol-treated WT controls, while sedation duration following high-dose ethanol challenge was unaffected. These data indicate that the maturational parameters examined in the current study may not be sensitive enough to detect effects of a single ethanol exposure during the brain growth spurt period. Genetic deletion of AC1/8 reveals a role for these cylases in attenuating ethanol-induced behavioral effects in the neonatally-exposed adolescent. Published by Elsevier B.V.

Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila.

PubMed

Bainton, R J; Tsai, L T; Singh, C M; Moore, M S; Neckameyer, W S; Heberlein, U

2000-02-24

Drugs of abuse have a common property in mammals, which is their ability to facilitate the release of the neurotransmitter and neuromodulator dopamine in specific brain regions involved in reward and motivation. This increase in synaptic dopamine levels is believed to act as a positive reinforcer and to mediate some of the acute responses to drugs. The mechanisms by which dopamine regulates acute drug responses and addiction remain unknown. We present evidence that dopamine plays a role in the responses of Drosophila to cocaine, nicotine or ethanol. We used a startle-induced negative geotaxis assay and a locomotor tracking system to measure the effect of psychostimulants on fly behavior. Using these assays, we show that acute responses to cocaine and nicotine are blunted by pharmacologically induced reductions in dopamine levels. Cocaine and nicotine showed a high degree of synergy in their effects, which is consistent with an action through convergent pathways. In addition, we found that dopamine is involved in the acute locomotor-activating effect, but not the sedating effect, of ethanol. We show that in Drosophila, as in mammals, dopaminergic pathways play a role in modulating specific behavioral responses to cocaine, nicotine or ethanol. We therefore suggest that Drosophila can be used as a genetically tractable model system in which to study the mechanisms underlying behavioral responses to multiple drugs of abuse.

Increased Sensitivity to Alcohol Induced Changes in ERK Map Kinase Phosphorylation and Memory Disruption in Adolescent as Compared to Adult C57BL/6J Mice

PubMed Central

Spanos, Marina; Besheer, Joyce; Hodge, Clyde W.

2012-01-01

Adolescence is a critical period of brain development that is accompanied by increased probability of risky behavior, such as alcohol use. Emerging research indicates that adolescents are differentially sensitive to the behavioral effects of acute ethanol as compared to adults but the neurobiological mechanisms of this effect remain to be fully elucidated. This study was designed to evaluate effects of acute ethanol on extracellular signal-regulated kinase phosphorylation (p-ERK1/2) in mesocorticolimbic brain regions. We also sought to determine if age-specific effects of ethanol on p-ERK1/2 are associated with ethanol-induced behavioral deficits on acquisition of the hippocampal-dependent novel object recognition (NOR) test. Adolescent and adult C57BL/6J mice were administered acute ethanol (0 0.5, 1, or 3 g/kg, i.p.). Brains were removed 30-min post injection and processed for analysis of p-ERK1/2 immunoreactivity (IR). Additional groups of mice were administered ethanol (0 or 1 g/kg) prior to the NOR test. Analysis of p-ERK1/2 IR showed that untreated adolescent mice had significantly higher levels of p-ERK1/2 IR in the nucleus accumbens shell, basolateral amygdala (BLA), central amygdala (CeA), and medial prefrontal cortex (mPFC) as compared to adults. Ethanol (1 g/kg) selectively reduced p-ERK1/2 IR in the dentate gyrus and increased p-ERK1/2 IR in the BLA only in adolescent mice. Ethanol (3 g/kg) produced the same effects on p-ERK1/2 IR in both age groups with increases in CeA and mPFC, but a decrease in the dentate gyrus, as compared to age-matched saline controls. Pretreatment with ethanol (1 g/kg) disrupted performance on the NOR test specifically in adolescents, which corresponds with the ethanol-induced inhibition of p-ERK1/2 IR in the hippocampus. These data show that adolescent mice have differential expression of basal p-ERK1/2 IR in mesocorticolimbic brain regions. Acute ethanol produces a unique set of changes in ERK1/2 phosphorylation in the adolescent brain that are associated with disruption of hippocampal-dependent memory acquisition. PMID:22348893

Adolescent and adult rat cortical protein kinase A display divergent responses to acute ethanol exposure

PubMed Central

Gigante, Eduardo D.; Santerre, Jessica L.; Carter, Jenna M.; Werner, David F.

2014-01-01

Adolescent rats display reduced sensitivity to many dysphoria-related effects of alcohol (ethanol) including motor ataxia and sedative hypnosis, but the underlying neurobiological factors that contribute to these differences remain unknown. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway, particularly the type II regulatory subunit (RII), has been implicated in ethanol-induced molecular and behavioral responses in adults. Therefore, the current study examined cerebral cortical PKA in adolescent and adult ethanol responses. With the exception of early adolescence, PKA RIIα and RIIβ subunit levels largely did not differ from adult levels in either whole cell lysate or P2 synaptosomal expression. However, following acute ethanol exposure, PKA RIIβ P2 synaptosomal expression and activity were increased in adults, but not in adolescents. Behaviorally, intracerebroventricular administration of the PKA activator Sp-cAMP and inhibitor Rp-cAMP prior to ethanol administration increased adolescent sensitivity to the sedative-hypnotic effects of ethanol compared to controls. Sp-cAMP was ineffective in adults whereas Rp-cAMP suggestively reduced loss of righting reflex (LORR) with paralleled increases in blood ethanol concentrations. Overall, these data suggest that PKA activity modulates the sedative/hypnotic effects of ethanol and may potentially play a wider role in the differential ethanol responses observed between adolescents and adults. PMID:24874150

Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain.

PubMed

Saito, Mariko; Chakraborty, Goutam; Hui, Maria; Masiello, Kurt; Saito, Mitsuo

2016-08-16

Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD). While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy). Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7) mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.

Acute Ethanol Inhibition of γ Oscillations Is Mediated by Akt and GSK3β

PubMed Central

Wang, JianGang; Zhao, JingXi; Liu, ZhiHua; Guo, FangLi; Wang, Yali; Wang, Xiaofang; Zhang, RuiLing; Vreugdenhil, Martin; Lu, Chengbiao

2016-01-01

Hippocampal network oscillations at gamma band frequency (γ, 30–80 Hz) are closely associated with higher brain functions such as learning and memory. Acute ethanol exposure at intoxicating concentrations (≥50 mM) impairs cognitive function. This study aimed to determine the effects and the mechanisms of acute ethanol exposure on γ oscillations in an in vitro model. Ethanol (25–100 mM) suppressed kainate-induced γ oscillations in CA3 area of the rat hippocampal slices, in a concentration-dependent, reversible manner. The ethanol-induced suppression was reduced by the D1R antagonist SCH23390 or the PKA inhibitor H89, was prevented by the Akt inhibitor triciribine or the GSk3β inhibitor SB415286, was enhanced by the NMDA receptor antagonist D-AP5, but was not affected by the MAPK inhibitor U0126 or PI3K inhibitor wortmanin. Our results indicate that the intracellular kinases Akt and GSk3β play a critical role in the ethanol-induced suppression of γ oscillations and reveal new cellular pathways involved in the ethanol-induced cognitive impairment. PMID:27582689

ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis.

PubMed

Tsai, Wen-Wei; Matsumura, Shigenobu; Liu, Weiyi; Phillips, Naomi G; Sonntag, Tim; Hao, Ergeng; Lee, Soon; Hai, Tsonwin; Montminy, Marc

2015-03-03

Increases in circulating glucagon during fasting maintain glucose balance by stimulating hepatic gluconeogenesis. Acute ethanol intoxication promotes fasting hypoglycemia through an increase in hepatic NADH, which inhibits hepatic gluconeogenesis by reducing the conversion of lactate to pyruvate. Here we show that acute ethanol exposure also lowers fasting blood glucose concentrations by inhibiting the CREB-mediated activation of the gluconeogenic program in response to glucagon. Ethanol exposure blocked the recruitment of CREB and its coactivator CRTC2 to gluconeogenic promoters by up-regulating ATF3, a transcriptional repressor that also binds to cAMP-responsive elements and thereby down-regulates gluconeogenic genes. Targeted disruption of ATF3 decreased the effects of ethanol in fasted mice and in cultured hepatocytes. These results illustrate how the induction of transcription factors with overlapping specificity can lead to cross-coupling between stress and hormone-sensitive pathways.

Ethanol modifies the effect of handling stress on gene expression: problems in the analysis of two-way gene expression studies in mouse brain.

PubMed

Rulten, Stuart L; Ripley, Tamzin L; Manerakis, Ektor; Stephens, David N; Mayne, Lynne V

2006-08-02

Studies analysing the effects of acute treatments on animal behaviour and brain biochemistry frequently use pairwise comparisons between sham-treated and -untreated animals. In this study, we analyse expression of tPA, Grik2, Smarca2 and the transcription factor, Sp1, in mouse cerebellum following acute ethanol treatment. Expression is compared to saline-injected and -untreated control animals. We demonstrate that acute i.p. injection of saline may alter gene expression in a gene-specific manner and that ethanol may modify the effects of sham treatment on gene expression, as well as inducing specific effects independent of any handling related stress. In addition to demonstrating the complexity of gene expression in response to physical and environmental stress, this work raises questions on the interpretation and validity of studies relying on pairwise comparisons.

Memantine reduces alcohol drinking but not relapse in alcohol-dependent rats.

PubMed

Alaux-Cantin, Stéphanie; Buttolo, Romain; Houchi, Hakim; Jeanblanc, Jérôme; Naassila, Mickaël

2015-09-01

Alcoholism is a chronic relapsing disorder with consequences on health and that requires more effective treatments. Among alternative therapies, the therapeutic potential of the non-competitive N-methyl-D-aspartate receptor antagonist memantine has been suggested. Despite promising results, its efficiency in the treatment of alcoholism remains controversial. Currently, there is no pre-clinical data regarding its effects on the motivation for ethanol in post-dependent (PD) animals exposed to intermittent ethanol vapor, a validated model of alcoholism. Thus, the objectives of this study were to evaluate the effects of acute injections of memantine (0, 12.5, 25 and 50 mg/kg) on operant ethanol self-administration in non-dependent (ND) and PD rats tested either during acute withdrawal or relapse after protracted abstinence. Our results showed that memantine (25 mg/kg) abolished ethanol self-administration in ND rats and reduced by half the one of PD rats during acute withdrawal. While this effect was observed only 6 hours after treatment in ND rats, it was long lasting in PD rats (at least 30 hours after injection). Furthermore, our results indicated that memantine did not modify the breaking point for ethanol. This suggests that memantine probably act by potentiating the pharmacological effect of ethanol but not by reducing motivation for ethanol. Finally, memantine was also ineffective in reducing relapse after protracted abstinence. Altogether, our pre-clinical results highlighted a potential therapeutic use of memantine that may be used as a replacement therapy drug but not as relapse-preventing drug. © 2014 Society for the Study of Addiction.

Stereological study of rat spleen following acute ethanol treatment.

PubMed

Budec, M; Milićević, Z; Koko, V

2000-05-01

To investigate the acute effect of ethanol (4 g/kg, i.p.) on spleen adult female Wistar rats were treated intraperitoneally with: a) ethanol (4 g/kg body wt), b) naltrexone (5 mg/kg body wt) followed 45 minutes later by ethanol (4 g/kg body wt) and c) naltrexone (5 mg/kg body wt) alone. Untreated and saline-treated rats were used as controls. Twenty hours after the ethanol treatment the animals were sacrificed and the spleens were removed. A piece of tissue from the central part of each organ was fixed in Bouin's solution. Paraffin sections were stained with hematoxylin-eosin and analysed using stereological measurements. The volume densities of the following tissue compartments: red pulp, white pulp (divided in follicles, periarterioral lymphatic sheath and marginal zone) and the connective tissue were determined. Stereological analysis also included parameters of follicles: the areal numerical density (the number of follicles per 1 mm2 of tissue section), the numerical density (the number of follicles per mm3 of tissue) and the mean follicle diameter. The immunoarchitecture of the spleen was preserved following acute ethanol treatment. Unlike other parameters that were unaffected, ethanol evoked a decrease in both volume density of follicle and the mean follicle diameter. Naltrexone pretreatment had no influence on ethanol-induced changes. The data obtained indicate that a single dose of ethanol has a profound effect on rat spleen affecting the follicles, but the mechanism of its action remains to be elucidated.

In situ rat brain and liver spontaneous chemiluminescence after acute ethanol intake.

PubMed

Boveris, A; Llesuy, S; Azzalis, L A; Giavarotti, L; Simon, K A; Junqueira, V B; Porta, E A; Videla, L A; Lissi, E A

1997-09-19

The influence of acute ethanol administration on the oxidative stress status of rat brain and liver was assessed by in situ spontaneous organ chemiluminescence (CL). Brain and liver CL was significantly increased after acute ethanol administration to fed rats, a response that is time-dependent and evidenced at doses higher than 1 g/kg. Ethanol-induced CL development is faster in liver compared with brain probably due to the greater ethanol metabolic capacity of the liver, whereas the net enhancement in brain light emission at 3 h after ethanol treatment is higher than that of the liver, which could reflect the greater susceptibility of brain to oxidative stress. The effect of ethanol on brain and liver CL seems to be mediated by acetaldehyde, due to its abolishment by the alcohol dehydrogenase inhibitor 4-methylpyrazole and exacerbation by the aldehyde dehydrogenase inhibitor disulfiram. In brain, these findings were observed in the absence of changes in the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase. However, the content of brain glutathione was significantly decreased by 31%, by ethanol, thus establishing an enhanced oxidative stress in this tissue.

Adolescent and Adult Rats Differ in the Amnesic Effects of Acute Ethanol in Two Hippocampus-Dependent Tasks: Trace and Contextual Fear Conditioning

PubMed Central

Hunt, Pamela S.; Barnet, Robert C.

2015-01-01

Experience-produced deficits in trace conditioning and context conditioning have been useful tools for examining the role of the hippocampus in learning. It has also been suggested that learning in these tasks is especially vulnerable to neurotoxic effects of alcohol during key developmental periods such as adolescence. In five experiments we systematically examined the presence and source of age-dependent vulnerability to the memory-disrupting effects of acute ethanol in trace conditioning and contextual fear conditioning. In Experiment 1a pre-training ethanol disrupted trace conditioning more strongly in adolescent (postnatal day, PD30-35) than adult rats (PD65-75). In Experiment 1b when pre-training ethanol was accompanied by pre-test ethanol no deficit in trace conditioning was observed in adolescents, suggesting that state-dependent retrieval failure mediated ethanol's disruption of trace conditioning at this age. Experiments 2a and 2b examined the effect of ethanol pretreatment on context conditioning. Here, adult but not adolescent rats were impaired in conditioned freezing to context cues. Experiment 2c explored state-dependency of this effect. Pre-training ethanol continued to disrupt context conditioning in adults even when ethanol was also administered prior to test. Collectively these findings reveal clear age-dependent and task-dependent vulnerabilities in ethanol's disruptive effects on hippocampus-dependent memory. Adolescents were more disrupted by ethanol in trace conditioning than adults, and adults were more disrupted by ethanol in context conditioning than adolescents. We suggest that adolescents may be more susceptible to changes in internal state (state-dependent retrieval failure) than adults and that ethanol disrupted performance in trace and context conditioning through different mechanisms. Relevance of these findings to theories of hippocampus function is discussed. PMID:26192910

Agmatine blocks ethanol-induced locomotor hyperactivity in male mice.

PubMed

Ozden, Onder; Kayir, Hakan; Ozturk, Yusuf; Uzbay, Tayfun

2011-05-20

Ethanol-induced locomotor activity is associated to rewarding effects of ethanol and ethanol dependence. Agmatine is a novel endogenous ligand at α2-adrenoceptors, imidazoline and N-methyl-d-aspartate (NMDA) receptors, as well as a nitric oxide synthase (NOS) inhibitor. There is no evidence presented for the relationship between the acute locomotor stimulating effect of ethanol and agmatine. Thus, the present study investigated the effects of agmatine on acute ethanol-induced locomotor hyperactivity in mice. Adult male Swiss-Webster mice (26-36g) were used as subjects. Locomotor activity of the mice was recorded for 30min immediately following intraperitoneal administration of ethanol (0.5, 1 and 2g/kg) or saline (n=8 for each group). Agmatine (5, 10 and 20mg/kg) or saline was administered intraperitoneally to another four individual groups (n=8 for each group) of the mice 20min before the ethanol injection. In these groups, locomotor activity was also recorded immediately following ethanol (0.5g/kg) injection for 30min. Ethanol (0.5g/kg) produced some significant increases in locomotor activity of the mice. Agmatine (5-20mg/kg) significantly blocked the ethanol (0.5g/kg)-induced locomotor hyperactivity. These doses of agmatine did not affect the locomotor activity in naive mice when they were administered alone. Our results suggest that agmatine has an important role in ethanol-induced locomotor hyperactivity in mice. There may be a relationship between the addictive psychostimulant effects of the ethanol and central agmatinergic system. Copyright © 2011 Elsevier B.V. All rights reserved.

Ethanol Reversal of Oxycodone Tolerance in Dorsal Root Ganglia Neurons.

PubMed

Jacob, Joanna C; Sakakibara, Kensuke; Mischel, Ryan A; Henderson, Graeme; Dewey, William L; Akbarali, Hamid I

2018-05-01

Oxycodone is a semisynthetic opioid compound that is widely prescribed, used, and abused today, and has a well-established role in shaping the current opioid epidemic. Previously, we have shown that tolerance develops to the antinociceptive and respiratory depressive effects of oxycodone in mice, and that a moderate dose of acute ethanol or a protein kinase C (PKC) inhibitor reversed that tolerance. To investigate further if tolerance was occurring through neuronal mechanisms, our aims for this study were to assess the effects of acute and prolonged oxycodone in isolated dorsal root ganglia (DRG) neurons and to determine if this tolerance was reversed by either ethanol or a PKC inhibitor. We found that an acute exposure to 3 μ M oxycodone reduced neuronal excitability, as measured by increased threshold potentials and reduced action potential amplitude, without eliciting measurable changes in resting membrane potential. Exposure to 10 μ M oxycodone for 18-24 hours prevented oxycodone's effect on neuronal excitability, indicative of tolerance development. The development of opioid tolerance was mitigated in DRG neurons from β -arrestin 2 knockout mice. Oxycodone tolerance was reversed in isolated DRG neurons by the acute application of either ethanol (20 mM) or the PKC inhibitor, bisindolylmaleimide XI hydrochloride (Bis XI), when a challenge of 3 µ M oxycodone significantly reduced neuronal excitability following prolonged exposure. Through these studies, we concluded that oxycodone acutely reduced neuronal excitability, tolerance developed to this effect, and reversal of that tolerance occurred at the level of a single neuron, suggesting that reversal of oxycodone tolerance by either ethanol or Bis XI involves cellular mechanisms. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Protective effect of Allium neapolitanum Cyr. versus Allium sativum L. on acute ethanol-induced oxidative stress in rat liver.

PubMed

Nencini, Cristina; Franchi, Gian Gabriele; Cavallo, Federica; Micheli, Lucia

2010-04-01

This study investigated the protective effect of Allium neapolitanum Cyr., a spontaneous species of the Italian flora, compared with garlic (Allium sativum L.) on liver injury induced by ethanol in rats. Male albino Wistar rats were orally treated with fresh Allium homogenates (leaves or bulbs, 250 mg/kg) daily for 5 days, whereas controls received vehicle only. At the end of the experimental 5-day period, the animals received an acute ethanol dose (6 mL/kg, i.p.) 2 hours before the last Allium administration and were sacrificed 6 hours after ethanol administration. The activities of catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) and the levels of malondialdehyde (MDA), ascorbic acid (AA), and reduced (GSH) and oxidized glutathione in liver tissue were determined. Administration of both Allium species for 5 days (leaves or bulbs) led to no statistical variation of nonenzymatic parameters versus the control group; otherwise Allium treatment caused an increase of GSH and AA levels compared with the ethanol group and a diminution of MDA levels, showing in addition that A. neapolitanum bulb had the best protective effect. Regarding to enzymatic parameters, GR and CAT activities were enhanced significantly compared with the ethanol group, whereas SOD activity showed a trend different from other parameters estimated. However, the treatment with both Allium species followed by acute ethanol administration reestablished the nonenzymatic parameters similar to control values and enhanced the activities of the enzymes measured. These results suggest that fresh Allium homogenates (leaves or bulbs) possess antioxidant properties and provide protection against ethanol-induced liver injury.

Short Communication: Is Ethanol-Based Hand Sanitizer Involved in Acute Pancreatitis after Excessive Disinfection?—An Evaluation with the Use of PBPK Model

PubMed Central

Huynh-Delerme, Céline; Artigou, Catherine; Bodin, Laurent; Tardif, Robert; Charest-Tardif, Ginette; Verdier, Cécile; Sater, Nessryne; Ould-Elhkim, Mostafa; Desmares, Catherine

2012-01-01

An occupational physician reported to the French Health Products Safety Agency (Afssaps) a case of adverse effect of acute pancreatitis (AP) in a teaching nurse, after multiple demonstrations with ethanol-based hand sanitizers (EBHSs) used in a classroom with defective mechanical ventilation. It was suggested by the occupational physician that the exposure to ethanol may have produced a significant blood ethanol concentration and subsequently the AP. In order to verify if the confinement situation due to defective mechanical ventilation could increase the systemic exposure to ethanol via inhalation route, a physiologically based pharmacokinetic (PBPK) modeling was used to predict ethanol blood levels. Under the worst case scenario, the simulation by PBPK modeling showed that the maximum blood ethanol concentration which can be predicted of 5.9 mg/l is of the same order of magnitude to endogenous ethanol concentration (mean = 1.1 mg/L; median = 0.4 mg/L; range = 0–35 mg/L) in nondrinker humans (Al-Awadhi et al., 2004). The present study does not support the likelihood that EBHS leads to an increase in systemic ethanol concentration high enough to provoke an acute pancreatitis. PMID:22577377

ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis

PubMed Central

Tsai, Wen-Wei; Matsumura, Shigenobu; Liu, Weiyi; Phillips, Naomi G.; Sonntag, Tim; Hao, Ergeng; Lee, Soon; Hai, Tsonwin; Montminy, Marc

2015-01-01

Increases in circulating glucagon during fasting maintain glucose balance by stimulating hepatic gluconeogenesis. Acute ethanol intoxication promotes fasting hypoglycemia through an increase in hepatic NADH, which inhibits hepatic gluconeogenesis by reducing the conversion of lactate to pyruvate. Here we show that acute ethanol exposure also lowers fasting blood glucose concentrations by inhibiting the CREB-mediated activation of the gluconeogenic program in response to glucagon. Ethanol exposure blocked the recruitment of CREB and its coactivator CRTC2 to gluconeogenic promoters by up-regulating ATF3, a transcriptional repressor that also binds to cAMP-responsive elements and thereby down-regulates gluconeogenic genes. Targeted disruption of ATF3 decreased the effects of ethanol in fasted mice and in cultured hepatocytes. These results illustrate how the induction of transcription factors with overlapping specificity can lead to cross-coupling between stress and hormone-sensitive pathways. PMID:25730876

Sir2/Sirt1 Links Acute Inebriation to Presynaptic Changes and the Development of Alcohol Tolerance, Preference, and Reward.

PubMed

Engel, Gregory L; Marella, Sunanda; Kaun, Karla R; Wu, Julia; Adhikari, Pratik; Kong, Eric C; Wolf, Fred W

2016-05-11

Acute ethanol inebriation causes neuroadaptive changes in behavior that favor increased intake. Ethanol-induced alterations in gene expression, through epigenetic and other means, are likely to change cellular and neural circuit function. Ethanol markedly changes histone acetylation, and the sirtuin Sir2/SIRT1 that deacetylates histones and transcription factors is essential for the rewarding effects of long-term drug use. The molecular transformations leading from short-term to long-term ethanol responses mostly remain to be discovered. We find that Sir2 in the mushroom bodies of the fruit fly Drosophila promotes short-term ethanol-induced behavioral plasticity by allowing changes in the expression of presynaptic molecules. Acute inebriation strongly reduces Sir2 levels and increases histone H3 acetylation in the brain. Flies lacking Sir2 globally, in the adult nervous system, or specifically in the mushroom body α/β-lobes show reduced ethanol sensitivity and tolerance. Sir2-dependent ethanol reward is also localized to the mushroom bodies, and Sir2 mutants prefer ethanol even without a priming ethanol pre-exposure. Transcriptomic analysis reveals that specific presynaptic molecules, including the synaptic vesicle pool regulator Synapsin, depend on Sir2 to be regulated by ethanol. Synapsin is required for ethanol sensitivity and tolerance. We propose that the regulation of Sir2/SIRT1 by acute inebriation forms part of a transcriptional program in mushroom body neurons to alter presynaptic properties and neural responses to favor the development of ethanol tolerance, preference, and reward. We identify a mechanism by which acute ethanol inebriation leads to changes in nervous system function that may be an important basis for increasing ethanol intake and addiction liability. The findings are significant because they identify ethanol-driven transcriptional events that target presynaptic properties and direct behavioral plasticity. They also demonstrate that multiple forms of ethanol behavioral plasticity that are relevant to alcoholism are initiated by a shared mechanism. Finally, they link these events to the Drosophila brain region that associates context with innate approach and avoidance responses to code for reward and other higher-order behavior, similar in aspects to the role of the vertebrate mesolimbic system. Copyright © 2016 the authors 0270-6474/16/365241-11$15.00/0.

Role of adenosine and the orexinergic perifornical hypothalamus in sleep-promoting effects of ethanol.

PubMed

Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M

2014-03-01

Strong clinical and preclinical evidence suggests that acute ethanol promotes sleep. However, very little is known about how and where ethanol acts to promote sleep. We hypothesized that ethanol may induce sleep by increasing extracellular levels of adenosine and inhibiting orexin neurons in the perifornical hypothalamus. Experiments 1 and 2: Within-Subject Design; Experiment 3: Between-Subject Design. N/A. N/A. N/A. Using adult male Sprague-Dawley rats as our animal model, we performed three experiments to test our hypothesis. Our first experiment examined the effect of A1 receptor blockade in the orexinergic perifornical hypothalamus on sleep- promoting effects of ethanol. Bilateral microinjection of the selective A1 receptor antagonist 1,3-dipropyl-8-phenylxanthine (500 μM; 250 nL/side) into orexinergic perifornical hypothalamus significantly reduced nonrapid eye movement sleep with a concomitant increase in wakefulness, suggesting that blockade of adenosine A1 receptor attenuates ethanol-induced sleep promotion. Our second experiment examined adenosine release in the orexinergic perifornical hypothalamus during local ethanol infusion. Local infusion of pharmacologically relevant doses of ethanol significantly and dose-dependently increased adenosine release. Our final experiment used c-Fos immunohistochemistry to examine the effects of ethanol on the activation of orexin neurons. Acute ethanol exposure significantly reduced the number of orexin neurons containing c-Fos, suggesting an inhibition of orexin neurons after ethanol intake. Based on our results, we believe that ethanol promotes sleep by increasing adenosine in the orexinergic perifornical hypothalamus, resulting in A1 receptor-mediated inhibition of orexin neurons.

Ethanol induces taurine release in the amygdala: an in vivo microdialysis study.

PubMed

Quertemont, E; Dahchour, A; Ward, R J; Witte, P

1999-01-01

The effect of acute IP ethanol injections on the extracellular aspartate, glutamate, taurine and GABA content of the basolateral amygdala microdialysate was investigated in relationship with total brain ethanol. Each acute intraperitoneal injection of ethanol, 0.5, 1.0, 2.0 and 3.0 g/kg body weight, induced an immediate increase in microdialysate taurine; both 0.5 and 1.0 g/kg ethanol evoked an increase during the first 20 minutes following injection which returned to baseline value by 40 minutes, despite the fact that ethanol was detectable in the brain until 60 or 120 minutes, respectively. After either 2.0 or 3.0 g/kg ethanol there was an increase in taurine of gradual intensity which gradually declined to reach baseline values by 100 minutes. In contrast, the ethanol concentration for 2.0 g/kg remained elevated at the end of the 120 minutes; approximately 25 mg ethanol/mg protein. The stimulated release of taurine within the amygdala could participate in the regulation of ethanoli-nduced changes in osmolarity, since taurine is postulated to act as an osmoregulator in the brain. Taurine could also mediate or interact with ethanol-induced central nervous system effects, as it exerts a modulatory action on cell excitability and neurotransmitter processes.

Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic- pituitary-adrenal axis activation

PubMed Central

Reynolds, Anna R.; Saunders, Meredith A.; Brewton, Honoree’ W.; Winchester, Sydney R.; Elgumati, Ibrahim S.; Prendergast, Mark A.

2015-01-01

Background The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. Methods Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 1100 hrs on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60 mg/kg/i.g.) or a placebo and withdrawal was monitored. Results Peak BELs of 225.52 mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g. aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. Conclusions The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence. PMID:26143299

Acute prenatal exposure to ethanol on gestational day 12 elicits opposing deficits in social behaviors and anxiety-like behaviors in Sprague Dawley rats.

PubMed

Diaz, Marvin R; Mooney, Sandra M; Varlinskaya, Elena I

2016-09-01

Our previous research has shown that in Long Evans rats acute prenatal exposure to a high dose of ethanol on gestational day (G) 12 produces social deficits in male offspring and elicits substantial decreases in social preference relative to controls, in late adolescents and adults regardless of sex. In order to generalize the observed detrimental effects of ethanol exposure on G12, pregnant female Sprague Dawley rats were exposed to ethanol or saline and their offspring were assessed in a modified social interaction (SI) test as early adolescents, late adolescents, or young adults. Anxiety-like behavior was also assessed in adults using the elevated plus maze (EPM) or the light/dark box (LDB) test. Age- and sex-dependent social alterations were evident in ethanol-exposed animals. Ethanol-exposed males showed deficits in social investigation at all ages and age-dependent alterations in social preference. Play fighting was not affected in males. In contrast, ethanol-exposed early adolescent females showed no changes in social interactions, whereas older females demonstrated social deficits and social indifference. In adulthood, anxiety-like behavior was decreased in males and females prenatally exposed to ethanol in the EPM, but not the LDB. These findings suggest that social alterations associated with acute exposure to ethanol on G12 are not strain-specific, although they are more pronounced in Long Evans males and Sprague Dawley females. Furthermore, given that anxiety-like behaviors were attenuated in a test-specific manner, this study indicates that early ethanol exposure can have differential effects on different forms of anxiety. Copyright © 2016 Elsevier B.V. All rights reserved.

Acute prenatal exposure to ethanol on gestational day 12 elicits opposing deficits in social behaviors and anxiety-like behaviors in Sprague Dawley rats

PubMed Central

Diaz, Marvin R.; Mooney, Sandra M.; Varlinskaya, Elena I.

2016-01-01

Our previous research has shown that in Long Evans rats acute prenatal exposure to a high dose of ethanol on gestational day (G) 12 produces social deficits in male offspring and elicits substantial decreases in social preference relative to controls, in late adolescents and adults regardless of sex. In order to generalize the observed detrimental effects of ethanol exposure on G12, pregnant female Sprague Dawley rats were exposed to ethanol or saline and their offspring were assessed in a modified social interaction (SI) test as early adolescents, late adolescents, or young adults. Anxiety-like behavior was also assessed in adults using the elevated plus maze (EPM) or the light/dark box (LDB) test. Age- and sex-dependent social alterations were evident in ethanol-exposed animals. Ethanol-exposed males showed deficits in social investigation at all ages and age-dependent alterations in social preference. Play fighting was not affected in males. In contrast, ethanol-exposed early adolescent females showed no changes in social interactions, whereas older females demonstrated social deficits and social indifference. In adulthood, anxiety-like behavior was decreased in males and females prenatally exposed to ethanol in the EPM, but not the LDB. These findings suggest that social alterations associated with acute exposure to ethanol on G12 are not strain-specific, although they are more pronounced in Long Evans males and Sprague Dawley females. Furthermore, given that anxiety-like behaviors were attenuated in a test-specific manner, this study indicates that early ethanol exposure can have differential effects on different forms of anxiety. PMID:27154534

Cholinesterase inhibitors, donepezil and rivastigmine, attenuate spatial memory and cognitive flexibility impairment induced by acute ethanol in the Barnes maze task in rats.

PubMed

Gawel, Kinga; Labuz, Krzysztof; Gibula-Bruzda, Ewa; Jenda, Malgorzata; Marszalek-Grabska, Marta; Filarowska, Joanna; Silberring, Jerzy; Kotlinska, Jolanta H

2016-10-01

Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases-enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments-probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission.

Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic-pituitary-adrenal axis activation.

PubMed

Reynolds, Anna R; Saunders, Meredith A; Brewton, Honoree' W; Winchester, Sydney R; Elgumati, Ibrahim S; Prendergast, Mark A

2015-09-01

The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 11:00hours on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60mg/kg/i.g.) or a placebo and withdrawal was monitored. Peak BELs of 225.52mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g., aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Acute neuropsychological effects of MDMA and ethanol (co-)administration in healthy volunteers.

PubMed

Dumont, G J H; Wezenberg, E; Valkenberg, M M G J; de Jong, C A J; Buitelaar, J K; van Gerven, J M A; Verkes, R J

2008-04-01

In Western societies, a considerable percentage of young people expose themselves to 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). Commonly, ecstasy is used in combination with other substances, in particular alcohol (ethanol). MDMA induces both arousing as well as hallucinogenic effects, whereas ethanol is a general central nervous system depressant. The aim of the present study is to assess the acute effects of single and co-administration of MDMA and ethanol on executive, memory, psychomotor, visuomotor, visuospatial and attention function, as well as on subjective experience. We performed a four-way, double-blind, randomised, crossover, placebo-controlled study in 16 healthy volunteers (nine male, seven female) between the ages of 18-29. MDMA was given orally (100 mg) and blood alcohol concentration was maintained at 0.6 per thousand by an ethanol infusion regime. Co-administration of MDMA and ethanol was well tolerated and did not show greater impairment of performance compared to the single-drug conditions. Impaired memory function was consistently observed after all drug conditions, whereas impairment of psychomotor function and attention was less consistent across drug conditions. Co-administration of MDMA and ethanol did not exacerbate the effects of either drug alone. Although the impairment of performance by all drug conditions was relatively moderate, all induced significant impairment of cognitive function.

Protective Effect of Camellia Oil (Camellia oleifera Abel.) against Ethanol-Induced Acute Oxidative Injury of the Gastric Mucosa in Mice.

PubMed

Tu, Pang-Shuo; Tung, Yu-Tang; Lee, Wei-Ting; Yen, Gow-Chin

2017-06-21

Camellia oil, a common edible oil in Taiwan and China, has health effects for the gastrointestinal tract in folk medicine, and it contains abundant unsaturated fatty acids and phytochemicals. However, the preventive effect of camellia oil on ethanol-induced gastric ulcers remains unclear. This study was aimed to evaluate the preventive effect of camellia oil on ethanol-induced gastric injury in vitro and in vivo as well as its mechanisms of action. In an in vitro study, our results showed that pretreatment of RGM-1 cells with camellia oil enhanced the migration ability as well as increased heat shock protein expression and reduced apoptotic protein expression. In animal experiments, mice pretreated with camellia oil effectively showed improved ethanol-induced acute injury of the gastric muscosa and oxidative damage through the enhancement of antioxidant enzyme activities and heat shock protein and PGE 2 production, as well as the suppression of lipid peroxidation, apoptosis-related proteins, pro-inflammatory cytokines, and NO production. Histological injury score and hemorrhage score in ethanol-induced gastric mucosal damage dramatically elevated from the control group (0.00 ± 0.0) to 3.40 ± 0.7 and 2.60 ± 0.5, respectively. However, treatments with camellia oil or olive oil (2 mL/kg bw) and lansoprazole (30 mg/kg bw) showed significant decreases in elevation of injury score and hemorrhage score (p < 0.05). Therefore, camellia oil has the potential to ameliorate ethanol-induced acute gastric mucosal injury through the inhibition of inflammation and oxidative stress.

Fyn-Dependent Gene Networks in Acute Ethanol Sensitivity

PubMed Central

Farris, Sean P.; Miles, Michael F.

2013-01-01

Studies in humans and animal models document that acute behavioral responses to ethanol are predisposing factor for the risk of long-term drinking behavior. Prior microarray data from our laboratory document strain- and brain region-specific variation in gene expression profile responses to acute ethanol that may be underlying regulators of ethanol behavioral phenotypes. The non-receptor tyrosine kinase Fyn has previously been mechanistically implicated in the sedative-hypnotic response to acute ethanol. To further understand how Fyn may modulate ethanol behaviors, we used whole-genome expression profiling. We characterized basal and acute ethanol-evoked (3 g/kg) gene expression patterns in nucleus accumbens (NAC), prefrontal cortex (PFC), and ventral midbrain (VMB) of control and Fyn knockout mice. Bioinformatics analysis identified a set of Fyn-related gene networks differently regulated by acute ethanol across the three brain regions. In particular, our analysis suggested a coordinate basal decrease in myelin-associated gene expression within NAC and PFC as an underlying factor in sensitivity of Fyn null animals to ethanol sedation. An in silico analysis across the BXD recombinant inbred (RI) strains of mice identified a significant correlation between Fyn expression and a previously published ethanol loss-of-righting-reflex (LORR) phenotype. By combining PFC gene expression correlates to Fyn and LORR across multiple genomic datasets, we identified robust Fyn-centric gene networks related to LORR. Our results thus suggest that multiple system-wide changes exist within specific brain regions of Fyn knockout mice, and that distinct Fyn-dependent expression networks within PFC may be important determinates of the LORR due to acute ethanol. These results add to the interpretation of acute ethanol behavioral sensitivity in Fyn kinase null animals, and identify Fyn-centric gene networks influencing variance in ethanol LORR. Such networks may also inform future design of pharmacotherapies for the treatment and prevention of alcohol use disorders. PMID:24312422

Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis

PubMed Central

Huang, Wei; Booth, David M; Cane, Matthew C; Chvanov, Michael; Javed, Muhammad A; Elliott, Victoria L; Armstrong, Jane A; Dingsdale, Hayley; Cash, Nicole; Li, Yan; Greenhalf, William; Mukherjee, Rajarshi; Kaphalia, Bhupendra S; Jaffar, Mohammed; Petersen, Ole H; Tepikin, Alexei V; Sutton, Robert; Criddle, David N

2014-01-01

Objective Non-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury and acute pancreatitis (AP). This study investigated the relative importance of oxidative and non-oxidative pathways in mitochondrial dysfunction, pancreatic damage and development of alcoholic AP, and whether deleterious effects of NOME are preventable. Design Intracellular calcium ([Ca2+]C), NAD(P)H, mitochondrial membrane potential and activation of apoptotic and necrotic cell death pathways were examined in isolated pancreatic acinar cells in response to ethanol and/or palmitoleic acid (POA) in the presence or absence of 4-methylpyrazole (4-MP) to inhibit oxidative metabolism. A novel in vivo model of alcoholic AP induced by intraperitoneal administration of ethanol and POA was developed to assess the effects of manipulating alcohol metabolism. Results Inhibition of OME with 4-MP converted predominantly transient [Ca2+]C rises induced by low ethanol/POA combination to sustained elevations, with concurrent mitochondrial depolarisation, fall of NAD(P)H and cellular necrosis in vitro. All effects were prevented by 3-benzyl-6-chloro-2-pyrone (3-BCP), a CEL inhibitor. 3-BCP also significantly inhibited rises of pancreatic FAEE in vivo and ameliorated acute pancreatic damage and inflammation induced by administration of ethanol and POA to mice. Conclusions A combination of low ethanol and fatty acid that did not exert deleterious effects per se became toxic when oxidative metabolism was inhibited. The in vitro and in vivo damage was markedly inhibited by blockade of CEL, indicating the potential for development of specific therapy for treatment of alcoholic AP via inhibition of FAEE generation. PMID:24162590

Effects of acute administration of ethanol on the rat adrenal cortex.

PubMed

Milovanović, Tatjana; Budec, Mirela; Balint-Perić, Ljiljana; Koko, Vesna; Todorović, Vera

2003-09-01

The purpose of this study was to investigate the effect of a single dose of ethanol on rat adrenal cortex and to determine whether the estrous cycle can influence this effect of ethanol. Adult female Wistar rats showing proestrus or diestrus Day 1 (n = 12) were treated intraperitoneally with ethanol (4 g/kg body weight). Untreated (n = 15) and saline-injected (n = 14) rats were used as controls. The animals were sacrificed by decapitation 0.5 hour after ethanol administration. Stereological analysis was performed on paraffin sections of adrenal glands stained with AZAN, and the following parameters were determined: absolute volume of the zona glomerulosa, the zona fasciculata and the zona reticularis, numerical density, volume and the mean diameter of adrenocortical cells and of their nuclei, and diameter and length of capillaries. The diameter and volume of adrenocortical cells in the zona fasciculata and the zona reticularis were significantly increased by acute ethanol treatment at proestrus. In the same group of animals, a single dose of ethanol induced significant decrease in numerical density of adrenocortical cells and of their nuclei in all three zones. Increased length of capillaries of the zona fasciculata as well as enhanced level of serum corticosterone was found in ethanol-treated rats at both phases of the estrous cycle, proestrus and diestrus Day 1. The obtained results indicate that a single dose of ethanol activates adrenal cortex in female rats and that the effect is more pronounced on morphometric parameters at proestrus.

Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol).

PubMed

Chan, Lingtak-Neander; Anderson, Gail D

2014-12-01

Ethanol (alcohol) is one of the most widely used legal drugs in the world. Ethanol is metabolized by alcohol dehydrogenase (ADH) and the cytochrome P450 (CYP) 2E1 drug-metabolizing enzyme that is also responsible for the biotransformation of xenobiotics and fatty acids. Drugs that inhibit ADH or CYP2E1 are the most likely theoretical compounds that would lead to a clinically significant pharmacokinetic interaction with ethanol, which include only a limited number of drugs. Acute ethanol primarily alters the pharmacokinetics of other drugs by changing the rate and extent of absorption, with more limited effects on clearance. Both acute and chronic ethanol use can cause transient changes to many physiologic responses in different organ systems such as hypotension and impairment of motor and cognitive functions, resulting in both pharmacokinetic and pharmacodynamic interactions. Evaluating drug interactions with long-term use of ethanol is uniquely challenging. Specifically, it is difficult to distinguish between the effects of long-term ethanol use on liver pathology and chronic malnutrition. Ethanol-induced liver disease results in decreased activity of hepatic metabolic enzymes and changes in protein binding. Clinical studies that include patients with chronic alcohol use may be evaluating the effects of mild cirrhosis on liver metabolism, and not just ethanol itself. The definition of chronic alcohol use is very inconsistent, which greatly affects the quality of the data and clinical application of the results. Our study of the literature has shown that a significantly higher volume of clinical studies have focused on the pharmacokinetic interactions of ethanol and other drugs. The data on pharmacodynamic interactions are more limited and future research addressing pharmacodynamic interactions with ethanol, especially regarding the non-central nervous system effects, is much needed.

The nociceptin/orphanin FQ receptor agonist Ro 64-6198 reduces alcohol self-administration and prevents relapse-like alcohol drinking.

PubMed

Kuzmin, Alexander; Kreek, Mary Jeanne; Bakalkin, Georgy; Liljequist, Sture

2007-04-01

Effects of the opioid receptor like-1 (ORL-1) receptor agonist Ro 64-6198 (0.1, 0.3, and 1.0 mg/kg intraperitoneally (i.p.)) on operant ethanol self-administration and activation of self-administration by ethanol deprivation were studied in male Wistar rats. Acute administration of Ro 64-6198 caused a dose-dependent reduction of ethanol self-administration. In comparison, the opioid antagonist naltrexone (0.1, 0.3, and 1.0 mg/kg i.p.) inhibited ethanol self-administration at all doses tested. Ethanol deprivation for 10 days significantly increased ethanol self-administration during the first 2 days after deprivation. Daily pretreatment with Ro 64-6198 (0.3 mg/kg) or naltrexone (0.3 mg/kg) during the last 3 days of ethanol deprivation abolished the deprivation-induced increase in ethanol intake. Thus, stimulation of the ORL-1 receptors by Ro 64-6198 reduced the acute reinforcing effects of ethanol and prevented relapse-like behavior in the ethanol-deprivation model in a similar manner as a blockade of opioid receptors by naltrexone. Ro 64-6198 at 0.1 and 0.3 mg/kg doses did not alter self-administration of 0.2% saccharin solution, indicating an apparent selectivity of this compound in modification of ethanol reward. These findings add further support to the idea that Ro 64-6198 and potentially other synthetic ORL-1 receptor agonists are as effective as naltrexone in blocking the actions of ethanol important for its addictive potential in animal experiments, and therefore may have therapeutic value in the treatment of alcoholism.

Acute administration of 3-nitropropionic acid, a reactive oxygen species generator, boosts ethanol-induced locomotor stimulation. New support for the role of brain catalase in the behavioural effects of ethanol.

PubMed

Manrique, Héctor M; Miquel, Marta; Aragon, Carlos M G

2006-12-01

The antioxidant enzyme catalase by reacting with H(2)O(2), forms the compound known as compound I (catalase-H(2)O(2)). This compound is able to oxidise ethanol to acetaldehyde in the CNS. It has been demonstrated that 3-nitropropionic acid (3-NPA) induces the activity of the brain catalase-H(2)O(2) system. In this study, we tested the effect of 3-NPA on both the brain catalase-H(2)O(2) system and on the acute locomotor effect of ethanol. To find the optimal interval for the 3-NPA-ethanol interaction mice were treated with 3-NPA 0, 45, 90 and 135min before an ethanol injection (2.4mg/kg). In a second study, 3-NPA (0, 15, 30 or 45mg/kg) was administered SC to animals 90min before saline or several doses of ethanol (1.6 or 2.4g/kg), and the open-field behaviour was registered. The specificity of the effect of 3-NPA (45mg/kg) was evaluated on caffeine (10mg/kg IP) and cocaine (4mg/kg)-induced locomotion. The prevention of 3-NPA effects on both ethanol-induced locomotion and brain catalase activity by L-carnitine, a potent antioxidant, was also studied. Nitropropionic acid boosted ethanol-induced locomotion and brain catalase activity after 90min. The effect of 3-NPA was prevented by l-carnitine administration. These results indicate that 3-NPA enhanced ethanol-induced locomotion by increasing the activity of the brain catalase system.

Sex differences in the behavioral sequelae of chronic ethanol exposure.

PubMed

Jury, Nicholas J; DiBerto, Jeffrey F; Kash, Thomas L; Holmes, Andrew

2017-02-01

Rates of alcohol use disorders (AUDs) differ between men and women, and there is also marked variation between sexes in the effects of acute and chronic alcohol. In parallel to observations in humans, prior studies in rodents have described male/female differences across a range of ethanol-related behaviors, including ethanol drinking. Nonetheless, there remain gaps in our knowledge of the role of sex in moderating the effects of ethanol, particularly in models of chronic ethanol exposure. The goal of the current study was to assess various behavioral sequelae of exposing female C57BL/6J mice to chronic intermittent ethanol (CIE) via ethanol vapors. Following four weeks of CIE exposure, adult male and female mice were compared for ethanol drinking in a two-bottle paradigm, for sensitivity to acute ethanol intoxication (via loss of righting reflex [LORR]) and for anxiety-like behaviors in the novelty-suppressed feeding and marble burying assays. Next, adult and adolescent females were tested on two different two-bottle drinking preparations (fixed or escalating ethanol concentration) after CIE. Results showed that males and females exhibited significantly blunted ethanol-induced LORR following CIE, whereas only males showed increased anxiety-like behavior after CIE. Increased ethanol drinking after CIE was also specific to males, but high baseline drinking in females may have occluded detection of a CIE-induced effect. The failure to observe elevated drinking in females in response to CIE was also seen in females exposed to CIE during adolescence, regardless of whether a fixed or escalating ethanol-concentration two-bottle procedure was employed. Collectively, these data add to the literature on sex differences in ethanol-related behaviors and provide a foundation for future studies examining how the neural consequences of CIE might differ between males and females. Published by Elsevier Inc.

Sex differences in the behavioral sequelae of chronic ethanol exposure

PubMed Central

Jury, Nicholas J.; DiBerto, Jeffrey F.; Kash, Thomas L.; Holmes, Andrew

2016-01-01

Rates of alcohol use disorders (AUDs) differ between men and women, and there is also marked variation between sexes in the effects of acute and chronic alcohol. In parallel to observations in humans, prior studies in rodents have described male/female differences across a range of ethanol-related behaviors, including ethanol drinking. Nonetheless, there remain gaps in our knowledge of the role of sex in moderating the effects of ethanol, particularly in models of chronic ethanol exposure. The goal of the current study was to assess various behavioral sequelae of exposing female C57BL/6J mice to chronic intermittent ethanol (CIE) via ethanol vapors. Following four weeks of CIE exposure, adult male and female mice were compared for ethanol drinking in a two-bottle paradigm, for sensitivity to acute ethanol intoxication (via loss of righting reflex [LORR]) and for anxiety-like behaviors in the novelty-suppressed feeding and marble burying assays. Next, adult and adolescent females were tested on two different two-bottle drinking preparations (fixed or escalating ethanol concentration) after CIE. Results showed that males and females exhibited significantly blunted ethanol-induced LORR following CIE, whereas only males showed increased anxiety-like behavior after CIE. Increased ethanol drinking after CIE was also specific to males, but high baseline drinking in females may have occluded detection of a CIE-induced effect. The failure to observe elevated drinking in females in response to CIE was also seen in females exposed to CIE during adolescence, regardless of whether a fixed or escalating ethanol-concentration two-bottle procedure was employed. Collectively, these data add to the literature on sex differences in ethanol-related behaviors and provide a foundation for future studies examining how the neural consequences of CIE might differ between males and females. PMID:27624846

[Metabolic disturbances and ways of their pharmacological correction in acute poisoning with ethanol in patients with chronic alcoholism].

PubMed

Livanov, G A; Lodyagin, A N; Lubsanova, S V; Kovalenko, A L; Batotsyrenov, B V; Sergeev, O A; Loladze, A T; Andrianov, A Yu

2015-01-01

To study an influence of chronic alcoholism on the clinical course and severity of metabolic disturbances in patients with acute poisoning with ethanol and to improve the treatment. Authors examined 93 patients stratified into three groups (acute poisoning with ethanol in patients with chronic alcoholism, without chronic alcoholism and those treated with reamberin). The presence of chronic alcoholism significantly augmented metabolic disturbances and influenced the disturbance of oxygen-transport function and free-radical processes in patients with acute intoxication with ethanol. Using of reamberin in the complex intensive therapy led to the decrease in metabolic disorders, which improved the clinical course of acute poisoning with ethanol in patients with chronic alcoholism.

Modifications in adrenal hormones response to ethanol by prior ethanol dependence.

PubMed

Guaza, C; Borrell, S

1985-03-01

Ethanol was administered to rats by means of a liquid diet for 16 days; after an ethanol-free interval of four weeks, animals received a test (IP) dose of ethanol (2 g/kg), and the adrenocortical and adrenomedullary responses were evaluated. Chronically ethanol-exposed animals showed tolerance to the stimulatory effect of ethanol in the pituitary-adrenal axis. Likewise, previously dependent rats showed tolerance to the increase in the activity of the adrenomedullary function induced by acute administration of the drug. Our results indicate that chronic ethanol ingestion can induce persistent changes after complete alcohol abstinence.

Acute ethanol administration results in a protective cytokine and neuroinflammatory profile in traumatic brain injury.

PubMed

Chandrasekar, Akila; Heuvel, Florian Olde; Palmer, Annette; Linkus, Birgit; Ludolph, Albert C; Boeckers, Tobias M; Relja, Borna; Huber-Lang, Markus; Roselli, Francesco

2017-10-01

Ethanol intoxication is a common comorbidity in traumatic brain injury. To date, the effect of ethanol on TBI pathogenic cascades and resulting outcomes remains debated. A closed blunt weight-drop murine TBI model has been implemented to investigate behavioral (by sensorimotor and neurological tests), and neuro-immunological (by tissue cytokine arrays and immuno-histology) effects of ethanol intoxication on TBI. The effect of the occurrence of traumatic intracerebral hemorrhage was also studied. The results indicate that ethanol pretreatment results in a faster and better recovery after TBI with reduced infiltration of leukocytes and reduced microglia activation. These outcomes correspond to reduced parenchymal levels of GM-CSF, IL-6 and IL-3 and to the transient upregulation of IL-13 and VEGF, indicating an early shift in the cytokine profile towards reduced inflammation. A significant difference in the cytokine profile was still observed 24h post injury in the ethanol pretreated mice, as shown by the delayed peak in IL-6 and by the suppression of GM-CSF, IFN-γ, and IL-3. Seven days post-injury, ethanol-pretreated mice displayed a significant decrease both in CD45+ cells infiltration and in microglial activation. On the other hand, in the case of traumatic intracerebral hemorrhage, the cytokine profile was dominated by KC, CCL5, M-CSF and several interleukins and ethanol pretreatment did not produce any modification. We can thus conclude that ethanol intoxication suppresses the acute neuro-inflammatory response to TBI, an effect which is correlated with a faster and complete neurological recovery, whereas, the presence of traumatic intracerebral hemorrhage overrides the effects of ethanol. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of ethanol on the visual-evoked potential in rat: dynamics of ON and OFF responses.

PubMed

Dulinskas, Redas; Buisas, Rokas; Vengeliene, Valentina; Ruksenas, Osvaldas

2017-01-01

The effect of acute ethanol administration on the flash visual-evoked potential (VEP) was investigated in numerous studies. However, it is still unclear which brain structures are responsible for the differences observed in stimulus onset (ON) and offset (OFF) responses and how these responses are modulated by ethanol. The aim of our study was to investigate the pattern of ON and OFF responses in the visual system, measured as amplitude and latency of each VEP component following acute administration of ethanol. VEPs were recorded at the onset and offset of a 500 ms visual stimulus in anesthetized male Wistar rats. The effect of alcohol on VEP latency and amplitude was measured for one hour after injection of 2 g/kg ethanol dose. Three VEP components - N63, P89 and N143 - were analyzed. Our results showed that, except for component N143, ethanol increased the latency of both ON and OFF responses in a similar manner. The latency of N143 during OFF response was not affected by ethanol but its amplitude was reduced. Our study demonstrated that the activation of the visual system during the ON response to a 500 ms visual stimulus is qualitatively different from that during the OFF response. Ethanol interfered with processing of the stimulus duration at the level of the visual cortex and reduced the activation of cortical regions.

Acute ethanol responses in Drosophila are sexually dimorphic

PubMed Central

Devineni, Anita V.; Heberlein, Ulrike

2012-01-01

In mammalian and insect models of ethanol intoxication, low doses of ethanol stimulate locomotor activity whereas high doses induce sedation. Sex differences in acute ethanol responses, which occur in humans, have not been characterized in Drosophila. In this study, we find that male flies show increased ethanol hyperactivity and greater resistance to ethanol sedation compared with females. We show that the sex determination gene transformer (tra) acts in the developing nervous system, likely through regulation of fruitless (fru), to at least partially mediate the sexual dimorphism in ethanol sedation. Although pharmacokinetic differences may contribute to the increased sedation sensitivity of females, neuronal tra expression regulates ethanol sedation independently of ethanol pharmacokinetics. We also show that acute activation of fru-expressing neurons affects ethanol sedation, further supporting a role for fru in regulating this behavior. Thus, we have characterized previously undescribed sex differences in behavioral responses to ethanol, and implicated fru in mediating a subset of these differences. PMID:23213244

Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain.

PubMed

Tiwari, Vivek; Veeraiah, Pandichelvam; Subramaniam, Vaidyanathan; Patel, Anant Bahadur

2014-03-01

This study investigates the effects of ethanol on neuronal and astroglial metabolism using (1)H-[(13)C]-NMR spectroscopy in conjunction with infusion of [1,6-(13)C2]/[1-(13)C]glucose or [2-(13)C]acetate, respectively. A three-compartment metabolic model was fitted to the (13)C turnover of GluC3 , GluC4, GABAC 2, GABAC 3, AspC3 , and GlnC4 from [1,6-(13)C2 ]glucose to determine the rates of tricarboxylic acid (TCA) and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The ratio of neurotransmitter cycle to TCA cycle fluxes for glutamatergic and GABAegic neurons was obtained from the steady-state [2-(13)C]acetate experiment and used as constraints during the metabolic model fitting. (1)H MRS measurement suggests that depletion of ethanol from cerebral cortex follows zero order kinetics with rate 0.18 ± 0.04 μmol/g/min. Acute exposure of ethanol reduces the level of glutamate and aspartate in cortical region. GlnC4 labeling was found to be unchanged from a 15 min infusion of [2-(13)C]acetate suggesting that acute ethanol exposure does not affect astroglial metabolism in naive mice. Rates of TCA and neurotransmitter cycle associated with glutamatergic and GABAergic neurons were found to be significantly reduced in cortical and subcortical regions. Acute exposure of ethanol perturbs the level of neurometabolites and decreases the excitatory and inhibitory activity differentially across the regions of brain. Depletion of ethanol and its effect on brain functions were measured using (1)H and (1)H-[(13)C]-NMR spectroscopy in conjunction with infusion of (13)C-labeled substrates. Ethanol depletion from brain follows zero order kinetics. Ethanol perturbs level of glutamate, and the excitatory and inhibitory activity in mice brain. © 2013 International Society for Neurochemistry.

[Acute diuretic effect of ethanolic and aqueous extracts of Ceratopteris pteridoides (Hook) in normal rats].

PubMed

Alviz, Antistio Aníbal; Salas, Rubén Darío; Franco, Luis Alberto

2013-01-01

Ceratopteris pteridoides is a semiaquatic fern of the Parkeriacea family, widely used in the Colombian folk medicine as a diuretic and cholelithiasic, of which there are no scientific reports that validate its popular use. To evaluate the acute and short-term repeated-dose diuretic effect of the ethanolic and aqueous extracts of C. pteridoides in an in vivo model. The total ethanolic extract was obtained by maceration of the whole plant of C. pteridoides with ethanol and the aqueous extract by decoction at 60°C for 15 minutes. Both extracts were evaluated in preliminary phytochemical analysis and histological studies after the administration of the extracts for 8 consecutive days (1000 mg/Kg). The diuretic effect was evaluated using Wistar rats treated with the extracts (500 mg/Kg), using an acute and a short-term repeated-dose model, and quantifying water elimination, sodium and potassium excretion by atomic absorption spectrophotometry, and chloride excretion by mercurimetric titration. In the acute model both extracts showed significant diuretic, natriuretic, and kaliuretic effect compared to the control group. Whereas, a short-term repeated-dose administration showed a diuretic effect without elimination of electrolytes. The histopathologic study did not suggest a toxic effect in liver or kidney. The results represent evidence of the diuretic activity of C. pteridoides and give support the popular use given to this plant in the north coast of Colombia. Further studies are required to isolate and identify the compounds responsible for the activity and the mechanism of action involved.

Age-Dependent Effects of Acute Alcohol Administration in the Hippocampal Phosphoproteome.

PubMed

Contreras, Ana; Morales, Lidia; Tebourbi, Ali; Miguéns, Miguel; Olmo, Nuria Del; Pérez-García, Carmen

2017-12-18

Alcohol consumption during adolescence is deleterious to the developing brain and leads to persistent deficits in adulthood. Several results provide strong evidence for ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the hippocampus. Protein phosphorylation is a well-known and well-documented mechanism in memory processes, but information on phosphoprotein alterations in hippocampus after ethanol exposure is limited. This study focuses on age-related changes in the hippocampal phosphoproteome after acute alcohol administration. We have compared the phosphoprotein expression in the hippocampus of adult and adolescent Wistar rats treated with a single dose of ethanol (5 g/kg i.p.), using a proteomic approach including phosphoprotein enrichment by immobilized metal affinity chromatography (IMAC). Our proteomic analysis revealed that 13 proteins were differentially affected by age, ethanol administration, or both. Most of these proteins are involved in neuroprotection and are expressed less in young rats treated with ethanol. We conclude that acute alcohol induces important changes in the expression of phosphoproteins in the hippocampus that could increase the risk of neurodegenerative disorders, especially when the alcohol exposure begins in adolescence.

Acute ethanol effects on neural encoding of reward size and delay in the nucleus accumbens

PubMed Central

Gutman, Andrea L.

2016-01-01

Acute ethanol administration can cause impulsivity, resulting in increased preference for immediately available rewards over delayed but more valuable alternatives. The manner in which reward size and delay are represented in neural firing is not fully understood, and very little is known about ethanol effects on this encoding. To address this issue, we used in vivo electrophysiology to characterize neural firing in the core of the nucleus accumbens (NAcc) in rats responding for rewards that varied in size or delay after vehicle or ethanol administration. The NAcc is a central element in the circuit that governs decision-making and importantly, promotes choice of delayed rewards. We found that NAcc firing in response to reward-predictive cues encoded anticipated reward value after vehicle administration, but ethanol administration disrupted this encoding, resulting in a loss of discrimination between immediate and delayed rewards in cue-evoked neural responses. In addition, NAcc firing occurring at the time of the operant response (lever pressing) was inversely correlated with behavioral response latency, such that increased firing rates were associated with decreased latencies to lever press. Ethanol administration selectively attenuated this lever press-evoked firing when delayed but not immediate rewards were expected. These effects on neural firing were accompanied by increased behavioral latencies to respond for delayed rewards. Our results suggest that ethanol effects on NAcc cue- and lever press-evoked encoding may contribute to ethanol-induced impulsivity. PMID:27169507

Ethanol Inhibition of Recombinant NMDA Receptors Is Not Altered by Co-Expression of CaMKII-α or CaMKII-β

PubMed Central

Xu, Minfu; Chandler, L. Judson; Woodward, John J.

2008-01-01

Previous studies have shown that the N-methyl-D-aspartate (NMDA) receptor is an important target for the actions of ethanol in the brain. NMDA receptors are glutamate-activated ion channels that are highly expressed in neurons. They are activated during periods of significant glutamatergic synaptic activity and are an important source of the signaling molecule calcium in the post-synaptic spine. Alterations in the function of NMDA receptors by drugs or disease are associated with deficits in motor, sensory and cognitive processes of the brain. Acutely, ethanol inhibits ion flow through NMDA receptors while sustained exposure to ethanol can induce compensatory changes in the density and localization of the receptor. Defining factors that govern the acute ethanol sensitivity of NMDA receptors is an important step in how an individual responds to ethanol. In the present study, we investigated the effect of calcium-calmodulin dependent protein kinase II (CaMKII) on the ethanol sensitivity of recombinant NMDA receptors. CaMKII is a major constituent of the post-synaptic density and is critically involved in various forms of learning and memory. NMDA receptor subunits were transiently expressed in human embryonic kidney 293 cells (HEK 293) along with CaMKII-α or CaMKII-β tagged with the green fluorescent protein (GFP). Whole cell currents were elicited by brief exposures to glutamate and were measured using patchclamp electrophysiology. Neither CaMKII-α or CaMKII-β had any significant effect on the ethanol inhibition of NR1/2A or NR1/2B receptors. Ethanol inhibition was also unaltered by deletion of CaMKII binding domains in NR1 or NR2 subunits or by phospho-site mutants that mimic or occlude CaMKII phosphorylation. Chronic treatment of cortical neurons with ethanol had no significant effect on the expression of CaMKII-α or CaMKII-β. The results of this study suggest that CaMKII is not involved in regulating the acute ethanol sensitivity of NMDA receptors. PMID:18562151

[The effects of ethanol on the evolution of the acute benzodiazepine poisoning].

PubMed

Puha, Gabriela; Hurjui, J; Lupuşoru, Cătălina Elena; Sorodoc, L

2011-01-01

The depressing effects on the nervous central system (NCS) induced by benzodiazepines and ethanol are similar. The complications are rare in the benzodiazepine poisoning, but are a lot more frequent in association with other depressing drugs for the NCS (especially alcohol). We analyzed retrospectively patients with benzodiazepine poisoning admitted in the Internal Medicine Clinic - Toxicology during 2003 - 2009.The study attempted a complex evaluation of the consequences of acute and chronic alcoholism on the evolution of acute benzodiazepinepoisoning and the description of the clinic evolution and paraclinical particularities of the patients under investigation. 343 patients with benzodiazepine poisoning were admitted, 150 were tested through measurement of alcohol level, leading to values between 1 - 415 mg/dl. Chronic alcoholism in personal pathological antecedents of the patients determined a relative risk of intoxication 1.46 times higher. The hospitalization period varied from 1 to 8 days for patients with chronic alcoholism and from 1 to 14 days for patients with acute alcoholism, a statistically important difference. During the period under investigation, from the total of patients admitted for acute benzodiazepine poisoning, 2 deaths were registered. Of the two deaths, one patient showed ethanol coingestion.

Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala

PubMed Central

Varodayan, Florence P.; Soni, Neeraj; Bajo, Michal; Luu, George; Madamba, Samuel G.; Schweitzer, Paul; Parsons, Loren H.; Roberto, Marisa

2015-01-01

The endogenous cannabinoids (eCBs) influence the acute response to ethanol and the development of tolerance, dependence and relapse. Chronic alcohol exposure alters eCB levels and type 1 cannabinoid receptor (CB1) expression and function in brain regions associated with addiction. CB1 inhibits GABA release, and GABAergic dysregulation in the central nucleus of the amygdala (CeA) is critical in the transition to alcohol dependence. We investigated possible disruptions in CB1 signaling of rat CeA GABAergic transmission following intermittent ethanol exposure. In the CeA of alcohol-naïve rats, CB1 agonist WIN 55,212-2 (WIN) decreased the frequency of spontaneous and miniature GABAA receptor-mediated inhibitory postsynaptic currents (s/mIPSCs). This effect was prevented by CB1 antagonism, but not type 2 cannabinoid receptor (CB2) antagonism. After 2–3 weeks of intermittent ethanol exposure, these WIN inhibitory effects were attenuated, suggesting ethanol-induced impairments in CB1 function. The CB1 antagonist AM251 revealed a tonic eCB/CB1 control of GABAergic transmission in the alcohol-naïve CeA that was occluded by calcium chelation in the postsynaptic cell. Chronic ethanol exposure abolished this tonic CB1 influence on mIPSC, but not sIPSC, frequency. Finally, acute ethanol increased CeA GABA release in both naïve and ethanol exposed rats. Although CB1 activation prevented this effect, the AM251- and ethanol-induced GABA release were additive, ruling out a direct participation of CB1 signaling in the ethanol effect. Collectively, these observations demonstrate an important CB1 influence on CeA GABAergic transmission and indicate that the CeA is particularly sensitive to alcohol-induced disruptions of CB1 signaling. PMID:25940135

Biliopancreatic duct injection of ethanol as an experimental model of acute and chronic pancreatitis in rats

PubMed Central

Unal, Ethem; Atalay, Suleyman; Tolan, Huseyin Kerem; Yuksekdag, Sema; Yucel, Metin; Acar, Aylin; Basak, Fatih; Gunes, Pembegul; Bas, Gurhan

2015-01-01

In the present study, we described an easily reproducable experimental pancreatits model induced by biliopancreatic duct injection of ethyl alcohol. Seventy Wistar albino rats were divided equally into seven groups randomly: the control group (group 1), acute pancreatitis groups; induced by 20% ethanol (group 2), 48% ethanol (group 3), 80% ethanol (group 4), chronic pancreatitis groups; induced by 20% ethanol (group 5), 48% ethanol (group 6) and by 80% ethanol (group 7). Acute pancreatitis groups were sacrified on postoperative day 3, while the control group and chronic pancreatitis groups were killed on postoperative day 7. Histopathologic evaluation was done, and P < 0.05 was accepted as statistically significant. All rats in group 3 developed acute pancreatitis (100%). Inflammatory infiltration of neutrophils and mononuclear cells, interstitial edema, and focal necrotic areas were seen in the pancreatic tissues. Similarly, all rats in group 6 developed chronic pancreatitis (100%). Interstitial fibrosis, lymphotic infiltration, ductal dilatation, acinar cell atrophy, periductal hyperplasia were seen in the pancreatic tissues. Mortality was seen only in group 7. The biliopancreatic ductal injection of 48% ethanol induced acute and chronic pancreatitis has 100% success rate. PMID:25785001

Preclinical Evaluation of Riluzole: Assessments of Ethanol Self-Administration and Ethanol Withdrawal Symptoms

PubMed Central

Besheer, Joyce; Lepoutre, Veronique; Hodge, Clyde W.

2010-01-01

Background Many of the neurobehavioral effects of ethanol are mediated by inhibition of excitatory N-methyl-d-aspartate (NMDA) and enhancement of inhibitory γ-amino-butyric-acid (GABA) receptor systems. There is growing interest in drugs that alter these systems as potential medications for problems associated with alcoholism. The drug riluzole, approved for treatment of amyotrophic lateral sclerosis (ALS), inhibits NMDA and enhances GABAA receptor system activity. This study was designed to determine the preclinical efficacy of riluzole to modulate ethanol self-administration and withdrawal. Methods Male C57BL/6J mice were trained to lever press on a concurrent fixed-ratio 1 schedule of ethanol (10% v/v) versus water reinforcement during daily 16-hour sessions. Riluzole (1 to 40 mg/kg, IP) was evaluated on ethanol self-administration after acute and chronic (2 week) treatment. To determine if riluzole influences ethanol withdrawal-associated seizures, mice were fed an ethanol-containing or control liquid diet for 18 days. The effects of a single injection of riluzole (30 mg/kg) were examined on handling-induced convulsions after ethanol withdrawal. Results Acute riluzole (30 and 40 mg/kg) reduced ethanol self-administration during the first 4 hours of the session, which corresponds to the known pharmacokinetics of this drug. Ethanol self-administration was also reduced by riluzole after chronic treatment. Riluzole (30 mg/kg) significantly decreased the severity of ethanol-induced convulsions 2 hours after ethanol withdrawal. Conclusions These results demonstrate that riluzole decreases ethanol self-administration and may reduce ethanol withdrawal severity in mice. Thus, riluzole may have utility in the treatment of problems associated with alcoholism. PMID:19426166

GABAA Receptor Regulation of Voluntary Ethanol Drinking Requires PKCε

PubMed Central

Besheer, Joyce; Lepoutre, Veronique; Mole, Beth; Hodge, Clyde W.

2010-01-01

Protein kinase C (PKC) regulates a variety of neural functions, including ion channel activity, neurotransmitter release, receptor desensitization and differentiation. We have shown previously that mice lacking the ε-isoform of PKC (PKCε) self-administer 75% less ethanol and exhibit supersensitivity to acute ethanol and allosteric positive modulators of GABAA receptors when compared with wild-type controls. The purpose of the present study was to examine involvement of PKCε in GABAA receptor regulation of voluntary ethanol drinking. To address this question, PKCε null-mutant and wild-type control mice were allowed to drink ethanol (10% v/v) vs. water on a two-bottle continuous access protocol. The effects of diazepam (nonselective GABAA BZ positive modulator), zolpidem (GABAA α1 agonist), L-655,708 (BZ-sensitive GABAA α5 inverse agonist), and flumazenil (BZ antagonist) were then tested on ethanol drinking. Ethanol intake (grams/kg/day) by wild-type mice decreased significantly after diazepam or zolpidem but increased after L-655,708 administration. Flumazenil antagonized diazepam-induced reductions in ethanol drinking in wild-type mice. However, ethanol intake by PKCε null mice was not altered by any of the GABAergic compounds even though effects were seen on water drinking in these mice. Increased acute sensitivity to ethanol and diazepam, which was previously reported, was confirmed in PKCε null mice. Thus, results of the present study show that PKCε null mice do not respond to doses of GABAA BZ receptor ligands that regulate ethanol drinking by wild-type control mice. This suggests that PKCε may be required for GABAA receptor regulation of chronic ethanol drinking. PMID:16881070

Innate BDNF expression is associated with ethanol intake in alcohol-preferring AA and alcohol-avoiding ANA rats.

PubMed

Raivio, Noora; Miettinen, Pekka; Kiianmaa, Kalervo

2014-09-04

We have shown recently that acute administration of ethanol modulates the expression of brain-derived neurotrophic factor (BDNF) in several rat brain areas known to be involved in the development of addiction to ethanol and other drugs of abuse, suggesting that BDNF may be a factor contributing to the neuroadaptive changes set in motion by ethanol exposure. The purpose of the present study was to further clarify the role of BDNF in reinforcement from ethanol and in the development of addiction to ethanol by specifying the effect of acute administration of ethanol (1.5 or 3.0 g/kg i.p.) on the expression profile of BDNF mRNA in the ventral tegmental area and in the terminal areas of the mesolimbic dopamine pathway in the brain of alcohol-preferring AA and alcohol-avoiding ANA rats, selected for high and low voluntary ethanol intake, respectively. The level of BDNF mRNA expression was higher in the amygdala and ventral tegmental area of AA than in those of ANA rats, and there was a trend for a higher level in the nucleus accumbens. In the amygdala and hippocampus, a biphasic change in the BDNF mRNA levels was detected: the levels were decreased at 3 and 6h but increased above the basal levels at 24h. Furthermore, there was a difference between the AA and ANA lines in the effect of ethanol, the ANA rats showing an increase in BDNF mRNA levels while such a change was not seen in AA rats. These findings suggest that the innate levels of BDNF expression may play a role in the mediation of the reinforcing effects of ethanol and in the control of ethanol intake. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of chronic fluvoxamine on ethanol- and food-maintained behaviors

PubMed Central

Ginsburg, Brett C.; Lamb, R.J.

2011-01-01

Acute treatment with fluvoxamine reduces responding for ethanol more than responding for food. However, pharmacotherapy for alcoholism is likely to require chronic treatment. These experiments were performed to assess the effects of chronic fluvoxamine on ethanol- and food-maintained behaviors. Effects of chronic fluvoxamine (10 and 17.8 mg/kg/day × 30 days) on ethanol- and food-maintained responding were compared to responding during saline treatment in four Sprague-Dawley rats responding for ethanol and food under a multiple fixed-ratio 5, fixed-ratio 5 schedule. In two subjects, chronic fluvoxamine reduced ethanol-maintained responding more than food-maintained responding; however this effect was transient. In another subject, treatment persistently decreased food-maintained responding relative to ethanol-maintained responding. Finally, in one subject, fluvoxamine nonspecifically disrupted responding for food and ethanol. Similar to results in humans, outbred Sprague-Dawley rats had differential responses to chronic fluvoxamine. The effect was transient in rats that responded favorably (greater reduction of ethanol relative to food responding), while response reductions persisted throughout treatment in rats that responded unfavorably (greater reduction of food relative to ethanol or nonspecific reductions). PMID:16647721

Preservation of Intestinal Structural Integrity by Zinc Is Independent of Metallothionein in Alcohol-Intoxicated Mice

PubMed Central

Lambert, Jason C.; Zhou, Zhanxiang; Wang, Lipeng; Song, Zhenyuan; McClain, Craig J.; Kang, Y. James

2004-01-01

Intestinal-derived endotoxins are importantly involved in alcohol-induced liver injury. Disruption of intestinal barrier function and endotoxemia are common features associated with liver inflammation and injury due to acute ethanol exposure. Zinc has been shown to inhibit acute alcohol-induced liver injury. This study was designed to determine the inhibitory effect of zinc on alcohol-induced endotoxemia and whether the inhibition is mediated by metallothionein (MT) or is independent of MT. MT knockout (MT-KO) mice were administered three oral doses of zinc sulfate (2.5 mg zinc ion/kg body weight) every 12 hours before being administered a single dose of ethanol (6 g/kg body weight) by gavage. Ethanol administration caused liver injury as determined by increased serum transaminases, parenchymal fat accumulation, necrotic foci, and an elevation of tumor necrosis factor (TNF-α). Increased plasma endotoxin levels were detected in ethanol-treated animals whose small intestinal structural integrity was compromised as determined by microscopic examination. Zinc supplementation significantly inhibited acute ethanol-induced liver injury and suppressed hepatic TNF-α production in association with decreased circulating endotoxin levels and a significant protection of small intestine structure. As expected, MT levels remained undetectable in the MT-KO mice under the zinc treatment. These results thus demonstrate that zinc preservation of intestinal structural integrity is associated with suppression of endotoxemia and liver injury induced by acute exposure to ethanol and the zinc protection is independent of MT. PMID:15161632

Inactivation of surrogate coronaviruses on hard surfaces by health care germicides.

PubMed

Hulkower, Rachel L; Casanova, Lisa M; Rutala, William A; Weber, David J; Sobsey, Mark D

2011-06-01

In the 2003 severe acute respiratory syndrome outbreak, finding viral nucleic acids on hospital surfaces suggested surfaces could play a role in spread in health care environments. Surface disinfection may interrupt transmission, but few data exist on the effectiveness of health care germicides against coronaviruses on surfaces. The efficacy of health care germicides against 2 surrogate coronaviruses, mouse hepatitis virus (MHV) and transmissible gastroenteritis virus (TGEV), was tested using the quantitative carrier method on stainless steel surfaces. Germicides were o-phenylphenol/p-tertiary amylphenol) (a phenolic), 70% ethanol, 1:100 sodium hypochlorite, ortho-phthalaldehyde (OPA), instant hand sanitizer (62% ethanol), and hand sanitizing spray (71% ethanol). After 1-minute contact time, for TGEV, there was a log(10) reduction factor of 3.2 for 70% ethanol, 2.0 for phenolic, 2.3 for OPA, 0.35 for 1:100 hypochlorite, 4.0 for 62% ethanol, and 3.5 for 71% ethanol. For MHV, log(10) reduction factors were 3.9 for 70% ethanol, 1.3 for phenolic, 1.7 for OPA, 0.62 for 1:100 hypochlorite, 2.7 for 62% ethanol, and 2.0 for 71% ethanol. Only ethanol reduced infectivity of the 2 coronaviruses by >3-log(10) after 1 minute. Germicides must be chosen carefully to ensure they are effective against viruses such as severe acute respiratory syndrome coronavirus. Copyright © 2011 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.

Acute ethanol ingestion produces dose-dependent effects on motor behavior in the honey bee (Apis mellifera).

PubMed

Maze, Ian S; Wright, Geraldine A; Mustard, Julie A

2006-01-01

Ethanol consumption produces characteristic behavioral states in animals that include sedation, disorientation, and disruption of motor function. Using individual honey bees, we assessed the effects of ethanol ingestion on motor function via continuous observations of their behavior. Consumption of 1 M sucrose solutions containing a range of ethanol doses led to hemolymph ethanol levels of approximately 40-100 mM. Using ethanol doses in this range, we observed time and dose-dependent effects of ethanol on the percent of time our subjects spent walking, stopped, or upside down, and on the duration and frequency of bouts of behavior. The effects on grooming and flying behavior were more complex. Behavioral recovery from ethanol treatment was both time and ethanol dose dependent, occurring between 12 and 24 h post-ingestion for low doses and at 24-48 h for higher doses. Furthermore, the amount of ethanol measured in honey bee hemolymph appeared to correlate with recovery. We predict that the honey bee will prove to be an excellent model system for studying the influence of ethanol on the neural mechanisms underlying behavior.

Acute ethanol treatment increases level of progesterone in ovariectomized rats.

PubMed

Budec, Mirela; Koko, Vesna; Milovanović, Tatjana; Balint-Perić, Ljiljana; Petković, Aleksandra

2002-04-01

To determine whether an increased level of progesterone in adult female rats after acute ethanol treatment, described previously in our study, is the result of activation of adrenal glands, we analyzed adrenal cortex morphologically and measured serum levels of corticosterone and progesterone in ovariectomized rats. In addition, a possible involvement of the opioid system in an observed phenomenon was tested. Adult female Wistar rats were ovariectomized, and 3 weeks after surgery they were treated intraperitoneally with (a) ethanol (4 g/kg), (b) naltrexone (5 mg/kg), followed by ethanol (4 g/kg) 45 min later, and (c) naltrexone (5 mg/kg), followed by saline 45 min later. Untreated and saline-injected rats were used as controls. The animals were killed 0.5 h after ethanol administration. Morphometric analysis was carried out on paraffin sections of adrenal glands, stained with hematoxylin-eosin, and the following parameters were determined: absolute volume of the zona glomerulosa, the zona fasciculata, and the zona reticularis; numerical density, volume, and the mean diameter of adrenocortical cells and of their nuclei; and mean diameter and length of capillaries. The results showed that acute ethanol treatment significantly increased absolute volume of the zona fasciculata and length of its capillaries but did not alter other stereological parameters. Also, serum levels of corticosterone and progesterone were enhanced. Pretreatment with naltrexone had no effect on ethanol-induced changes. These findings are consistent with our previous hypothesis that an ethanol-induced increase of the progesterone level in adult female rats originates from the adrenal cortex.

Sex Differences in Ethanol's Anxiolytic Effect and Chronic Ethanol Withdrawal Severity in Mice with a Null Mutation of the 5α-Reductase Type 1 Gene.

PubMed

Tanchuck-Nipper, Michelle A; Ford, Matthew M; Hertzberg, Anna; Beadles-Bohling, Amy; Cozzoli, Debra K; Finn, Deborah A

2015-05-01

Manipulation of endogenous levels of the GABAergic neurosteroid allopregnanolone alters sensitivity to some effects of ethanol. Chronic ethanol withdrawal decreases activity and expression of 5α-reductase-1, an important enzyme in allopregnanolone biosynthesis encoded by the 5α-reductase-1 gene (Srd5a1). The present studies examined the impact of Srd5a1 deletion in male and female mice on several acute effects of ethanol and on chronic ethanol withdrawal severity. Genotype and sex did not differentially alter ethanol-induced hypothermia, ataxia, hypnosis, or metabolism, but ethanol withdrawal was significantly lower in female versus male mice. On the elevated plus maze, deletion of the Srd5a1 gene significantly decreased ethanol's effect on total entries versus wildtype (WT) mice and significantly decreased ethanol's anxiolytic effect in female knockout (KO) versus WT mice. The limited sex differences in the ability of Srd5a1 genotype to modulate select ethanol effects may reflect an interaction between developmental compensations to deletion of the Srd5a1 gene with sex hormones and levels of endogenous neurosteroids.

Effects of S-Adenosylmethionine and Its Combinations With Taurine and/or Betaine on Glutathione Homeostasis in Ethanol-induced Acute Hepatotoxicity

PubMed Central

Lee, Seo Yeon; Ko, Kwang Suk

2016-01-01

Background Exposure to ethanol abuse and severe oxidative stress are risk factors for hepatocarcinoma. The aim of this study was to evaluate the effects of S-adenosylmethionine (SAMe) and its combinations with taurine and/or betaine on the level of glutathione (GSH), a powerful antioxidant in the liver, in acute hepatotoxicity induced by ethanol. Methods To examine the effects of SAMe and its combinations with taurine and/or betaine on ethanol-induced hepatotoxicity, AML12 cells and C57BL/6 mice were pretreated with SAMe, taurine, and/or betaine, followed by ethanol challenge. Cell viability was detected with an MTT assay. GSH concentration and mRNA levels of GSH synthetic enzymes were measured using GSH reductase and quantitative real-time reverse transcriptase-PCR. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured with commercially available kits. Results Pretreatment of SAMe, with or without taurine and/or betaine, attenuated decreases in GSH levels and mRNA expression of the catalytic subunit of glutamate-cysteine ligase (GCL), the rate-limiting enzyme for GSH synthesis, in ethanol-treated cells and mice. mRNA levels of the modifier subunit of GCL and glutathione synthetase were increased in mice treated with SAMe combinations. SAMe, taurine, and/or betaine pretreatment restored serum ALT and AST levels to control levels in the ethanol-treated group. Conclusions Combinations of SAMe with taurine and/or betaine have a hepatoprotective effect against ethanol-induced liver injury by maintaining GSH homeostasis. PMID:27722142

Effects of acute ethanol administration and chronic stress exposure on social investigation and 50kHz ultrasonic vocalizations in adolescent and adult male Sprague-Dawley rats.

PubMed

Willey, Amanda R; Spear, Linda P

2013-04-01

Adolescents drink largely in social situations, likely in an attempt to facilitate social interactions. This study sought to examine alterations in the incentive salience of a social stimulus following repeated stress exposure and acute ethanol administration in adolescent and adult male Sprague-Dawley rats. Subjects were either exposed to 5days of restraint stress, chronic variable stress (CVS), which consisted of a different stressor every day, or non-stressed. On test day, the animals were injected with 0, 0.25, 0.5, or 0.75g/kg ethanol and placed in a social approach test in which they could see, hear, and smell a social conspecific, but could not physically interact with it. All the animals showed an interest in the social stimulus, with adolescents engaging in more social investigation than adults. Restraint stressed adults showed ethanol-induced increases in social investigation, while ethanol effects were not seen in any other group. An ethanol-associated increase in 50kHz ultrasonic vocalization (USV) production was only evident in restraint stressed adolescents following 0.75g/kg ethanol. 50kHz USVs were not correlated with time spent investigating the social stimulus in any test condition. These results show that age differences in the facilitatory effects of ethanol on incentive salience of social stimuli are moderated by stress, with the facilitation of social approach by ethanol only evident in restraint stressed adults. Copyright © 2013 Elsevier Inc. All rights reserved.

Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.

PubMed

Guo, Rui; Ren, Jun

2010-01-18

Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH). ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways) were examined. Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-). Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-alpha, Fas receptor, Fas L and cytosolic AIF. Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.

Effect of age increase on metabolism and toxicity of ethanol in female rats.

PubMed

Kim, Young C; Kim, Sung Y; Sohn, Young R

2003-12-12

Age-dependent change in the effects of acute ethanol administration on female rat liver was investigated. Female Sprague-Dawley rats, each aged 4, 12, or 50 weeks, received ethanol (2 g/kg) via a catheter inserted into a jugular vein. Ethanol elimination rate (EER), most rapid in the 4 weeks old rats, was decreased as the age advanced. Hepatic alcohol dehydrogenase activity was not altered by age, but microsomal p-nitrophenol hydroxylase activity was significantly greater in the 4 weeks old rats. Relative liver weight decreased with age increase in proportion to reduction of EER. Hepatic triglyceride and malondialdehyde concentrations increased spontaneously in the 50 weeks old nai;ve rats. Ethanol administration (3 g/kg, ip) elevated malondialdehyde and triglyceride contents only in the 4 and the 12 weeks old rats. Hepatic glutathione concentration was increasingly reduced by ethanol with age increase. Ethanol decreased cysteine concentration in the 4 weeks old rats, but elevated it significantly in the older rats. Inhibition of gamma-glutamylcysteine synthetase activity by ethanol was greater with age increase, which appeared to be responsible for the increase in hepatic cysteine. The results indicate that age does not affect the ethanol metabolizing capacity of female rat liver, but the overall ethanol metabolism is decreased in accordance with the reduction of relative liver size. Accordingly induction of acute alcoholic fatty liver is less significant in the old rats. However, progressively greater depletion of glutathione by ethanol in older rats suggests that susceptibility of liver to oxidative damage would be increased as animals grow old.

Beer Is Less Harmful for the Liver than Plain Ethanol: Studies in Male Mice Using a Binge-Drinking Model.

PubMed

Landmann, Marianne; Wagnerberger, Sabine; Kanuri, Giridhar; Ziegenhardt, Doreen; Bergheim, Ina

2015-09-01

Mechanisms involved in the less damaging effects of beer in comparison to hard spirits have not yet been fully understood. The aim of the study was to determine if the effect of beer intake on the liver differs from that of plain ethanol and if so to determine mechanisms involved. Male C57BL/6J mice received either ethanol, beer (ethanol content: 6 g/kg body weight) or iso-caloric maltodextrin solution. Markers of steatosis, lipogenesis, activation of the toll-like receptor-4 signaling cascade and lipid export in liver and tight junction proteins in duodenum were measured 6 and 12 h after acute ethanol or beer intake. Alcohol ingestion resulted in a significant increase of hepatic triglyceride accumulation 6 and 12 h after ingestion, respectively, being markedly lower in mice fed beer. Expression of sterol regulatory element-binding protein-1c mRNA was significantly lower 12 h after alcohol or beer exposure, while fatty acid synthase mRNA expression was induced in livers of ethanol-fed mice and to a lesser extent in mice fed beer 6 h after acute alcohol ingestion. Protein levels of tight junction proteins in the small intestine were similar between groups while expression of myeloid differentiation primary response gene 88 in livers was significantly induced in ethanol- but not in beer-fed mice. Concentrations of 4-hydroxynonenal protein adducts and inducible nitric oxide synthase protein were also only induced in livers of mice fed ethanol. Protein levels of apolipoprotein B were induced in livers of beer-fed mice only. Our data suggest that beer is less harmful on the development of acute alcohol-induced liver damage than plain ethanol in male mice. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Food deprivation increases the low-dose locomotor stimulant response to ethanol in Drosophila melanogaster.

PubMed

Kliethermes, Christopher L

2013-10-01

Acute and chronic states of food deprivation result in increased sensitivity to a variety of natural reinforcers as well as to drugs of abuse. Food deprived animals show increased locomotor activity during periods of food deprivation, as well as increased locomotor stimulant responses to drugs of abuse, including cocaine, amphetamine, morphine, and ethanol, implying that drugs of abuse act in part on neural systems that underlie responses towards food. To determine whether this effect extends to an invertebrate, highly genetically tractable animal, the locomotor stimulant effects of low dose ethanol were assessed under a variety of feeding conditions in the fruit fly, Drosophila melanogaster. Food deprivation resulted in strain specific increases in ethanol-stimulated locomotor activity in most strains tested, although elevated baseline activity confounded interpretation in some strains. Experiments conducted with Canton S flies found that the effects of food deprivation on the locomotor stimulant response to ethanol increased with the duration of deprivation, and could be blocked by refeeding the flies with standard food or sucrose, but not yeast, immediately prior to the ethanol exposure. Life-span extending dietary depletion procedures or previous periods of food deprivation did not affect the response to ethanol, indicating that only animals in an acutely food deprived state are more sensitive to the stimulant effects of ethanol. These results suggest that increased sensitivity to the stimulant effects of some drugs of abuse might reflect an evolutionarily conserved neural mechanism that underlies behavioral responses to natural reinforcers and drugs of abuse. The identification of this mechanism, and the genes that underlie its development and function, will constitute a novel approach towards the study of alcohol abuse and dependence. © 2013.

A pair of dopamine neurons target the D1-like dopamine receptor DopR in the central complex to promote ethanol-stimulated locomotion in Drosophila.

PubMed

Kong, Eric C; Woo, Katherine; Li, Haiyan; Lebestky, Tim; Mayer, Nasima; Sniffen, Melissa R; Heberlein, Ulrike; Bainton, Roland J; Hirsh, Jay; Wolf, Fred W

2010-04-01

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol.

Acute and chronic ethanol intake: effects on spatial and non-spatial memory in rats.

PubMed

García-Moreno, Luis M; Cimadevilla, Jose M

2012-12-01

Abusive alcohol consumption produces neuronal damage and biochemical alterations in the mammal brain followed by cognitive disturbances. In this work rats receiving chronic and acute alcohol intake were evaluated in a spontaneous delayed non-matching to sample/position test. Chronic alcohol-treated rats had free access to an aqueous ethanol solution as the only available liquid source from the postnatal day 21 to the end of experiment (postnatal day 90). Acute alcoholic animals received an injection of 2 g/kg ethanol solution once per week. Subjects were evaluated in two tests (object recognition and spatial recognition) based on the spontaneous delayed non-matching to sample or to position paradigm using delays of 1 min, 15 min and 60 min. Results showed that chronic and acute alcohol intake impairs the rats' performance in both tests. Moreover, chronic alcohol-treated rats were more altered than acute treated animals in both tasks. Our results support the idea that chronic and acute alcohol administration during postnatal development caused widespread brain damage resulting in behavioral disturbances and learning disabilities. Copyright © 2012 Elsevier Inc. All rights reserved.

ESTIMATED RATE OF FATAL AUTOMOBILE ACCIDENTS ATTRIBUTABLE TO ACUTE SOLVENT EXPOSURE AT LOW INHALED CONCENTRATIONS

EPA Science Inventory

Acute solvent exposures may contribute to automobile accidents because they increase reaction time and decrease attention, in addition to impairing other behaviors. These effects resemble those of ethanol consumption, both with respect to behavioral effects and neurological mecha...

A small group of neurosecretory cells expressing the transcriptional regulator apontic and the neuropeptide corazonin mediate ethanol sedation in Drosophila.

PubMed

McClure, Kimberly D; Heberlein, Ulrike

2013-02-27

In the fruit fly Drosophila melanogaster, as in mammals, acute exposure to a high dose of ethanol leads to stereotypical behavioral changes beginning with increased activity, followed by incoordination, loss of postural control, and eventually, sedation. The mechanism(s) by which ethanol impacts the CNS leading to ethanol-induced sedation and the genes required for normal sedation sensitivity remain largely unknown. Here we identify the gene apontic (apt), an Myb/SANT-containing transcription factor that is required in the nervous system for normal sensitivity to ethanol sedation. Using genetic and behavioral analyses, we show that apt mediates sensitivity to ethanol sedation by acting in a small set of neurons that express Corazonin (Crz), a neuropeptide likely involved in the physiological response to stress. The activity of Crz neurons regulates the behavioral response to ethanol, as silencing and activating these neurons affects sedation sensitivity in opposite ways. Furthermore, this effect is mediated by Crz, as flies with reduced crz expression show reduced sensitivity to ethanol sedation. Finally, we find that both apt and crz are rapidly upregulated by acute ethanol exposure. Thus, we have identified two genes and a small set of peptidergic neurons that regulate sensitivity to ethanol-induced sedation. We propose that Apt regulates the activity of Crz neurons and/or release of the neuropeptide during ethanol exposure.

A Small Group of Neurosecretory Cells Expressing the Transcriptional Regulator apontic and the Neuropeptide corazonin Mediate Ethanol Sedation in Drosophila

PubMed Central

2013-01-01

In the fruit fly Drosophila melanogaster, as in mammals, acute exposure to a high dose of ethanol leads to stereotypical behavioral changes beginning with increased activity, followed by incoordination, loss of postural control, and eventually, sedation. The mechanism(s) by which ethanol impacts the CNS leading to ethanol-induced sedation and the genes required for normal sedation sensitivity remain largely unknown. Here we identify the gene apontic (apt), an Myb/SANT-containing transcription factor that is required in the nervous system for normal sensitivity to ethanol sedation. Using genetic and behavioral analyses, we show that apt mediates sensitivity to ethanol sedation by acting in a small set of neurons that express Corazonin (Crz), a neuropeptide likely involved in the physiological response to stress. The activity of Crz neurons regulates the behavioral response to ethanol, as silencing and activating these neurons affects sedation sensitivity in opposite ways. Furthermore, this effect is mediated by Crz, as flies with reduced crz expression show reduced sensitivity to ethanol sedation. Finally, we find that both apt and crz are rapidly upregulated by acute ethanol exposure. Thus, we have identified two genes and a small set of peptidergic neurons that regulate sensitivity to ethanol-induced sedation. We propose that Apt regulates the activity of Crz neurons and/or release of the neuropeptide during ethanol exposure. PMID:23447613

Effect of chronic ethanol consumption on the response of parathyroid hormone to hypocalcemia in the pregnant rat.

PubMed

Duggal, Shalu; Simpson, Mary Elizabeth; Keiver, Kathy

2007-01-01

Chronic alcohol (ethanol) consumption during pregnancy results in maternal/fetal hypocalcemia, which may underlie some of ethanol's adverse effects on maternal and fetal bone, and fetal/neonatal health. Ethanol appears to alter the relationship between parathyroid hormone (PTH) and blood calcium (Ca) level, and PTH does not increase in response to ethanol-induced hypocalcemia. However, it is not known whether ethanol actually prevents PTH from responding, or whether the ability to regulate blood Ca is intact, but ethanol lowers the level of Ca maintained. The objective of this study was to determine whether chronic ethanol consumption impairs the ability of the pregnant female to increase PTH in response to acute hypocalcemia. Rats were fed isocaloric diets with ethanol (36% ethanol-derived calories, E group) or without ethanol [pair-fed (PF) and control (C) groups], before and throughout 21 days of gestation. On day 21 gestation, rats received an intraperitoneal injection of ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) (300 or 500 mumol/kg body weight) or saline (saline group), or no injection (baseline group). Blood was collected from the baseline group, and at 30 or 60 minutes postinjection (saline and EGTA groups), and analyzed for ionized Ca (iCa), pH, and PTH. Consistent with previous studies, ethanol consumption decreased blood iCa levels at baseline, but PTH levels did not differ among groups. Administration of EGTA significantly decreased blood iCa levels by 30 minutes, but ethanol did not prevent PTH from increasing in response to the hypocalcemia. In all diet groups, PTH levels were significantly increased by 30 minutes. Ethanol did, however, appear to decrease the maximum PTH level achievable in blood. These data suggest that chronic ethanol consumption does not impair the ability of the pregnant rat to raise serum PTH levels in response to acute hypocalcemia, but ethanol's effect on maximal PTH secretion could impair the ability of the pregnant female to sustain high PTH levels in response to chronic hypocalcemia.

Acute effects of ethanol and acetate on glucose kinetics in normal subjects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yki-Jaervinen, H.; Koivisto, V.A.; Ylikahri, R.

1988-02-01

The authors compared the effects of two ethanol doses on glucose kinetics and assessed the role of acetate as a mediator of ethanol-induced insulin resistance. Ten normal males were studied on four occasions, during which either a low or moderate ethanol, acetate, or saline dose was administered. Both ethanol doses similarly inhibited basal glucose production. The decrease in R{sub a} was matched by a comparable decrease in glucose utilization (R{sub d}), resulting in maintenance of normoglycemia. During hyperinsulinemia glucose disposal was lower in the moderate than the low-dose ethanol or saline studies. During acetate infusion, the blood acetate level wasmore » comparable with those in the ethanol studies. Acetate had no effect on glucose kinetics. In conclusion, (1) in overnight fasted subjects, ethanol does not cause hypoglycemia because its inhibitory effect on R{sub a} is counterbalanced by equal inhibition of R{sub d}; (2) basal R{sub a} and R{sub d} are maximally inhibited already by small ethanol doses, whereas inhibition of insulin-stimulated glucose disposal requires a moderate ethanol dose; and (3) acetate is not the mediator of ethanol-induced insulin resistance.« less

Acute ethanol ingestion produces dose-dependent effects on motor behavior in the honey bee (Apis mellifera)

PubMed Central

Maze, Ian S.; Wright, Geraldine A.; Mustard, Julie A.

2006-01-01

Ethanol consumption produces characteristic behavioral states in animals that include sedation, disorientation, and disruption of motor function. Using individual honey bees, we assessed the effects of ethanol ingestion on motor function via continuous observations of their behavior. Consumption of 1 M sucrose solutions containing a range of ethanol doses lead to hemolymph ethanol levels of approximately 40 to 100 mM. Using ethanol doses in this range, we observed time and dose-dependent effects of ethanol on the percent of time our subjects spent walking, stopped, or upside down, and on the duration and frequency of bouts of behavior. The effects on grooming and flying behavior were more complex. Behavioral recovery from ethanol treatment was both time and ethanol dose dependent, occurring between 12 and 24 hr post-ingestion for low doses and at 24 to 48 hours for higher doses. Furthermore, the amount of ethanol measured in honey bee hemolymph appeared to correlate with recovery. We predict that the honey bee will prove to be an excellent model system for studying the influence of ethanol on the neural mechanisms underlying behavior. PMID:17070538

Period 2 gene deletion abolishes β-endorphin neuronal response to ethanol

PubMed Central

Agapito, Maria; Mian, Nadia; Boyadjieva, Nadka I.; Sarkar, Dipak K.

2010-01-01

Background Ethanol exposure during early life has been shown to permanently alter the circadian expression of clock regulatory genes and the β-endorphin precursor proopiomelanocortin (POMC) gene in the hypothalamus. Ethanol also alters the stress- and immune-regulatory functions of β-endorphin neurons in laboratory rodents. Our aim was to determine whether the circadian clock regulatory Per2 gene modulates the action of ethanol on β-endorphin neurons in mice. Methods Per2 mutant (mPer2Brdml) and wild type (C57BL/6J) mice were used to determine the effect of Per2 mutation on ethanol-regulated β-endorphin neuronal activity during neonatal period using an in vitro mediobasal hypothalamic (MBH) cell culture model and an in vivo milk formula feeding animal model. The β-endorphin neuronal activity following acute and chronic ethanol treatments, was evaluated by measuring the peptide released from cultured cells or peptide levels in the MBH tissues, using enzyme-linked immunosorbent assay (ELISA). Results Per2 mutant mice showed a higher basal level of β-endorphin release from cultured MBH cells and a moderate increase in the peptide content in the MBH in comparison to control mice. However, unlike wild type mice, Per2 mutant mice showed no stimulatory or inhibitory β-endorphin secretory responses to acute and chronic ethanol challenges in vitro. Furthermore, Per2 mutant mice, but not wild type mice, failed to show the stimulatory and inhibitory responses of MBH β-endorphin levels to acute and chronic ethanol challenges in vivo. Conclusions These results suggest for the first time that the Per2 gene may be critically involved in regulating β-endorphin neuronal function. Furthermore, the data revealed an involvement of the Per2 gene in regulating β-endorphin neuronal responses to ethanol. PMID:20586752

Hops (Humulus lupulus) Content in Beer Modulates Effects of Beer on the Liver After Acute Ingestion in Female Mice.

PubMed

Landmann, Marianne; Sellmann, Cathrin; Engstler, Anna Janina; Ziegenhardt, Doreen; Jung, Finn; Brombach, Christine; Bergheim, Ina

2017-01-01

Using a binge-drinking mouse model, we aimed to determine whether hops (Humulus lupulus) in beer is involved in the less damaging effects of acute beer consumption on the liver in comparison with ethanol. Female C57BL/6 J mice were either fed one iso-alcoholic and iso-caloric bolus dose of ethanol, beer, beer without hops (6 g ethanol/kg body weight) or an iso-caloric bolus of maltodextrin control solution. Markers of steatosis, intestinal barrier function, activation of toll-like receptor 4 signaling cascades, lipid peroxidation and lipogenesis were determined in liver, small intestine and plasma 2 h and 12 h after acute alcohol ingestion. Alcohol-induced hepatic fat accumulation was significantly attenuated in mice fed beer whereas in those fed beer without hops, hepatic fat accumulation was similar to that found in ethanol-fed mice. While markers of intestinal barrier function e.g. portal endotoxin levels and lipogenesis only differed slightly between groups, hepatic concentrations of myeloid differentiation primary response gene 88, inducible nitric oxide synthase (iNOS) and plasminogen-activator inhibitor 1 protein as well as of 4-hydroxynonenal and 3-nitrotyrosine protein adducts were similarly elevated in livers of mice fed ethanol or beer without hops when compared with controls. Induction of these markers was markedly attenuated in mice fed hops-containing beer. Taken together, our data suggest that hops in beer markedly attenuated acute alcohol-induced liver steatosis in female mice through mechanisms involving a suppression of iNOS induction in the liver. © The Author 2016. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Adolescent binge-like alcohol alters sensitivity to acute alcohol effects on dopamine release in the nucleus accumbens of adult rats

PubMed Central

Shnitko, Tatiana A.; Spear, Linda P.; Robinson, Donita L.

2015-01-01

Rationale Early onset of alcohol drinking has been associated with alcohol abuse in adulthood. The neurobiology of this phenomenon is unclear, but mesolimbic dopamine pathways, which are dynamic during adolescence, may play a role. Objectives We investigated the impact of adolescent binge-like alcohol on phasic dopaminergic neurotransmission during adulthood. Methods Rats received intermittent intragastric ethanol, water or nothing during adolescence. In adulthood, electrically-evoked dopamine release and subsequent uptake were measured in the nucleus accumbens core at baseline and after acute challenge of ethanol or saline. Results Adolescent ethanol exposure did not alter basal measures of evoked dopamine release or uptake. Ethanol challenge dose-dependently decreased the amplitude of evoked dopamine release in rats by 30–50% in control groups, as previously reported, but did not alter evoked release in ethanol-exposed animals. To address the mechanism by which ethanol altered dopamine signaling, the evoked signals were modeled to estimate dopamine efflux per impulse and the velocity of the dopamine transporter. Dopamine uptake was slower in all exposure groups after ethanol challenge compared to saline, while dopamine efflux per pulse of electrical stimulation was reduced by ethanol only in ethanol-naive rats. Conclusions The results demonstrate that exposure to binge levels of ethanol during adolescence blunts the effect of ethanol challenge to reduce the amplitude of phasic dopamine release in adulthood. Large dopamine transients may result in more extracellular dopamine after alcohol challenge in adolescent-exposed rats, and may be one mechanism by which alcohol is more reinforcing in people who initiated drinking at an early age. PMID:26487039

Pleiotrophin differentially regulates the rewarding and sedative effects of ethanol.

PubMed

Vicente-Rodríguez, Marta; Pérez-García, Carmen; Ferrer-Alcón, Marcel; Uribarri, María; Sánchez-Alonso, María G; Ramos, María P; Herradón, Gonzalo

2014-12-01

Pleiotrophin (PTN) is a cytokine with important roles in dopaminergic neurons. We found that an acute ethanol (2.0 g/kg, i.p.) administration causes a significant up-regulation of PTN mRNA and protein levels in the mouse prefrontal cortex, suggesting that endogenous PTN could modulate behavioural responses to ethanol. To test this hypothesis, we studied the behavioural effects of ethanol in PTN knockout (PTN(-/-) ) mice and in mice with cortex- and hippocampus-specific transgenic PTN over-expression (PTN-Tg). Ethanol (1.0 and 2.0 g/kg) induced an enhanced conditioned place preference in PTN(-/-) compared to wild type mice, suggesting that PTN prevents ethanol rewarding effects. Accordingly, the conditioning effects of ethanol were completely abolished in PTN-Tg mice. The ataxic effects induced by ethanol (2.0 g/kg) were not affected by the genotype. However, the sedative effects of ethanol (3.6 g/kg) tested in a loss of righting reflex paradigm were significantly reduced in PTN-Tg mice, suggesting that up-regulation of PTN levels prevents the sedative effects of ethanol. These results indicate that PTN may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of the PTN signalling pathway may be a promising therapeutic strategy in the treatment of these disorders. © 2014 International Society for Neurochemistry.

Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice

PubMed Central

Deshpande, Krutika T.; Liu, Shinlan; McCracken, Jennifer M.; Jiang, Lu; Gaw, Ta Ehpaw; Kaydo, Lindsey N.; Richard, Zachary C.; O’Neil, Maura F.; Pritchard, Michele T.

2016-01-01

Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24–96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure. PMID:26751492

A hot water extract of turmeric (Curcuma longa) suppresses acute ethanol-induced liver injury in mice by inhibiting hepatic oxidative stress and inflammatory cytokine production.

PubMed

Uchio, Ryusei; Higashi, Yohei; Kohama, Yusuke; Kawasaki, Kengo; Hirao, Takashi; Muroyama, Koutarou; Murosaki, Shinji

2017-01-01

Turmeric ( Curcuma longa ) is a widely used spice that has various biological effects, and aqueous extracts of turmeric exhibit potent antioxidant activity and anti-inflammatory activity. Bisacurone, a component of turmeric extract, is known to have similar effects. Oxidative stress and inflammatory cytokines play an important role in ethanol-induced liver injury. This study was performed to evaluate the influence of a hot water extract of C. longa (WEC) or bisacurone on acute ethanol-induced liver injury. C57BL/6 mice were orally administered WEC (20 mg/kg body weight; BW) or bisacurone (60 µg/kg BW) at 30 min before a single dose of ethanol was given by oral administration (3·0 g/kg BW). Plasma levels of aspartate aminotransferase and alanine aminotransferase were markedly increased in ethanol-treated mice, while the increase of these enzymes was significantly suppressed by prior administration of WEC. The increase of alanine aminotransferase was also significantly suppressed by pretreatment with bisacurone. Compared with control mice, animals given WEC had higher hepatic tissue levels of superoxide dismutase and glutathione, as well as lower hepatic tissue levels of thiobarbituric acid-reactive substances, TNF-α protein and IL-6 mRNA. These results suggest that oral administration of WEC may have a protective effect against ethanol-induced liver injury by suppressing hepatic oxidation and inflammation, at least partly through the effects of bisacurone.

Gastroprotective effect of Cymbopogon citratus infusion on acute ethanol-induced gastric lesions in rats.

PubMed

Sagradas, Joana; Costa, Gustavo; Figueirinha, Artur; Castel-Branco, Maria Margarida; Silvério Cabrita, António Manuel; Figueiredo, Isabel Vitória; Batista, Maria Teresa

2015-09-15

Treatment of gastric ulcers with medicinal plants is quite common in traditional medicine worldwide. Cymbopogon citratus (DC) Stapf. leaves infusion has been used in folk medicine of many tropical and subtropical regions to treat gastric disturbances. The aim of this study was to assess the potential gastroprotective activity of an essential oil-free infusion from C. citratus leaves in acute gastric lesions induced by ethanol in rat. The study was performed on adult male Wistar rats (234.0±22.7g) fasted for 24h but with free access to water. The extract was given orally before (prevention) or after (treatment) intragastric administration of absolute ethanol. Effects of dose (28 or 56mg/kg of body weight) and time of contact of the extract with gastric mucosa (1 or 2h) were also assessed. Animals were sacrificed, being the stomachs removed and the lesions were assessed by macroscopic observation and histopathology. C. citratus extract, given orally before or after ethanol, significantly (P<0.01) reduced gastric mucosal injury compared with control group (vehicle+ethanol). The effect does not appear to be dose-dependent. Results also suggested that the extract is more effective when the time of contact with gastric mucosa increases. The results of this assay confirm the gastroprotective activity of C. citratus extract on experimental gastric lesions induced by ethanol, contributing for the pharmacological validation of its traditional use. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effect of caffeic acid phenethyl ester on oxidant and anti-oxidant status of liver and serum in a rat model with acute methanol intoxication.

PubMed

Yazgan, Ü C; Elbey, B; Kuş, S; Baykal, B; Keskin, I; Yılmaz, A; Şahin, A

2017-05-01

Methanol toxicity is one of the major public health problems because it can cause severe morbidity and mortality. Methanol intoxication causes changes in the balance between the production of free radicals and antioxidant capacity. We aimed to investigate the effects of caffeic acid phenethyl ester (CAPE) on the total oxidant status, total antioxidant status (TAS), and oxidative stress index (OSI) parameters of the liver and the serum in a rat model of acute methanol intoxication. Rats were treated with intraperitoneal (i.p.) Methotrexate (MTX) for 7 days. On the 8th day, i.p. Methanol was administered in the methanol, ethanol and CAPE groups. Four hours after methanol treatment, ethanol was injected i.p. in the ethanol group; CAPE (i.p.) in the CAPE group; serum physiologic i.p. in other groups. After 8 hours, rats were killed and the serum and the liver samples were obtained for biochemical analyses. The OSI value was significantly higher in the methanol group compared to the ethanol and CAPE groups. Serum TAS levels of the methanol group were significantly different compared to the control group, but not compared to the MTX group. The amelioration of oxidative stress was greater in the CAPE group compared to the ethanol group but was not statistically significant. This study demonstrates that CAPE treatment ameliorates oxidative stress in the serum and liver in a rat model of acute methanol intoxication.

Anti-fatty liver effects of oils from Zingiber officinale and Curcuma longa on ethanol-induced fatty liver in rats.

PubMed

Nwozo, Sarah Onyenibe; Osunmadewa, Damilola Adeola; Oyinloye, Babatunji Emmanuel

2014-01-01

The present study is aimed at evaluating the protective effects of oils from Zingiber officinale (ginger) and Curcuma longa (turmeric) on acute ethanol-induced fatty liver in male Wistar rats. Ferric reducing antioxidant power activity and oxygen radical absorbance capacity of the oils were evaluated ex vivo. Rats were pretreated for 28 d with standard drug (Livolin Forte) and oils from Z. officinale and C. longa before they were exposed to 45% ethanol (4.8 g/kg) to induce acute fatty liver. Histological changes were observed and the degree of protection was measured by using biochemical parameters such as alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities. Serum triglyceride (TG) level, total cholesterol (TC) level and the effects of both oils on reduced gluthatione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and hepatic malondialdehyde (MDA) levels were estimated. Oils from Z. officinale and C. longa at a dose of 200 mg/kg showed hepatoprotection by decreasing the activities of serum enzymes, serum TG, serum TC and hepatic MDA, while they significantly restored the level of GSH as well as GST and SOD activities. Histological examination of rats tissues was related to the obtained results. From the results it may be concluded that oils from Z. officinale and C. longa (200 mg/kg) exhibited hepatoprotective activity in acute ethanol-induced fatty liver and Z. officinale oil was identified to have better effects than C. longa oil.

Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice.

PubMed

Yan, Sheng-Lei; Wang, Zhi-Hong; Yen, Hsiu-Fang; Lee, Yi-Ju; Yin, Mei-Chin

2016-12-01

Ethanol was used to induce acute hepatotoxicity in mice. Effects of cinnamic acid (CA) and syringic acid (SA) post-intake for hepatic recovery from alcoholic injury was investigated. Ethanol treated mice were supplied by CA or SA at 40 or 80 mg/kg BW/day for 5 days. Results showed that ethanol stimulated protein expression of CYP2E1, p47 phox , gp91 phox , cyclooxygenase-2 and nuclear factor kappa B in liver. CA or SA post-intake restricted hepatic expression of these molecules. Ethanol suppressed nuclear factor erythroid 2-related factor (Nrf2) expression, and CA or SA enhanced Nrf2 expression in cytosolic and nuclear fractions. Ethanol increased the release of reactive oxygen species, oxidized glutathione, interleukin-6, tumor necrosis factor-alpha, nitric acid and prostaglandin E 2 . CA or SA lowered hepatic production of these oxidative and inflammatory factors. Histological data revealed that ethanol administration caused obvious foci of inflammatory cell infiltration, and CA or SA post-intake improved hepatic inflammatory infiltration. These findings support that cinnamic acid and syringic acid are potent nutraceutical agents for acute alcoholic liver disease therapy. However, potential additive or synergistic benefits of cinnamic and syringic acids against ethanol-induced hepatotoxicity need to be investigated. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ethanol-Induced Effects on Sting Extension Response and Punishment Learning in the Western Honey Bee (Apis mellifera)

PubMed Central

Giannoni-Guzmán, Manuel A.; Giray, Tugrul; Agosto-Rivera, Jose Luis; Stevison, Blake K.; Freeman, Brett; Ricci, Paige; Brown, Erika A.; Abramson, Charles I.

2014-01-01

Acute ethanol administration is associated with sedation and analgesia as well as behavioral disinhibition and memory loss but the mechanisms underlying these effects remain to be elucidated. During the past decade, insects have emerged as important model systems to understand the neural and genetic bases of alcohol effects. However, novel assays to assess ethanol's effects on complex behaviors in social or isolated contexts are necessary. Here we used the honey bee as an especially relevant model system since bees are typically exposed to ethanol in nature when collecting standing nectar crop of flowers, and there is recent evidence for independent biological significance of this exposure for social behavior. Bee's inhibitory control of the sting extension response (SER) and a conditioned-place aversion assay were used to study ethanol effects on analgesia, behavioral disinhibition, and associative learning. Our findings indicate that although ethanol, in a dose-dependent manner, increases SER thresholds (analgesic effects), it disrupts the ability of honey bees to inhibit SER and to associate aversive stimuli with their environment. These results suggest that ethanol's effects on analgesia, behavioral disinhibition and associative learning are common across vertebrates and invertebrates. These results add to the use of honey bees as an ethanol model to understand ethanol's effects on complex, socially relevant behaviors. PMID:24988309

Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors.

PubMed

Somkuwar, Sucharita S; Vendruscolo, Leandro F; Fannon, McKenzie J; Schmeichel, Brooke E; Nguyen, Tran Bao; Guevara, Jasmin; Sidhu, Harpreet; Contet, Candice; Zorrilla, Eric P; Mandyam, Chitra D

2017-10-01

Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary-adrenal axis. Here, we investigated effects of repeated ethanol intoxication-withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h-28d) after cessation of CIE. Results show that peak CORT increased during CIE, transiently decreased during early abstinence (1-11d), and returned to pre-abstinence levels during protracted abstinence (17-27d). Acute withdrawal from CIE enhanced aggression- and anxiety-like behaviors. Early abstinence from CIE reduced anxiety-like behavior. mPFC-GR signaling (indexed by relative phosphorylation of GR at Ser211) was transiently decreased when measured at time points during early and protracted abstinence. Further, voluntary ethanol drinking in CIE (CIE-ED) and CIE-naïve (ED) rats, and effects of CIE-ED and ED on peak CORT levels and mPFC-GR were investigated during acute withdrawal (8h) and protracted abstinence (28d). CIE-ED and ED increased peak CORT during drinking. CIE-ED and ED decreased expression and signaling of mPFC-GR during acute withdrawal, an effect that was reversed by systemic mifepristone treatment. CIE-ED and ED demonstrate robust reinstatement of ethanol seeking during protracted abstinence and show increases in mPFC-GR expression. Collectively, the data demonstrate that acute withdrawal from CIE produces robust alterations in GR signaling, CORT and negative affect symptoms which could facilitate excessive drinking. The findings also show that CIE-ED and ED demonstrate enhanced relapse vulnerability triggered by ethanol cues and these changes are partially mediated by altered GR expression in the mPFC. Taken together, transition to alcohol dependence could be accompanied by alterations in mPFC stress-related pathways that may increase negative emotional symptoms and increase vulnerability to relapse. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acute Alcohol Intoxication Exacerbates Rhabdomyolysis-Induced Acute Renal Failure in Rats.

PubMed

Tsai, Jen-Pi; Lee, Chung-Jen; Subeq, Yi-Maun; Lee, Ru-Ping; Hsu, Bang-Gee

2017-01-01

Traumatic and nontraumatic rhabdomyolysis can lead to acute renal failure (ARF), and acute alcohol intoxication can lead to multiple abnormalities of the renal tubules. We examined the effect of acute alcohol intoxication in a rat model of rhabdomyolysis and ARF. Intravenous injections of 5 g/kg ethanol were given to rats over 3 h, followed by glycerol-induced rhabdomyolysis. Biochemical parameters, including blood urea nitrogen (BUN), creatinine (Cre), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and creatine phosphokinase (CPK), were measured before and after induction of rhabdomyolysis. Renal tissue injury score, renal tubular cell expression of E-cadherin, nuclear factor-κB (NF-κB), and inducible nitric oxide synthase (iNOS) were determined. Relative to rats in the vehicle group, rats in the glycerol-induced rhabdomyolysis group had significantly increased serum levels of BUN, Cre, GOT, GPT, and CPK, elevated renal tissue injury scores, increased expression of NF-κB and iNOS, and decreased expression of E-cadherin. Ethanol exacerbated all of these pathological responses. Our results suggest that acute alcohol intoxication exacerbates rhabdomyolysis-induced ARF through its pro-oxidant and inflammatory effects.

Acute Alcohol Intoxication Exacerbates Rhabdomyolysis-Induced Acute Renal Failure in Rats

PubMed Central

Tsai, Jen-Pi; Lee, Chung-Jen; Subeq, Yi-Maun; Lee, Ru-Ping; Hsu, Bang-Gee

2017-01-01

Traumatic and nontraumatic rhabdomyolysis can lead to acute renal failure (ARF), and acute alcohol intoxication can lead to multiple abnormalities of the renal tubules. We examined the effect of acute alcohol intoxication in a rat model of rhabdomyolysis and ARF. Intravenous injections of 5 g/kg ethanol were given to rats over 3 h, followed by glycerol-induced rhabdomyolysis. Biochemical parameters, including blood urea nitrogen (BUN), creatinine (Cre), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and creatine phosphokinase (CPK), were measured before and after induction of rhabdomyolysis. Renal tissue injury score, renal tubular cell expression of E-cadherin, nuclear factor-κB (NF-κB), and inducible nitric oxide synthase (iNOS) were determined. Relative to rats in the vehicle group, rats in the glycerol-induced rhabdomyolysis group had significantly increased serum levels of BUN, Cre, GOT, GPT, and CPK, elevated renal tissue injury scores, increased expression of NF-κB and iNOS, and decreased expression of E-cadherin. Ethanol exacerbated all of these pathological responses. Our results suggest that acute alcohol intoxication exacerbates rhabdomyolysis-induced ARF through its pro-oxidant and inflammatory effects. PMID:28824301

A Low Concentration of Ethanol Impairs Learning but Not Motor and Sensory Behavior in Drosophila Larvae

PubMed Central

Ghezzi, Alfredo; Cady, Amanda M.; Najjar, Kristina; Hatch, Michael M.; Shah, Ruchita R.; Bhat, Amar; Hariri, Omar; Haroun, Kareem B.; Young, Melvin C.; Fife, Kathryn; Hooten, Jeff; Tran, Tuan; Goan, Daniel; Desai, Foram; Husain, Farhan; Godinez, Ryan M.; Sun, Jeffrey C.; Corpuz, Jonathan; Moran, Jacxelyn; Zhong, Allen C.; Chen, William Y.; Atkinson, Nigel S.

2012-01-01

Drosophila melanogaster has proven to be a useful model system for the genetic analysis of ethanol-associated behaviors. However, past studies have focused on the response of the adult fly to large, and often sedating, doses of ethanol. The pharmacological effects of low and moderate quantities of ethanol have remained understudied. In this study, we tested the acute effects of low doses of ethanol (∼7 mM internal concentration) on Drosophila larvae. While ethanol did not affect locomotion or the response to an odorant, we observed that ethanol impaired associative olfactory learning when the heat shock unconditioned stimulus (US) intensity was low but not when the heat shock US intensity was high. We determined that the reduction in learning at low US intensity was not a result of ethanol anesthesia since ethanol-treated larvae responded to the heat shock in the same manner as untreated animals. Instead, low doses of ethanol likely impair the neuronal plasticity that underlies olfactory associative learning. This impairment in learning was reversible indicating that exposure to low doses of ethanol does not leave any long lasting behavioral or physiological effects. PMID:22624024

Sex Differences in Ethanol’s Anxiolytic Effect and Chronic Ethanol Withdrawal Severity in Mice With a Null Mutation of the 5α-Reductase Type 1 Gene

PubMed Central

Tanchuck-Nipper, Michelle A.; Ford, Matthew M.; Hertzberg, Anna; Beadles-Bohling, Amy; Cozzoli, Debra K.; Finn, Deborah A.

2015-01-01

Manipulation of endogenous levels of the GABAergic neurosteroid allopregnanolone alters sensitivity to some effects of ethanol. Chronic ethanol withdrawal decreases activity and expression of 5α-reductase-1, an important enzyme in allopregnanolone biosynthesis encoded by the 5α-reductase-1 gene (Srd5a1). The present studies examined the impact of Srd5a1 deletion in male and female mice on several acute effects of ethanol and on chronic ethanol withdrawal severity. Genotype and sex did not differentially alter ethanol-induced hypothermia, ataxia, hypnosis, or metabolism, but ethanol withdrawal was significantly lower in female versus male mice. On the elevated plus maze, deletion of the Srd5a1 gene significantly decreased ethanol’s effect on total entries versus wildtype (WT) mice and significantly decreased ethanol’s anxiolytic effect in female knockout (KO) versus WT mice. The limited sex differences in the ability of Srd5a1 genotype to modulate select ethanol effects may reflect an interaction between developmental compensations to deletion of the Srd5a1 gene with sex hormones and levels of endogenous neurosteroids. PMID:25355320

Mutation of the inhibitory ethanol site in GABAA ρ1 receptors promotes tolerance to ethanol-induced motor incoordination.

PubMed

Blednov, Yuri A; Borghese, Cecilia M; Ruiz, Carlos I; Cullins, Madeline A; Da Costa, Adriana; Osterndorff-Kahanek, Elizabeth A; Homanics, Gregg E; Harris, R Adron

2017-09-01

Genes encoding the ρ1/2 subunits of GABA A receptors have been associated with alcohol (ethanol) dependence in humans, and ρ1 was also shown to regulate some of the behavioral effects of ethanol in animal models. Ethanol inhibits GABA-mediated responses in wild-type (WT) ρ1, but not ρ1(T6'Y) mutant receptors expressed in Xenopus laevis oocytes, indicating the presence of an inhibitory site for ethanol in the second transmembrane helix. In this study, we found that ρ1(T6'Y) receptors expressed in oocytes display overall normal responses to GABA, the endogenous GABA modulator (zinc), and partial agonists (β-alanine and taurine). We generated ρ1 (T6'Y) knockin (KI) mice using CRISPR/Cas9 to test the behavioral importance of the inhibitory actions of ethanol on this receptor. Both ρ1 KI and knockout (KO) mice showed faster recovery from acute ethanol-induced motor incoordination compared to WT mice. Both KI and KO mutant strains also showed increased tolerance to motor impairment produced by ethanol. The KI mice did not differ from WT mice in other behavioral actions, including ethanol intake and preference, conditioned taste aversion to ethanol, and duration of ethanol-induced loss of righting reflex. WT and KI mice did not differ in levels of ρ1 or ρ2 mRNA in cerebellum or in ethanol clearance. Our findings indicate that the inhibitory site for ethanol in GABA A ρ1 receptors regulates acute functional tolerance to moderate ethanol intoxication. We note that low sensitivity to alcohol intoxication has been linked to risk for development of alcohol dependence in humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

NASA Astrophysics Data System (ADS)

Xia, Dong; Liu, Bing; Luan, Xiying; Sun, Junyan; Liu, Nana; Qin, Song; Du, Zhenning

2016-03-01

Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin (C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective effects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein (LDL), liver homogenate malondialdehyde (MDA), superoxide dismutase (SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory effects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

Sex differences in reinstatement of alcohol seeking in response to cues and yohimbine in rats with and without a history of adolescent corticosterone exposure.

PubMed

Bertholomey, M L; Nagarajan, V; Torregrossa, Mary M

2016-06-01

Women represent a vulnerable and growing population with respect to alcohol abuse. Elevated glucocorticoid exposure in adolescence increases addiction risk and stress sensitivity in adulthood. However, little is known about sex differences in ethanol craving-like behavior. This study characterized sex differences in ethanol-motivated behavior following ethanol-paired cues and/or acute stimulation of the HPA axis in male and female rats with or without exposure to chronically elevated glucocorticoids in adolescence. Adolescent corticosterone-treated (Experiment 1) or naïve (Experiment 2) male and female rats were trained as adults to self-administer ethanol paired with a cue, and tested for the effects of this cue, alone or in combination with yohimbine, on the reinstatement of ethanol seeking. Females showed elevated ethanol self-administration and seeking compared to males. In Experiment 1, corticosterone exposure in adolescence augmented cue-induced reinstatement of ethanol seeking in females only, and females were more sensitive to yohimbine in promoting reinstatement. Experiment 2 replicated these findings and showed that exposure to both yohimbine and alcohol-related cues enhanced the reinstatement of alcohol seeking, producing additive effects in females. Corticosterone levels were higher in females and in yohimbine-treated rats, and corticosterone and estradiol correlated with responding during reinstatement. Chronic manipulations in adolescence and acute manipulations in adulthood of the HPA axis increase cue-induced reinstatement of ethanol seeking to a greater degree in females than in males. Elucidating the mechanisms that underlie these effects may lead to the development of sex-specific interventions aimed at mitigating alcohol relapse risk in females.

Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone.

PubMed

Jacob, Joanna C; Poklis, Justin L; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L

2017-07-01

This study compared the development of tolerance to two orally bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine, and the reversal of this tolerance by ethanol. Oxycodone (s.c.) was significantly more potent in the mouse tail-withdrawal assay than either morphine or hydrocodone. Oxycodone was also significantly more potent in this assay than hydrocodone when administered orally. Tolerance was seen following chronic subcutaneous administration of each of the three drugs and by the chronic administration of oral oxycodone, but not following the chronic oral administration of hydrocodone. Ethanol (1 g/kg i.p.) significantly reversed the tolerance to the subcutaneous administration of each of the three opioids that developed when given 30 minutes prior to challenge doses. It took twice as much ethanol, when given orally, to reverse the tolerance to oxycodone. We investigated whether the observed tolerance to oxycodone and its reversal by ethanol were due to biodispositional changes or reflected a true neuronal tolerance. As expected, a relationship between brain oxycodone concentrations and activity in the tail-immersion test existed following administration of acute oral oxycodone. Following chronic treatment, brain oxycodone concentrations were significantly lower than acute concentrations. Oral ethanol (2 g/kg) reversed the tolerance to chronic oxycodone, but did not alter brain concentrations of either acute or chronic oxycodone. These studies show that there is a metabolic component of tolerance to oxycodone; however, the reversal of that tolerance by ethanol is not due to an alteration of the biodisposition of oxycodone, but rather is neuronal in nature. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Effects of aqueous extracts from Panax ginseng and Hippophae rhamnoides on acute alcohol intoxication: An experimental study using mouse model.

PubMed

Wen, Da-Chao; Hu, Xiao-Yu; Wang, Yan-Yan; Luo, Jian-Xing; Lin, Wu; Jia, Ling-Yan; Gong, Xin-Yue

2016-11-04

Acute alcohol intoxication (AAI) is a frequent emergency, but therapeutic drugs with superior efficacy and safety are lacking. Panax ginseng (PG) and Hippophae rhamnoides (HR) respectively has a wide application as a complementary therapeutic agent in China for the treatment of AAI and liver injury induced by alcohol. We investigated the effects of aqueous extracts from PG and HR (AEPH) on AAI mice and identified its underlying mechanisms. Models of AAI were induced by intragastric administration of ethanol (8g/kg). Seventy-two Specific pathogen-free (SPF) male Kunming mice were randomly divided into six groups: normal group, positive control group, AEPH of low dosage (100mg/kg) group, AEPH of medium dose (200mg/kg) group, AEPH of high dosage (400mg/kg) group and model group. The mice were treated with metadoxine (MTD, 500mg/kg) and AEPH. Thirty minutes later, the normal group was given normal saline, while the other groups were given ethanol (i.g., 8g/kg). The impact of AEPH was observed. In the same way, another seventy-two Kunming mice were randomly divided into six groups equally. The blood ethanol concentration at 0.5, 1, 1.5, 2, 3 and 6h after ethanol intake was determined by way of gas chromatography. The activity of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and microsomal ethanol oxidase (EO) in liver, and the concentration of β-endorphin (β-EP), leucine-enkephalin (LENK) in the brain were determined by enzyme-linked-immunosorbent serologic assay (ELISA). AEPH markedly prolonged alcohol tolerance time and shortened sober-up time after acute ethanol administration. AEPH decreased blood ethanol levels in six tests after ethanol intake. The 7-day survival rate of AEPH group was obviously superior to model group. AEPH increased the activities of ADH, ALDH, and decreased EO activity in liver. The crucial find was that AEPH markedly decreased β-EP and LENK concentration in the brain. AEPH can markedly increase the levels of ADH, ALDH, decrease EO activity in liver and decrease the concentration of β-EP and LENK in the brain to against acute alcohol intoxication in mice. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Adolescent rats are resistant to the development of ethanol-induced chronic tolerance and ethanol-induced conditioned aversion.

PubMed

Pautassi, Ricardo Marcos; Godoy, Juan Carlos; Molina, Juan Carlos

2015-11-01

The analysis of chronic tolerance to ethanol in adult and adolescent rats has yielded mixed results. Tolerance to some effects of ethanol has been reported in adolescents, yet other studies found adults to exhibit greater tolerance than adolescents or comparable expression of the phenomena at both ages. Another unanswered question is how chronic ethanol exposure affects subsequent ethanol-mediated motivational learning at these ages. The present study examined the development of chronic tolerance to ethanol's hypothermic and motor stimulating effects, and subsequent acquisition of ethanol-mediated odor conditioning, in adolescent and adult male Wistar rats given every-other-day intragastric administrations of ethanol. Adolescent and adult rats exhibited lack of tolerance to the hypothermic effects of ethanol during an induction phase; whereas adults, but not adolescents, exhibited a trend towards a reduction in hypothermia at a challenge phase (Experiment 1). Adolescents, unlike adults, exhibited ethanol-induced motor activation after the first ethanol administration. Adults, but not adolescents, exhibited conditioned odor aversion by ethanol. Subsequent experiments conducted only in adolescents (Experiment 2, Experiment 3 and Experiment 4) manipulated the context, length and predictability of ethanol administration. These manipulations did not promote the expression of ethanol-induced tolerance. This study indicated that, when moderate ethanol doses are given every-other day for a relatively short period, adolescents are less likely than adults to develop chronic tolerance to ethanol-induced hypothermia. This resistance to tolerance development could limit long-term maintenance of ethanol intake. Adolescents, however, exhibited greater sensitivity than adults to the acute motor stimulating effects of ethanol and a blunted response to the aversive effects of ethanol. This pattern of response may put adolescents at risk for early initiation of ethanol intake. Copyright © 2015 Elsevier Inc. All rights reserved.

Chronic tolerance to ethanol-induced sedation: implication for age-related differences in locomotor sensitization.

PubMed

Quoilin, Caroline; Didone, Vincent; Tirelli, Ezio; Quertemont, Etienne

2013-06-01

The adolescent brain has been suggested to be particularly sensitive to ethanol-induced neuroadaptations, which in turn could increase the risk of youths for alcohol abuse and dependence. Sensitization to the locomotor stimulant effects of ethanol has often been used as an animal model of ethanol-induced neuroadaptations. Previously, we showed that young mice were more sensitive than adults to the locomotor sensitization induced by high ethanol doses. However, this effect could be due to age-related differences in chronic tolerance to the sedative effects of ethanol. The aim of the present study is to assess chronic tolerance to the sedative effects of ethanol in weaning 21-day-old (P21), adolescent 35-day-old (P35) and adult 63-day-old (P63) female Swiss mice. After a daily injection of saline or 4 g/kg ethanol during 6 consecutive days, all P21, P35 and P63 mice were injected with 4 g/kg ethanol and submitted to the loss of righting reflex procedure. Our results confirm that the sensitivity to the acute sedative effects of ethanol gradually increases with age. Although this schedule of ethanol injections induces significant age-related differences in ethanol sensitization, it did not reveal significant differences between P21, P35 and P63 mice in the development of a chronic ethanol tolerance to its sedative effects. The present results show that age-related differences in the development of ethanol sensitization cannot be explained by differences in chronic ethanol tolerance to its sedative effects. More broadly, they do not support the idea that ethanol-induced sensitization is a by-product of chronic ethanol tolerance. Copyright © 2013 Elsevier Inc. All rights reserved.

Alcohol effects on drug-nutrient interactions.

PubMed

Seitz, H K

1985-01-01

The interaction of ethanol with drugs and xenobiotics is complex because ethanol can affect any of the following steps; absorption, plasma protein binding, hepatic blood flow, distribution, hepatic uptake of drugs, and phase I and II hepatic metabolism. The ingestion of ethanol can lead to malabsorption of a variety of nutrients and can modify the absorption of various drugs. High concentrations of ethanol in conjunction with aspirin causes gastric mucosal damage. The principal effect of acute ethanol ingestion on drug metabolism is inhibition of microsomal drug metabolism. The synergistic effects of ethanol on central nervous system depressants can be explained by this mechanism. In contrast, chronic ethanol consumption increases mixed function oxidation and drug metabolism. The cross tolerance between ethanol and sedatives in chronic alcoholics may be due to this effect of alcohol. In addition, enhanced production of hepatotoxic products from certain drugs and xenobiotics and an increased activation of procarcinogens to carcinogens can result from this microsomal induction. The increased susceptibility to hepatotoxins and the enhanced carcinogenesis in the alcoholic may be explained by this fact. Other effects of the interaction between drugs and ethanol are the result of changes in organ susceptibility, best demonstrated for the central nervous system. Subsequently, the presence of liver disease has a great effect on drug metabolism in alcoholics.

The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort

PubMed Central

van der Vaart, Andrew D.; Wolstenholme, Jennifer T.; Smith, Maren L.; Harris, Guy M.; Lopez, Marcelo F.; Wolen, Aaron R.; Becker, Howard C.; Williams, Robert W.; Miles, Michael F.

2016-01-01

The transition from acute to chronic ethanol exposure leads to lasting behavioral and physiological changes such as increased consumption, dependence, and withdrawal. Changes in brain gene expression are hypothesized to underlie these adaptive responses to ethanol. Previous studies on acute ethanol identified genetic variation in brain gene expression networks and behavioral responses to ethanol across the BXD panel of recombinant inbred mice. In this work, we have performed the first joint genetic and genomic analysis of transcriptome shifts in response to chronic intermittent ethanol (CIE) by vapor chamber exposure in a BXD cohort. CIE treatment is known to produce significant and sustained changes in ethanol consumption with repeated cycles of ethanol vapor. Using Affymetrix microarray analysis of prefrontal cortex (PFC) and nucleus accumbens (NAC) RNA, we compared CIE expression responses to those seen following acute ethanol treatment, and to voluntary ethanol consumption. Gene expression changes in PFC and NAC after CIE overlapped significantly across brain regions and with previously published expression following acute ethanol. Genes highly modulated by CIE were enriched for specific biological processes including synaptic transmission, neuron ensheathment, intracellular signaling, and neuronal projection development. Expression quantitative trait locus (eQTL) analyses identified genomic loci associated with ethanol-induced transcriptional changes with largely distinct loci identified between brain regions. Correlating CIE-regulated genes to ethanol consumption data identified specific genes highly associated with variation in the increase in drinking seen with repeated cycles of CIE. In particular, multiple myelin-related genes were identified. Furthermore, genetic variance in or near dynamin3 (Dnm3) on Chr1 at ~164 Mb may have a major regulatory role in CIE-responsive gene expression. Dnm3 expression correlates significantly with ethanol consumption, is contained in a highly ranked functional group of CIE-regulated genes in the NAC, and has a cis-eQTL within a genomic region linked with multiple CIE-responsive genes. PMID:27838001

Electrolyzed-reduced water inhibits acute ethanol-induced hangovers in Sprague-Dawley rats.

PubMed

Park, Seung-Kyu; Qi, Xu-Feng; Song, Soon-Bong; Kim, Dong-Heui; Teng, Yung-Chien; Yoon, Yang-Suk; Kim, Kwang-Yong; Li, Jian-Hong; Jin, Dan; Lee, Kyu-Jae

2009-10-01

Ethanol consumption disturbs the balance between the pro- and anti-oxidant systems of the organism, leading to oxidative stress. Electrolyzed-reduced water (ERW) is widely used by people in East Asia for drinking purposes because of its therapeutic properties including scavenging effect of reactive oxygen species. This study was performed to investigate the effect of ERW on acute ethanol-induced hangovers in Sprague-Dawley rats. Alcohol concentration in serum of ERW-treated rats showed significant difference at 1 h, 3 h and 5 h respectively as compared with the rats treated with distilled water. Both alcohol dehydrogenase type 1 and acetaldehyde dehydrogenase related with oxidation of alcohol were significantly increased in liver tissue while the level of aspartate aminotransferase and alanine aminotransferase in serum was markedly decreased 24 h after pre-oral administration of ERW. Moreover, oral administration of ERW significantly activated non-ezymatic (glutathione) and enzymatic (glutathione peroxidase, glutathione-S-transferase, Cu/Zn-superoxide dismutase and catalase) antioxidants in liver tissues compared with the control group. These results suggest that drinking ERW has an effect of alcohol detoxification by antioxidant mechanism and has potentiality for relief of ethanol-induced hangover symptoms.

Behavioral Characterization of Knockin Mice with Mutations M287L and Q266I in the Glycine Receptor α1 Subunit

PubMed Central

Blednov, Yuri A.; Benavidez, Jill M.; Homanics, Gregg E.

2012-01-01

We used behavioral pharmacology to characterize heterozygous knockin mice with mutations (Q266I or M287L) in the α1 subunit of the glycine receptor (GlyR) (J Pharmacol Exp Ther 340:304–316, 2012). These mutations were designed to reduce (M287L) or eliminate (Q266I) ethanol potentiation of GlyR function. We asked which behavioral effects of ethanol would be reduced more in the Q266I mutant than the M287L and found rotarod ataxia to be the behavior that fulfilled this criterion. Compared with controls, the mutant mice also differed in ethanol consumption, ethanol-stimulated startle response, signs of acute physical dependence, and duration of loss of righting response produced by ethanol, butanol, ketamine, pentobarbital, and flurazepam. Some of these behavioral changes were mimicked in wild-type mice by acute injections of low, subconvulsive doses of strychnine. Both mutants showed increased acoustic startle response and increased sensitivity to strychnine seizures. Thus, in addition to reducing ethanol action on the GlyRs, these mutations reduced glycinergic inhibition, which may also alter sensitivity to GABAergic drugs. PMID:22037202

Trait anxiety and ethanol: anxiolysis in high-anxiety mice and no relation to intake behavior in an addiction model.

PubMed

Correia, Diego; Ribeiro, Andrea Frozino; Brunialti Godard, Ana Lúcia; Boerngen-Lacerda, Roseli

2009-08-01

Anxiety has been proposed to play a role in the development of alcohol addiction, but the exact mechanisms by which this occurs remain unclear. The present study aimed to verify the relationship between basal anxiety levels, the anxiolytic-like effect of ethanol, and ethanol intake in mice exposed to an addiction model. In one experiment Swiss mice were characterized as high-anxiety (HA), medium-anxiety (MA), or non-anxiety (NA) in the elevated plus maze and then received saline or ethanol 2 g/kg acutely and chronically and were again exposed to the same test. NA mice decreased while MA mice maintained anxiety indices over the test days, regardless of treatment. HA ethanol-treated mice showed an anxiolytic-like effect, both acutely and chronically, while the saline-treated ones maintained their basal anxiety levels. In another experiment HA and MA mice were exposed to an addiction model based on a 3-bottle free-choice paradigm (ethanol 5% and 10%, and water) consisting of four phases: acquisition (10 weeks), withdrawal (W, 2 weeks), reexposure (2 weeks), and quinine-adulteration (2 weeks). HA and MA control mice had access only to water. Mice were characterized as addicted, heavy-drinker and light-drinker [Fachin-Scheit DJ, Ribeiro AF, Pigatto G, Goeldner FO, Boerngen-Lacerda R. Development of a mouse model of ethanol addiction: naltrexone efficacy in reducing consumption but not craving. J Neural Transm 2006;113:1305-21.]. No difference was observed between HA and MA mice in their preference for and intake of ethanol. No correlation was observed between ethanol intake, during any phase, and anxiety indices measured in the basal tests and during the W phase. The differences in anxiety indices between HA and MA groups persisted in the test performed during ethanol withdrawal, suggesting a "trait" anxiety profile. The data suggest that despite the fact that high anxiety trait levels are important for the anxiolytic-like effects of ethanol, they are not a determining factor for high ethanol intake, at least not under these experimental conditions.

Effects of ethanol and water extracts of propolis (bee glue) on acute inflammatory animal models.

PubMed

Hu, Fuliang; Hepburn, H R; Li, Yinghua; Chen, M; Radloff, S E; Daya, S

2005-09-14

The anti-inflammatory effects of ethanol (EEP) and water (WSD) extracts in ICR mice and Wistar rats were analyzed. Both WSD and EEP exhibited significant anti-inflammatory effects in animal models with respect to thoracic capillary vessel leakage in mice, carrageenan-induced oedema, carrageenan-induced pleurisy, acute lung damage in rats. The mechanisms for the anti-inflammatory effects probably involve decreasing prostaglandin-E(2) (PGE(2)) and nitric oxide (NO) levels. In rats with Freund's complete adjuvant (FCA) induced arthritis, propolis extracts significantly inhibited the increase of interleukin-6 (IL-6) in inflamed tissues, but had no significant effect on levels of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). The results are consistent with the interpretation that EEP and WSD may exert these effects by inhibiting the activation and differentiation of mononuclear macrophages.

Differential Modulation of Ethanol-Induced Sedation and Hypnosis by Metabotropic Glutamate Receptor Antagonists in C57BL/6J Mice

PubMed Central

Sharko, Amanda C.; Hodge, Clyde W.

2008-01-01

Background Emerging evidence implicates metabotropic glutamate receptor (mGluR) function in the neurobiological effects of ethanol. The recent development of subtype specific mGluR antagonists has made it possible to examine the roles of specific mGluRs in biochemical and behavioral responses to ethanol. The purpose of the present study was to determine if mGluRs modulate the acute sedative-hypnotic properties of ethanol in mice. Methods C57BL / 6J mice were tested for locomotor activity (sedation) and duration of loss of the righting reflex (hypnosis) following acute systemic administration of ethanol alone or in combination with the mGluR5-selective antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), the mGluR1-selective antagonist, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), or the mGluR2 / 3-selective antagonist (2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495)). Results MPEP (10 and 30 mg / kg) significantly enhanced both the sedative and hypnotic effects of ethanol, while LY341495 (10 and 30 mg / kg) significantly reduced the sedative-hypnotic effects of ethanol. CPCCOEt had no effect at any concentration tested. Further loss of righting reflex experiments revealed that LY341495 (30 mg / kg) significantly reduced hypnosis induced by the gamma-aminobutyric acid type A (GABAA) positive modulators, pentobarbital (50 mg / kg) and midazolam (60 mg / kg), and the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine (150 mg / kg), while MPEP (30 mg / kg) only significantly enhanced the hypnotic properties of ketamine (150 mg / kg). Conclusions These findings suggest that specific subtypes of the metabotropic glutamate receptor differentially modulate the sedative-hypnotic properties of ethanol through separate mechanisms of action, potentially involving GABAA and NMDA receptors. PMID:18070246

Ethanol Mediated Inhibition of Synaptic Vesicle Recycling at Amygdala Glutamate Synapses Is Dependent upon Munc13-2

PubMed Central

Gioia, Dominic A.; Alexander, Nancy; McCool, Brian A.

2017-01-01

Chronic exposure to alcohol produces adaptations within the basolateral amygdala (BLA) that are associated with the development of anxiety-like behaviors during withdrawal. In part, these adaptations are mediated by plasticity in glutamatergic synapses occurring through an AMPA receptor mediated form of post-synaptic facilitation in addition to a unique form of presynaptic facilitation. In comparison to the post-synaptic compartment, relatively less is understood about the mechanisms involved in the acute and chronic effects of ethanol in the presynaptic terminal. Previous research has demonstrated that glutamatergic terminals in the mouse BLA are sensitive to ethanol mediated inhibition of synaptic vesicle recycling in a strain-dependent fashion. Importantly, the strain-dependent differences in presynaptic ethanol sensitivity are in accordance with known strain-dependent differences in ethanol/anxiety interactions. In the present study, we have used a short-hairpin RNA to knockdown the expression of the presynaptic Munc13-2 protein in C57BL/6J mice, whose BLA glutamate terminals are normally ethanol-insensitive. We injected this shRNA, or a scrambled control virus, into the medial prefrontal cortex (mPFC) which sends dense projections to the BLA. Accordingly, this knockdown strategy reduces the expression of the Munc13-2 isoform in mPFC terminals within the BLA and alters presynaptic terminal function in C57BL/6J mice in a manner that phenocopies DBA/2J glutamate terminals which are normally ethanol-sensitive. Here, we provide evidence that manipulation of this single protein, Munc13-2, renders C57BL/6J terminals sensitive to ethanol mediated inhibition of synaptic vesicle recycling and post-tetanic potentiation. Furthermore, we found that this ethanol inhibition was dose dependent. Considering the important role of Munc13 proteins in synaptic plasticity, this study potentially identifies a molecular mechanism regulating the acute presynaptic effects of ethanol to the long lasting adaptations in the BLA that occur during chronic ethanol exposure. PMID:28785200

Cilnidipine, an L/N-type calcium channel blocker prevents acquisition and expression of ethanol-induced locomotor sensitization in mice.

PubMed

Bhutada, Pravinkumar; Mundhada, Yogita; Patil, Jayshree; Rahigude, Anand; Zambare, Krushna; Deshmukh, Prashant; Tanwar, Dhanshree; Jain, Kishor

2012-04-11

Several evidences indicated the involvement of L- and N-type calcium channels in behavioral effects of drugs of abuse, including ethanol. Calcium channels are implicated in ethanol-induced behaviors and neurochemical responses. Calcium channel antagonists block the psychostimulants induced behavioral sensitization. Recently, it is demonstrated that L-, N- and T-type calcium channel blockers attenuate the acute locomotor stimulant effects of ethanol. However, no evidence indicated the role of calcium channels in ethanol-induced psychomotor sensitization. Therefore, present study evaluated the influence of cilnidipine, an L/N-type calcium channel blocker on acquisition and expression of ethanol-induced locomotor sensitization. The results revealed that cilnidipine (0.1 and 1.0μg/mouse, i.c.v.) attenuates the expression of sensitization to locomotor stimulant effect of ethanol (2.0g/kg, i.p.), whereas pre- treatment of cilnidipine (0.1 and 1.0μg/mouse, i.c.v.) during development of sensitization blocks acquisition and attenuates expression of sensitization to locomotor stimulant effect of ethanol. Cilnidipine per se did not influence locomotor activity in tested doses. Further, cilnidipine had no influence on effect of ethanol on rotarod performance. These results support the hypothesis that neuroadaptive changes in calcium channels participate in the acquisition and the expression of ethanol-induced locomotor sensitization. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chronic intermittent ethanol exposure in early adolescent and adult male rats: effects on tolerance, social behavior, and ethanol intake.

PubMed

Broadwater, Margaret; Varlinskaya, Elena I; Spear, Linda P

2011-08-01

Given the prevalence of alcohol use in adolescence, it is important to understand the consequences of chronic ethanol exposure during this critical period in development. The purpose of this study was to assess possible age-related differences in susceptibility to tolerance development to ethanol-induced sedation and withdrawal-related anxiety, as well as voluntary ethanol intake after chronic exposure to relatively high doses of ethanol during adolescence or adulthood. Juvenile/adolescent and adult male Sprague-Dawley rats were assigned to one of five 10-day exposure conditions: chronic ethanol (4 g/kg every 48 hours), chronic saline (equivalent volume every 24 hours), chronic saline/acutely challenged with ethanol (4 g/kg on day 10), nonmanipulated/acutely challenged with ethanol (4 g/kg on day 10), or nonmanipulated. For assessment of tolerance development, duration of the loss of righting reflex (LORR) and blood ethanol concentrations (BECs) upon regaining of righting reflex (RORR) were tested on the first and last ethanol exposure days in the chronic ethanol group, with both saline and nonmanipulated animals likewise challenged on the last exposure day. Withdrawal-induced anxiety was indexed in a social interaction test 24 hours after the last ethanol exposure, with ethanol-naïve chronic saline and nonmanipulated animals serving as controls. Voluntary intake was assessed 48 hours after the chronic exposure period in chronic ethanol, chronic saline and nonmanipulated animals using an 8-day 2 bottle choice, limited-access ethanol intake procedure. In general, adolescent animals showed shorter durations of LORR and higher BECs upon RORR than adults on the first and last ethanol exposure days, regardless of chronic exposure condition. Adults, but not adolescents, developed chronic tolerance to the sedative effects of ethanol, tolerance that appeared to be metabolic in nature. Social deficits were observed after chronic ethanol in both adolescents and adults. Adolescents drank significantly more ethanol than adults on a gram per kilogram basis, with intake uninfluenced by prior ethanol exposure at both ages. Adolescents and adults may differ in their ability and/or propensity to adapt to chronic ethanol exposure, with adults, but not adolescents, developing chronic metabolic tolerance. However, this chronic exposure regimen was sufficient to disrupt baseline levels of social behavior at both ages. Taken together, these results suggest that, despite the age-related differences in tolerance development, adolescents are as susceptible as adults to consequences of chronic ethanol exposure, particularly in terms of disruptions in social behavior. Whether these effects would last into adulthood remains to be determined. Copyright © 2011 by the Research Society on Alcoholism.

Fluvoxamine effects on concurrent ethanol- and food-maintained behaviors

PubMed Central

Ginsburg, Brett C.; Lamb, R.J.

2011-01-01

In previous studies, the selective serotonin reuptake inhibitor fluvoxamine preferentially reduced responding for ethanol compared with responding for food under conditions in which each was available alone in separate groups or in the same subjects under a multiple schedule in which baseline response rates were matched. The impact of providing concurrent access to food on pharmacological effects on ethanol self-administration remains largely unexplored. In this study, acute doses of fluvoxamine (3.0-17.8 mg/kg) were administered 30-min before the experimental session to Lewis rats responding under a concurrent fixed-ratio, fixed-ratio schedule of ethanol and food presentation. Ratios for food were adjusted for each subject to provide matched rates of food and ethanol reinforcement across the 30-min session. Although the number of ethanol and food deliveries did not significantly differ under baseline conditions, response rates did differ. Following fluvoxamine administration, responding for food was decreased more than responding for ethanol. This differential effect did not appear to be related to response rate or fixed-ratio size. Thus, the selectivity of fluvoxamine on ethanol- versus food-maintained responding depends upon the context in which the behavior occurs. Such results may help explain inconsistencies between preclinical results and those in humans, and could provide insight into the behavioral determinants of pharmacological effects on ethanol self-administration. PMID:17115876

Effects of binge-like ethanol exposure during adolescence on the hyperalgesia observed during sickness syndrome in rats.

PubMed

de Oliveira, Bruna M T; Telles, Tatiane M B B; Lomba, Luiz A; Correia, Diego; Zampronio, Aleksander R

2017-09-01

Acute and chronic ethanol exposure increases the risk of infection by altering the innate host's defense system. Adolescence is a critical period for brain development. Insults during this period may have long-lasting consequences. The present study investigated the effects of binge-like ethanol exposure in adolescent rats on mechanical hyperalgesia during sickness syndrome that was induced by a systemic injection of lipopolysaccharide (LPS) or an intracerebroventricular (i.c.v.) injection of interleukin-1β (IL-1β) after the cessation of ethanol exposure. Male Wistar rats were exposed to ethanol from postnatal day (PND) 25 to PND 38 in a binge-like pattern. Hyperalgesia was assessed on the right hindpaw after an intraperitoneal injection of LPS (5 and 50μg/kg, intraperitoneally) on PND 51 and PND 63 or an i.c.v. or intraplantar (i.pl.) injection of IL-β (3 and 1ng, respectively) on PND 51. Ethanol exposure during adolescence did not alter mechanical thresholds which increased normally with age. The systemic injection of LPS (0.5-50μg/kg) in adult rats induced dose-related mechanical hyperalgesia. Binge-like ethanol exposure significantly increased mechanical hyperalgesia that was induced by 50μg/kg LPS on PND 51 and 63, which lasted until 24h after the injection. This change was not observed at a lower dose of LPS (5μg/kg). Acute oral treatment with ethanol 24h prior to LPS administration did not alter mechanical hyperalgesia. The i.c.v. injection of IL-1β (1-10ng) also induced dose-related mechanical hyperalgesia in the right hindpaw in non-exposed animals. In animals that were exposed to binge-like ethanol, the i.c.v. or i.pl. injection of IL-1β also increased hyperalgesia on PND 51. These results suggest that binge-like ethanol exposure during adolescence causes alterations in the central nervous system that can increase mechanical hyperalgesia that is observed during sickness syndrome, and this effect can be observed until adulthood after the cessation of ethanol exposure. Copyright © 2017 Elsevier Inc. All rights reserved.

Protective Effects of Ethanolic Extracts from Artichoke, an Edible Herbal Medicine, against Acute Alcohol-Induced Liver Injury in Mice

PubMed Central

Tang, Xuchong; Wei, Ruofan; Deng, Aihua; Lei, Tingping

2017-01-01

Oxidative stress and inflammation are well-documented pathological factors in alcoholic liver disease (ALD). Artichoke (Cynara scolymus L.) is a healthy food and folk medicine with anti-oxidative and anti-inflammatory properties. This study aimed to evaluate the preventive effects of ethanolic extract from artichoke against acute alcohol-induced liver injury in mice. Male Institute of Cancer Research mice were treated with an ethanolic extract of artichoke (0.4, 0.8, and 1.6 g/kg body weight) by gavage once daily. Up to 40% alcohol (12 mL/kg body weight) was administered orally 1 h after artichoke treatment. All mice were fed for 10 consecutive days. Results showed that artichoke extract significantly prevented elevated levels of aspartate aminotransferase, alanine aminotransferase, triglyceride, total cholesterol, and malondialdehyde. Meanwhile, the decreased levels of superoxide dismutase and glutathione were elevated by artichoke administration. Histopathological examination showed that artichoke attenuated degeneration, inflammatory infiltration and necrosis of hepatocytes. Immunohistochemical analysis revealed that expression levels of toll-like receptor (TLR) 4 and nuclear factor-kappa B (NF-κB) in liver tissues were significantly suppressed by artichoke treatment. Results obtained demonstrated that artichoke extract exhibited significant preventive protective effect against acute alcohol-induced liver injury. This finding is mainly attributed to its ability to attenuate oxidative stress and suppress the TLR4/NF-κB inflammatory pathway. To the best of our knowledge, the underlying mechanisms of artichoke on acute ALD have been rarely reported. PMID:28891983

Protective Effects of Ethanolic Extracts from Artichoke, an Edible Herbal Medicine, against Acute Alcohol-Induced Liver Injury in Mice.

PubMed

Tang, Xuchong; Wei, Ruofan; Deng, Aihua; Lei, Tingping

2017-09-11

Oxidative stress and inflammation are well-documented pathological factors in alcoholic liver disease (ALD). Artichoke ( Cynara scolymus L.) is a healthy food and folk medicine with anti-oxidative and anti-inflammatory properties. This study aimed to evaluate the preventive effects of ethanolic extract from artichoke against acute alcohol-induced liver injury in mice. Male Institute of Cancer Research mice were treated with an ethanolic extract of artichoke (0.4, 0.8, and 1.6 g/kg body weight) by gavage once daily. Up to 40% alcohol (12 mL/kg body weight) was administered orally 1 h after artichoke treatment. All mice were fed for 10 consecutive days. Results showed that artichoke extract significantly prevented elevated levels of aspartate aminotransferase, alanine aminotransferase, triglyceride, total cholesterol, and malondialdehyde. Meanwhile, the decreased levels of superoxide dismutase and glutathione were elevated by artichoke administration. Histopathological examination showed that artichoke attenuated degeneration, inflammatory infiltration and necrosis of hepatocytes. Immunohistochemical analysis revealed that expression levels of toll-like receptor (TLR) 4 and nuclear factor-kappa B (NF-κB) in liver tissues were significantly suppressed by artichoke treatment. Results obtained demonstrated that artichoke extract exhibited significant preventive protective effect against acute alcohol-induced liver injury. This finding is mainly attributed to its ability to attenuate oxidative stress and suppress the TLR4/NF-κB inflammatory pathway. To the best of our knowledge, the underlying mechanisms of artichoke on acute ALD have been rarely reported.

Age-related effects of chronic restraint stress on ethanol drinking, ethanol-induced sedation, and on basal and stress-induced anxiety response

PubMed Central

Fernández, Macarena Soledad; Fabio, María Carolina; Miranda-Morales, Roberto Sebastián; Virgolini, Miriam B.; De Giovanni, Laura N.; Hansen, Cristian; Wille-Bille, Aranza; Nizhnikov, Michael E.; Spear, Linda P.; Pautassi, Ricardo Marcos

2016-01-01

Adolescents are sensitive to the anxiolytic effect of ethanol, and evidence suggests that they may be more sensitive to stress than adults. Relatively little is known, however, about age-related differences in stress modulation of ethanol drinking or stress modulation of ethanol-induced sedation and hypnosis. We observed that chronic restraint stress transiently exacerbated free-choice ethanol drinking in adolescent, but not in adult, rats. Restraint stress altered exploration patterns of a light-dark box apparatus in adolescents and adults. Stressed animals spent significantly more time in the white area of the maze and made significantly more transfers between compartments than their non-stressed peers. Behavioral response to acute stress, on the other hand, was modulated by prior restraint stress only in adults. Adolescents, unlike adults, exhibited ethanol-induced motor stimulation in an open field. Stress increased the duration of loss of the righting reflex after a high ethanol dose, yet this effect was similar at both ages. Ethanol-induced sleep time was much higher in adult than in adolescent rats, yet stress diminished ethanol-induced sleep time only in adults. The study indicates age-related differences that may increase the risk for initiation and escalation in alcohol drinking. PMID:26830848

Dose-related effects of red wine and alcohol on hemodynamics, sympathetic nerve activity, and arterial diameter.

PubMed

Spaak, Jonas; Merlocco, Anthony C; Soleas, George J; Tomlinson, George; Morris, Beverley L; Picton, Peter; Notarius, Catherine F; Chan, Christopher T; Floras, John S

2008-02-01

The cardiovascular benefits of light to moderate red wine consumption often have been attributed to its polyphenol constituents. However, the acute dose-related hemodynamic, vasodilator, and sympathetic neural effects of ethanol and red wine have not been characterized and compared in the same individual. We sought to test the hypotheses that responses to one and two alcoholic drinks differ and that red wine with high polyphenol content elicits a greater effect than ethanol alone. Thirteen volunteers (24-47 yr; 7 men, 6 women) drank wine, ethanol, and water in a randomized, single-blind trial on three occasions 2 wk apart. One drink of wine and ethanol increased blood alcohol to 38 +/- 2 and 39 +/- 2 mg/dl, respectively, and two drinks to 72 +/- 4 and 83 +/- 3 mg/dl, respectively. Wine quadrupled plasma resveratrol (P < 0.001) and increased catechin (P < 0.03). No intervention affected blood pressure. One drink had no heart rate effect, but two drinks of wine increased heart rate by 5.7 +/- 1.6 beats/min; P < 0.001). Cardiac output fell 0.8 +/- 0.3 l/min after one drink of ethanol and wine (both P < 0.02) but increased after two drinks of ethanol (+0.8 +/- 0.3 l/min) and wine (+1.2 +/- 0.3 l/min) (P < 0.01). One alcoholic drink did not alter muscle sympathetic nerve activity (MSNA), while two drinks increased MSNA by 9-10 bursts/min (P < 0.001). Brachial artery diameter increased after both one and two alcoholic drinks (P < 0.001). No beverage augmented, and the second wine dose attenuated (P = 0.02), flow-mediated vasodilation. One drink of ethanol dilates the brachial artery without activating sympathetic outflow, whereas two drinks increase MSNA, heart rate, and cardiac output. These acute effects, which exhibit a narrow dose response, are not modified by red wine polyphenols.

Delta receptor antagonism, ethanol taste reactivity, and ethanol consumption in outbred male rats.

PubMed

Higley, Amanda E; Kiefer, Stephen W

2006-11-01

Naltrexone, a nonspecific opioid antagonist, produces significant changes in ethanol responsivity in rats by rendering the taste of ethanol aversive as well as producing a decrease in voluntary ethanol consumption. The present study investigated the effect of naltrindole, a specific antagonist of delta opioid receptors, on ethanol taste reactivity and ethanol consumption in outbred rats. In the first experiment, rats received acute treatment of naltrexone, naltrindole, or saline followed by the measurement of ethanol consumption in a short-term access period. The second experiment involved the same treatments and investigated ethanol palatability (using the taste-reactivity test) as well as ethanol consumption. Results indicated that treatment with 3 mg/kg naltrexone significantly affected palatability (rendered ethanol more aversive, Experiment 2) and decreased voluntary ethanol consumption (Experiments 1 and 2). The effects of naltrindole were inconsistent. In Experiment 1, 8 mg/kg naltrindole significantly decreased voluntary ethanol consumption but this was not replicated in Experiment 2. The 8 mg/kg dose produced a significant increase in aversive responding (Experiment 2) but did not affect ingestive responding. Lower doses of naltrindole (2 and 4 mg/kg) were ineffective in altering rats' taste-reactivity response to and consumption of ethanol. While these data suggest that delta receptors are involved in rats' taste-reactivity response to ethanol and rats' ethanol consumption, it is likely that multiple opioid receptors mediate both behavioral responses.

Estimated rate of fatal automobile accidents attributable to acute solvent exposure at low inhaled concentrations.

PubMed

Benignus, Vernon A; Bushnell, Philip J; Boyes, William K

2011-12-01

Acute solvent exposures may contribute to automobile accidents because they increase reaction time and decrease attention, in addition to impairing other behaviors. These effects resemble those of ethanol consumption, both with respect to behavioral effects and neurological mechanisms. These observations, along with the extensive data on the relationship between ethanol consumption and fatal automobile accidents, suggested a way to estimate the probability of fatal automobile accidents from solvent inhalation. The problem can be approached using the logic of the algebraic transitive postulate of equality: if A=B and B=C, then A=C. We first calculated a function describing the internal doses of solvent vapors that cause the same magnitude of behavioral impairment as ingestion of ethanol (A=B). Next, we fit a function to data from the literature describing the probability of fatal car crashes for a given internal dose of ethanol (B=C). Finally, we used these two functions to generate a third function to estimate the probability of a fatal car crash for any internal dose of organic solvent vapor (A=C). This latter function showed quantitatively (1) that the likelihood of a fatal car crash is increased by acute exposure to organic solvent vapors at concentrations less than 1.0 ppm, and (2) that this likelihood is similar in magnitude to the probability of developing leukemia from exposure to benzene. This approach could also be applied to other potentially adverse consequences of acute exposure to solvents (e.g., nonfatal car crashes, property damage, and workplace accidents), if appropriate data were available. © 2011 Society for Risk Analysis Published 2011. This article is a U.S. Government work and is in the public domain for the U.S.A.

Acute, food-induced moderate elevation of plasma uric acid protects against hyperoxia-induced oxidative stress and increase in arterial stiffness in healthy humans.

PubMed

Vukovic, Jonatan; Modun, Darko; Budimir, Danijela; Sutlovic, Davorka; Salamunic, Ilza; Zaja, Ivan; Boban, Mladen

2009-11-01

We examined the effects of acute, food-induced moderate increase of plasma uric acid (UA) on arterial stiffness and markers of oxidative damage in plasma in healthy males exposed to 100% normobaric oxygen. Acute elevation of plasma UA was induced by consumption of red wine, combination of ethanol and glycerol, or fructose. By using these beverages we were able to separate the effects of UA, wine polyphenols and ethanol. Water was used as a control beverage. Ten males randomly consumed test beverages in a cross-over design over the period of 4 weeks, one beverage per week. They breathed 100% O(2) between 60(th) and 90(th)min of the 4-h study protocol. Pulse wave augmentation index (AIx) at brachial and radial arteries, plasma antioxidant capacity (AOC), thiobarbituric acid-reactive substances (TBARS), lipid hydroperoxides (LOOH) assessed by xylenol orange method, UA and blood ethanol concentrations were determined before and 60, 90, 120, 150 and 240 min after beverage consumption. Consumption of the beverages did not affect the AIx, TBARS or LOOH values during 60 min before exposure to hyperoxia, while AOC and plasma UA increased except in the water group. Significant increase of AIx, plasma TBARS and LOOH, which occurred during 30 min of hyperoxia in the water group, was largely prevented in the groups that consumed red wine, glycerol+ethanol or fructose. In contrast to chronic hyperuricemia, generally considered as a risk factor for cardiovascular diseases and metabolic syndrome, acute increase of UA acts protectively against hyperoxia-induced oxidative stress and related increase of arterial stiffness in large peripheral arteries.

Acute toxicity of gasoline and some additives.

PubMed Central

Reese, E; Kimbrough, R D

1993-01-01

The acute toxicity of gasoline; its components benzene, toluene, and xylene; and the additives ethanol, methanol, and methyl tertiary butyl ether are reviewed. All of these chemicals are only moderately to mildly toxic at acute doses. Because of their volatility, these compounds are not extensively absorbed dermally unless the exposed skin is occluded. Absorption through the lungs and the gastrointestinal tract is quite efficient. After ingestion, the principal danger for a number of these chemicals, particularly gasoline, is aspiration pneumonia, which occurs mainly in children. It is currently not clear whether aspiration pneumonia would still be a problem if gasoline were diluted with ethanol or methanol. During the normal use of gasoline or mixtures of gasoline and the other solvents as a fuel, exposures would be much lower than the doses that have resulted in poisoning. No acute toxic health effects would occur during the normal course of using automotive fuels. PMID:8020435

Comparative effects of dietary corn oil, safflower oil, fish oil and palm oil on metabolism of ethanol and carnitine in the rat.

PubMed

Sachan, Dileep S; Yatim, Ayub M; Daily, James W

2002-06-01

This study was launched to determine comparative effects of corn oil (CO), safflower oil (SO), fish oil (FO) and palm oil (PO) on carnitine status and ethanol metabolism in rats. Twenty-four male Sprague-Dawley rats (300 g bw) were randomly divided into four groups (n = 6) and fed a semisynthetic diets containing fat as oils listed above. Blood and 24 hour urine samples were collected before and after dietary treatment and acute ethanol administration. Samples were analyzed for blood-ethanol concentration (BEC) and carnitine species. The diets containing FO and PO retarded ethanol metabolism compared to the diets containing CO and SO. The effect of these dietary fats on carnitine species in plasma and urine was varied before and after dietary treatment and following a single oral ethanol dose. The liver carnitine content was higher in the PO group after dietary and ethanol treatment. It is concluded that attenuation of ethanol clearance was related to unique fatty acid makeup of the oils that in part may be attributed to the composite ratio of saturated to unsaturated fatty acids in the oils.

Intrinsic Properties of Larval Zebrafish Neurons in Ethanol

PubMed Central

Ikeda, Hiromi; Delargy, Alison H.; Yokogawa, Tohei; Urban, Jason M.; Burgess, Harold A.; Ono, Fumihito

2013-01-01

The behavioral effects of ethanol have been studied in multiple animal models including zebrafish. Locomotion of zebrafish larvae is resistant to high concentrations of ethanol in bath solution. This resistance has been attributed to a lower systemic concentration of ethanol in zebrafish when compared with bath solution, although the mechanism to maintain such a steep gradient is unclear. Here we examined whether the intrinsic properties of neurons play roles in this resistance. In order to minimize the contribution of metabolism and diffusional barriers, larvae were hemisected and the anterior half immersed in a range of ethanol concentrations thereby ensuring the free access of bath ethanol to the brain. The response to vibrational stimuli of three types of reticulospinal neurons: Mauthner neurons, vestibulospinal neurons, and MiD3 neurons were examined using an intracellular calcium indicator. The intracellular [Ca2+] response in MiD3 neurons decreased in 100 mM ethanol, while Mauthner neurons and vestibulospinal neurons required >300 mM ethanol to elicit similar effects. The ethanol effect in Mauthner neurons was reversible following removal of ethanol. Interestingly, activities of MiD3 neurons displayed spontaneous recovery in 300 mM ethanol, suggestive of acute tolerance. Finally, we examined with mechanical vibration the startle response of free-swimming larvae in 300 mM ethanol. Ethanol treatment abolished long latency startle responses, suggesting a functional change in neural processing. These data support the hypothesis that individual neurons in larval zebrafish brains have distinct patterns of response to ethanol dictated by specific molecular targets. PMID:23658822

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

PubMed Central

Karkhanis, Anushree N.; Huggins, Kimberly N.; Rose, Jamie H.; Jones, Sara R.

2016-01-01

Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs “rescued” dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of KORs is a promising avenue for developing pharmacotherapies for alcoholism. PMID:27450094

Acute effects of ethanol or d-amphetamine on the locomotor activity of larval zebrafish in a microtiter plate format.

EPA Science Inventory

As part of an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae. We are assessing the acute effects of prototypic drugs that are known to act on the central ...

Adenosine signaling in striatal circuits and alcohol use disorders.

PubMed

Nam, Hyung Wook; Bruner, Robert C; Choi, Doo-Sup

2013-09-01

Adenosine signaling has been implicated in the pathophysiology of alcohol use disorders and other psychiatric disorders such as anxiety and depression. Numerous studies have indicated a role for A1 receptors (A1R) in acute ethanol-induced motor incoordination, while A2A receptors (A2AR) mainly regulate the rewarding effect of ethanol in mice. Recent findings have demonstrated that dampened A2AR-mediated signaling in the dorsomedial striatum (DMS) promotes ethanol-seeking behaviors. Moreover, decreased A2AR function is associated with decreased CREB activity in the DMS, which enhances goal-oriented behaviors and contributes to excessive ethanol drinking in mice. Interestingly, caffeine, the most commonly used psychoactive substance, is known to inhibit both the A1R and A2AR. This dampened adenosine receptor function may mask some of the acute intoxicating effects of ethanol. Furthermore, based on the fact that A2AR activity plays a role in goal-directed behavior, caffeine may also promote ethanol-seeking behavior. The A2AR is enriched in the striatum and exclusively expressed in striatopallidal neurons, which may be responsible for the regulation of inhibitory behavioral control over drug rewarding processes through the indirect pathway of the basal ganglia circuit. Furthermore, the antagonistic interactions between adenosine and dopamine receptors in the striatum also play an integral role in alcoholism and addiction-related disorders. This review focuses on regulation of adenosine signaling in striatal circuits and the possible implication of caffeine in goal-directed behaviors and addiction.

Pharmacological effects of ethanol on ingestive behavior of the preweanling rat

PubMed Central

Kozlov, Andrey P.; Nizhnikov, Michael E.; Varlinskaya, Elena I.; Spear, Norman E.

2009-01-01

The present study was designed to test the hypothesis that sensitivity of ingestive behavior of infant rat to the pharmacological effects of ethanol changes between postnatal (P) days 9 and 12. The intake of 0.1% saccharin and water, general motor activity, and myoclonic twitching activity were assessed following administration of three doses of ethanol (0, 0.25, 0.5g/kg) while fluids were free available to the animals. The 0.5g/kg dose of ethanol attenuated saccharin intake in P9 pups and enhanced saccharin intake in P12 rats. On P12 some sex-related differences emerged at 0.5g/kg of ethanol, with saccharin intake being higher in females than in their male counterparts. Taste reactivity probe revealed that 0.5 g/kg of ethanol increased taste responsiveness to saccharin on P12 but only to infusions presented at a high rate. The results of the present study indicate that ontogenetic changes in sensitivity to the effects of ethanol on ingestive behavior occur during the second postnatal week, with P9 animals being more sensitive to the inhibitory (sedative) effects on saccharin intake and P12 rats being more sensitive to the stimulatory effects of ethanol. We suggest that acute ethanol enhanced saccharin intake via sensitization of oral response to appetitive taste stimulation. PMID:19549546

In vivo relationship between monoamine oxidase type B and alcohol dehydrogenase: effects of ethanol and phenylethylamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aliyu, S.U.; Upahi, L.

The role of acute ethanol and phenylethylamine on the brain and platelet monoamine oxidase activities, hepatic cytosolic alcohol dehydrogenase, redox state and motor behavior were studied in male rats. Ethanol on its own decreased the redox couple ratio, as well as, alcohol dehydrogenase activity in the liver while at the same time it increased brain and platelet monoamine oxidase activity due to lower Km with no change in Vmax. The elevation in both brain and platelet MAO activity was associated with ethanol-induced hypomotility in the rats. Co-administration of phenylethylamine and ethanol to the animals, caused antagonism of the ethanol-induced effectsmore » described above. The effects of phenylethylamine alone, on the above mentioned biochemical and behavioral indices, are more complex. Phenylethylamine on its own, like ethanol, caused reduction of the cytosolic redox, ratio and elevation of monoamine oxidase activity in the brain and platelets. However, in contrast to ethanol, this monoamine produced hypermotility and activation of the hepatic cytosolic alcohol dehydrogenase activity in the animals.« less

The role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sato, Tomoki, E-mail: s13220@u-shizuoka-ken.ac.jp; Morita, Akihito, E-mail: moritaa@u-shizuoka-ken.ac.jp; Mori, Nobuko, E-mail: morin@b.s.osakafu-u.ac.jp

2014-02-21

Highlights: • Ethanol administration increased GPD1 mRNA expression. • Ethanol administration increased glucose incorporation into TG glycerol moieties. • No increase in hepatic TG levels was observed in ethanol-injected GPD1 null mice. • We propose that GPD1 is required for ethanol-induced TG accumulation in the liver. - Abstract: Acute ethanol consumption leads to the accumulation of triglycerides (TGs) in hepatocytes. The increase in lipogenesis and reduction of fatty acid oxidation are implicated as the mechanisms underlying ethanol-induced hepatic TG accumulation. Although glycerol-3-phosphate (Gro3P), formed by glycerol kinase (GYK) or glycerol-3-phosphate dehydrogenase 1 (GPD1), is also required for TG synthesis, themore » roles of GYK and GPD1 have been the subject of some debate. In this study, we examine (1) the expression of genes involved in Gro3P production in the liver of C57BL/6J mice in the context of hepatic TG accumulation after acute ethanol intake, and (2) the role of GPD1 in the progression of ethanol-induced fatty liver using GPD1 null mice. As a result, in C57BL/6J mice, ethanol-induced hepatic TG accumulation began within 2 h and was 1.7-fold greater than that observed in the control group after 6 h. The up-regulation of GPD1 began 2 h after administering ethanol, and significantly increased 6 h later with the concomitant escalation in the glycolytic gene expression. The incorporation of {sup 14}C-labelled glucose into TG glycerol moieties increased during the same period. On the other hand, in GPD1 null mice carrying normal GYK activity, no significant increase in hepatic TG level was observed after acute ethanol intake. In conclusion, GPD1 and glycolytic gene expression is up-regulated by ethanol, and GPD1-mediated incorporation of glucose into TG glycerol moieties together with increased lipogenesis, is suggested to play an important role in ethanol-induced hepatic TG accumulation.« less

SENSITIZATION TO SOCIAL ANXIOLYTIC EFFECTS OF ETHANOL IN ADOLESCENT AND ADULT SPRAGUE-DAWLEY RATS FOLLOWING REPEATED ETHANOL EXPOSURE

PubMed Central

Varlinskaya, Elena; Spear, Linda Patia

2009-01-01

Ontogenetic studies using a social interaction paradigm have shown that adolescent rats are less sensitive to anxiolytic properties of acute ethanol than their adult counterparts. It is not known, however, whether adaptations to these anxiolytic effects upon repeated experiences with ethanol would be similar in adolescents and adults. The present study investigated sensitivity to the anxiolytic effects of ethanol in adolescent and adult male and female Sprague-Dawley rats following 7 days of exposure [postnatal day (P) 27–33 for adolescents and P62–68 for adults] to 1 g/kg ethanol or saline (i.p.), as well as in animals left non-manipulated during this time. Anxiolytic effects of ethanol (0, 0.75, 1.0, 1.25, and 1.5 g/kg for adolescents and 0, 0.25, 0.5, 0.75, 1.0, and 1.25 g/kg for adults in Experiments 1 and 2, respectively) were examined 48 hours after the last exposure using a modified social interaction test under unfamiliar test circumstances. At both ages, repeated ethanol exposure resulted in the development of apparent sensitization to anxiolytic effects of ethanol indexed via enhancement of social investigation and transformation of social avoidance into social indifference or preference, as well as expression of tolerance to the socially inhibiting effects induced by higher ethanol doses. Evidence for the emergence of sensitization in adults and tolerance at both ages was seen not only following chronic ethanol, but also after chronic saline exposure, suggesting that chronic manipulation per se may be sufficient to alter the sensitivity of both adolescents and adults to socially-relevant effects of ethanol. PMID:20113878

Paracetamol, alcohol and the liver

PubMed Central

Prescott, Laurie F

2000-01-01

It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with ‘therapeutic intent’ had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol–alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic. The paracetamol–alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol–ethanol interaction is not specific for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical. In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the first few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insufficient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestion-ingly accepted this supposed interaction in man for so long with such scant regard for scientific objectivity. PMID:10759684

Loss of ethanol conditioned taste aversion and motor stimulation in knockin mice with ethanol-insensitive α2-containing GABA(A) receptors.

PubMed

Blednov, Y A; Borghese, C M; McCracken, M L; Benavidez, J M; Geil, C R; Osterndorff-Kahanek, E; Werner, D F; Iyer, S; Swihart, A; Harrison, N L; Homanics, G E; Harris, R A

2011-01-01

GABA type A receptors (GABA(A)-Rs) are potential targets of ethanol. However, there are multiple subtypes of this receptor, and, thus far, individual subunits have not been definitively linked with specific ethanol behavioral actions. Interestingly, though, a chromosomal cluster of four GABA(A)-R subunit genes, including α2 (Gabra2), was associated with human alcoholism (Am J Hum Genet 74:705-714, 2004; Pharmacol Biochem Behav 90:95-104, 2008; J Psychiatr Res 42:184-191, 2008). The goal of our study was to determine the role of receptors containing this subunit in alcohol action. We designed an α2 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity in a recombinant expression system. Knockin mice containing this mutant subunit were tested in a range of ethanol behavioral tests. These mutant mice did not develop the typical conditioned taste aversion in response to ethanol and showed complete loss of the motor stimulant effects of ethanol. Conversely, they also demonstrated changes in ethanol intake and preference in multiple tests. The knockin mice showed increased ethanol-induced hypnosis but no difference in anxiolytic effects or recovery from acute ethanol-induced motor incoordination. Overall, these studies demonstrate that the effects of ethanol at GABAergic synapses containing the α2 subunit are important for specific behavioral effects of ethanol that may be relevant to the genetic linkage of this subunit with human alcoholism.

Loss of Ethanol Conditioned Taste Aversion and Motor Stimulation in Knockin Mice with Ethanol-Insensitive α2-Containing GABAA Receptors

PubMed Central

Borghese, C. M.; McCracken, M. L.; Benavidez, J. M.; Geil, C. R.; Osterndorff-Kahanek, E.; Werner, D. F.; Iyer, S.; Swihart, A.; Harrison, N. L.; Homanics, G. E.; Harris, R. A.

2011-01-01

GABA type A receptors (GABAA-Rs) are potential targets of ethanol. However, there are multiple subtypes of this receptor, and, thus far, individual subunits have not been definitively linked with specific ethanol behavioral actions. Interestingly, though, a chromosomal cluster of four GABAA-R subunit genes, including α2 (Gabra2), was associated with human alcoholism (Am J Hum Genet 74:705–714, 2004; Pharmacol Biochem Behav 90:95–104, 2008; J Psychiatr Res 42:184–191, 2008). The goal of our study was to determine the role of receptors containing this subunit in alcohol action. We designed an α2 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity in a recombinant expression system. Knockin mice containing this mutant subunit were tested in a range of ethanol behavioral tests. These mutant mice did not develop the typical conditioned taste aversion in response to ethanol and showed complete loss of the motor stimulant effects of ethanol. Conversely, they also demonstrated changes in ethanol intake and preference in multiple tests. The knockin mice showed increased ethanol-induced hypnosis but no difference in anxiolytic effects or recovery from acute ethanol-induced motor incoordination. Overall, these studies demonstrate that the effects of ethanol at GABAergic synapses containing the α2 subunit are important for specific behavioral effects of ethanol that may be relevant to the genetic linkage of this subunit with human alcoholism. PMID:20876231

Modulation of Ethanol Withdrawal–Induced Anxiety-Like Behavior During Later Withdrawals by Treatment of Early Withdrawals With Benzodiazepine/γ-Aminobutyric Acid Ligands

PubMed Central

Knapp, Darin J.; Overstreet, David H.; Breese, George R.

2010-01-01

Background Anxiety states, including those arising during acute or protracted withdrawal periods, may be precipitating factors in alcoholic relapse. Given the cyclical nature of ethanol withdrawal associated with repeated cycles of ethanol intake and abstinence in a pattern that often spans years, meaningful attempts to model ethanol withdrawal–associated anxiety should incorporate cycled ethanol treatments. The studies reported herein examined the effects of γ-aminobutyric acid–modulating drugs on social interaction behavior—an established model of anxiety—in rats exposed to repeated cycles of ethanol treatment and withdrawal. Methods Rats were exposed to 8 to 12 g/kg/day ethanol during three 7-day dietary cycles (5 days on ethanol diet followed by 2 days on control diet). Ethanol was administered either at hour 4 of withdrawal after cessation of each of the first 2 ethanol cycles or during the final withdrawal only. In other groups, the early withdrawals were treated with alphaxalone, diazepam, PK11159, or flumazenil to block anxiety-like behavior during an untreated later (third) withdrawal. The benzodiazepine inverse agonist DMCM (methyl–6, 7–dymerhoxy–4–ethyl–beta–carboline–3–carboxylate) was also given repeatedly to determine whether it would sensitize anxiety-like behavior during a future withdrawal. Finally, the effects of all drugs on deficits in locomotor behavior were assessed. Results Pretreatment of earlier withdrawals with alphaxalone, diazepam, ethanol, or flumazenil reduced social interaction deficits during a later withdrawal, but pretreatment with PK11195 did not. In contrast, DMCM administered in lieu of early withdrawals increased social interaction deficits during an untreated later withdrawal. Locomotor deficits were significantly reversed only by the acute ethanol and diazepam treatment during the final withdrawal. Conclusions Single-dose administration of drugs that enhance or diminish activity at benzodiazepine–γ-aminobutyric acid- receptors during earlier withdrawals reduced or potentiated, respectively, anxiety-like behavior during later, drug-free withdrawals. These results support the potential of the novel strategy of using prophylactic therapy administered during early withdrawals to ameliorate symptoms of later withdrawals. PMID:15834220

Modulation of ethanol withdrawal-induced anxiety-like behavior during later withdrawals by treatment of early withdrawals with benzodiazepine/gamma-aminobutyric acid ligands.

PubMed

Knapp, Darin J; Overstreet, David H; Breese, George R

2005-04-01

Anxiety states, including those arising during acute or protracted withdrawal periods, may be precipitating factors in alcoholic relapse. Given the cyclical nature of ethanol withdrawal associated with repeated cycles of ethanol intake and abstinence in a pattern that often spans years, meaningful attempts to model ethanol withdrawal-associated anxiety should incorporate cycled ethanol treatments. The studies reported herein examined the effects of gamma-aminobutyric acid-modulating drugs on social interaction behavior-an established model of anxiety-in rats exposed to repeated cycles of ethanol treatment and withdrawal. Rats were exposed to 8 to 12 g/kg/day ethanol during three 7-day dietary cycles (5 days on ethanol diet followed by 2 days on control diet). Ethanol was administered either at hour 4 of withdrawal after cessation of each of the first 2 ethanol cycles or during the final withdrawal only. In other groups, the early withdrawals were treated with alphaxalone, diazepam, PK11159, or flumazenil to block anxiety-like behavior during an untreated later (third) withdrawal. The benzodiazepine inverse agonist DMCM (methyl-6, 7-dymerhoxy-4-ethyl-beta-carboline-3-carboxylate) was also given repeatedly to determine whether it would sensitize anxiety-like behavior during a future withdrawal. Finally, the effects of all drugs on deficits in locomotor behavior were assessed. Pretreatment of earlier withdrawals with alphaxalone, diazepam, ethanol, or flumazenil reduced social interaction deficits during a later withdrawal, but pretreatment with PK11195 did not. In contrast, DMCM administered in lieu of early withdrawals increased social interaction deficits during an untreated later withdrawal. Locomotor deficits were significantly reversed only by the acute ethanol and diazepam treatment during the final withdrawal. Single-dose administration of drugs that enhance or diminish activity at benzodiazepine-gamma-aminobutyric acid- receptors during earlier withdrawals reduced or potentiated, respectively, anxiety-like behavior during later, drug-free withdrawals. These results support the potential of the novel strategy of using prophylactic therapy administered during early withdrawals to ameliorate symptoms of later withdrawals.

Attenuation of ethanol abstinence-induced anxiety- and depressive-like behavior by the phosphodiesterase-4 inhibitor rolipram in rodents.

PubMed

Gong, Mei-Fang; Wen, Rui-Ting; Xu, Ying; Pan, Jian-Chun; Fei, Ning; Zhou, Yan-Meng; Xu, Jiang-Ping; Liang, Jian-Hui; Zhang, Han-Ting

2017-10-01

Withdrawal symptoms stand as a core feature of alcohol dependence. Our previous results have shown that inhibition of phosphodiesterase-4 (PDE4) decreased ethanol seeking and drinking in alcohol-preferring rodents. However, little is known about whether PDE4 is involved in ethanol abstinence-related behavior. The objective of this study was to characterize the role of PDE4 in the development of anxiety- and depressive-like behavior induced by abstinence from ethanol exposure in different animal models. Using three rodent models of ethanol abstinence, we examined the effects of rolipram, a prototypical, selective PDE4 inhibitor, on (1) anxiety-like behavior induced by repeated ethanol abstinence in the elevated plus maze test in fawn-hooded (FH/Wjd) rats, (2) anxiety-like behavior in the open-field test and light-dark transition test following acute ethanol abstinence in C57BL/6J mice, and (3) anxiety- and depressive-like behavior induced by protracted ethanol abstinence in the elevated plus maze, forced-swim, and tail-suspension tests in C57BL/6J mice. Pretreatment with rolipram (0.1 or 0.2 mg/kg) significantly increased entries and time spent in the open arms of the elevated plus maze test in rats with repeated ethanol abstinence. Similarly, in mice with acute ethanol abstinence, administration of rolipram (0.25 or 0.5 mg/kg) dose-dependently increased the crossings in the central zone of the open-field test and duration and transitions on the light side of the light-dark transition test, suggesting anxiolytic-like effects of rolipram. Consistent with these, chronic treatment with rolipram (0.1, 0.3, or 1.0 mg/kg) increased entries in the open arms of the elevated plus maze test; it also reduced the increased duration of immobility in both the forced-swim and tail-suspension tests in mice after protracted ethanol abstinence, suggesting antidepressant-like effects of rolipram. These results provide the first demonstration for that PDE4 plays a role in modulating the development of negative emotional reactions associated with ethanol abstinence, including anxiety and depression. PDE4 inhibitors may be a novel class of drugs for treatment of alcoholism.

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

PubMed Central

Cruz, Maureen T; Herman, Melissa A; Cote, Dawn M; Ryabinin, Andrey E; Roberto, Marisa

2013-01-01

The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists 𝒟-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. 𝒟-Lys3-GHRP-6 and JMV 3002 also blocked ghrelin-induced increases in GABAergic responses. Furthermore, 𝒟-Lys3-GHRP-6 did not affect ethanol-induced increases in IPSP amplitude. These studies implicate a potential role for the ghrelin system in regulating GABAergic transmission and a complex interaction with ethanol at CeA GABAergic synapses. PMID:22968812

An assay for evoked locomotor behavior in Drosophila reveals a role for integrins in ethanol sensitivity and rapid ethanol tolerance.

PubMed

Bhandari, Poonam; Kendler, Kenneth S; Bettinger, Jill C; Davies, Andrew G; Grotewiel, Mike

2009-10-01

Ethanol induces similar behavioral responses in mammals and the fruit fly, Drosophila melanogaster. By coupling assays for ethanol-related behavior to the genetic tools available in flies, a number of genes have been identified that influence physiological responses to ethanol. To enhance the utility of the Drosophila model for investigating genes involved in ethanol-related behavior, we explored the value of an assay that measures the sedative effects of ethanol on negative geotaxis, an evoked locomotor response. We established eRING (ethanol Rapid Iterative Negative Geotaxis) as an assay for quantitating the sedative effects of ethanol on negative geotaxis (i.e., startle-induced climbing). We validated the assay by assessing acute sensitivity to ethanol and rapid ethanol tolerance in several different control strains and in flies with mutations known to disrupt these behaviors. We also used eRING in a candidate screen to identify mutants with altered ethanol-related behaviors. Negative geotaxis measured in eRING assays was dose-dependently impaired by ethanol exposure. Flies developed tolerance to the intoxicating effects of ethanol when tested during a second exposure. Ethanol sensitivity and rapid ethanol tolerance varied across 4 control strains, but internal ethanol concentrations were indistinguishable in the 4 strains during a first and second challenge with ethanol. Ethanol sensitivity and rapid ethanol tolerance, respectively, were altered in flies with mutations in amnesiac and hangover, genes known to influence these traits. Additionally, mutations in the beta integrin gene myospheroid and the alpha integrin gene scab increased the initial sensitivity to ethanol and enhanced the development of rapid ethanol tolerance without altering internal ethanol concentrations. The eRING assay is suitable for investigating genetic mechanisms that influence ethanol sensitivity and rapid ethanol tolerance. Ethanol sensitivity and rapid ethanol tolerance depend on the function of alpha and beta integrins in flies.

Positive relationship between dietary fat, ethanol intake, triglycerides, and hypothalamic peptides: counteraction by lipid-lowering drugs.

PubMed

Barson, Jessica R; Karatayev, Olga; Chang, Guo-Qing; Johnson, Deanne F; Bocarsly, Miriam E; Hoebel, Bartley G; Leibowitz, Sarah F

2009-09-01

Studies in both humans and animals suggest a positive relationship between the intake of ethanol and intake of fat, which may contribute to alcohol abuse. This relationship may be mediated, in part, by hypothalamic orexigenic peptides such as orexin (OX), which stimulate both consumption of ethanol and fat, and circulating triglycerides (TGs), which stimulate these peptides and promote consummatory behavior. The present study investigated this vicious cycle between ethanol and fat, to further characterize its relation to TGs and to test the effects of lowering TG levels. In Experiment 1, the behavioral relationship between fat intake and ethanol was confirmed. Adult male Sprague-Dawley rats, chronically injected intraperitoneally with ethanol (1g/kg) and tested in terms of their preference for a high-fat diet (HFD) compared with low-fat diet (LFD), showed a significant increase in their fat preference, compared with rats injected with saline, in measures of 2h and 24h intake. Experiment 2 tested the relationship of circulating TGs in this positive association between ethanol and fat, in rats chronically consuming 9% ethanol versus water and given acute meal tests (25kcal) of a HFD versus LFD. Levels of TGs were elevated in response to both chronic drinking of ethanol versus water and acute eating of a high-fat versus low-fat meal. Most importantly, ethanol and a HFD showed an interaction effect, whereby their combination produced a considerably larger increase in TG levels (+172%) compared to ethanol with a LFD (+111%). In Experiment 3, a direct manipulation of TG levels was found to affect ethanol intake. After intragastric administration of gemfibrozil (50mg/kg) compared with vehicle, TG levels were lowered by 37%, and ethanol intake was significantly reduced. In Experiment 4, the TG-lowering drug gemfibrozil also caused a significant reduction in the expression of the orexigenic peptide, OX, in the perifornical lateral hypothalamus. These results support the existence of a vicious cycle between ethanol and fat, whereby each nutrient stimulates intake of the other. Within this vicious cycle, ethanol and fat act synergistically to increase TG levels, which in turn stimulate peptides that promote further consumption, and these phenomena are reversed by gemfibrozil, which lowers TG levels.

Positive relationship between dietary fat, ethanol intake, triglycerides and hypothalamic peptides: Counteraction by lipid-lowering drugs

PubMed Central

Barson, Jessica R.; Karatayev, Olga; Chang, Guo-Qing; Johnson, Deanne F.; Bocarsly, Miriam E.; Hoebel, Bartley G.; Leibowitz, Sarah F.

2009-01-01

Studies in both humans and animals suggest a positive relationship between the intake of ethanol and intake of fat, which may contribute to alcohol abuse. This relationship may be mediated, in part, by hypothalamic orexigenic peptides such as orexin (OX), which stimulate both consumption of ethanol and fat, and circulating triglycerides (TG), which stimulate these peptides and promote consummatory behavior. The present study investigated this vicious cycle between ethanol and fat, to further characterize its relation to TG and to test the effects of lowering TG levels. In Experiment 1, the behavioral relationship between fat intake and ethanol was confirmed. Adult male Sprague-Dawley rats, chronically injected with ethanol (1 g/kg i.p.) and tested in terms of their preference for a high-fat compared to low-fat diet, showed a significant increase in their fat preference, compared to rats injected with saline, in measures of 2 h and 24 h intake. Experiment 2 tested the relationship of circulating TG in this positive association between ethanol and fat, in rats chronically consuming 9% ethanol vs. water and given acute meal tests (25 kcal) of a high-fat vs. low-fat diet. Levels of TG were elevated in response to both chronic drinking of ethanol vs. water and acute eating of a high-fat vs. low-fat meal. Most importantly, ethanol and a high-fat diet showed an interaction effect, whereby their combination produced a considerably larger increase in TG levels (+172%) compared to ethanol with a low-fat diet (+111%). In Experiment 3, a direct manipulation of TG levels was found to affect ethanol intake. After administration of gemfibrozil (50 mg/kg i.g.) compared to vehicle, TG levels were lowered by 37%, and ethanol intake was significantly reduced. In Experiment 4, the TG-lowering drug gemfibrozil also caused a significant reduction in the expression of the orexigenic peptide OX, in the perifornical lateral hypothalamus. These results support the existence of a vicious cycle between ethanol and fat whereby each nutrient stimulates intake of the other. Within this vicious cycle, ethanol and fat act synergistically to increase TG levels, which in turn stimulate peptides that promote further consumption, and these phenomena are reversed by gemfibrozil, which lowers TG levels. PMID:19801273

[Effect of flavonoids of ginkgo biloba on anti-oxidizing system of mice after acute alcohol administration].

PubMed

Yao, Ping; Liu, Lie-Gang; Jia, Wen-Bo; Song, Fang-Fang; Zhou, Shaoliang; Zhang, Xiping; Sun, Xiufa

2005-05-01

To investigate the protective effects of flavonoids of ginkgo biloba on anti-oxidizing system damaged by acute alcohol administration. Adult male Kunming mice were employed and divided into randomly flavonoid intervention group, normal control and ethanol control group according to body weight. After pretreated with flavonoids of ginkgo biloba (96mg/kg bw), the mice in flavonoid intervention group ingested alcohol (ethanol 4.8g/kg bw) via i.g. and were decapitated after 0.5, 1, 2, 4, 6, 9, and 15 h of ethanol administration. The same treatment was carried out on ethanol control group except that physiological saline was applied instead of flavonoid of ginkgo biloba. Meanwhile, the normal control group was established. The concentration of glutathione (GSH), malondialdehyde (MDA) and the activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) in the serum and liver were determined. The experiment displays that the content of GSH and the activities of GSH-Px and SOD decreased rapidly after 1 h of treatment with alcohol and dropped to the lowest level at 4h of treatment. After 6h of treatment, these indexes came to the normal level rapidly. The level of MDA of serum and liver increased rapidly after 1 h of treatment and reached the climax at 4h and 6h respectively. It went back to the normal concentration until 15h and 9 h respectively. On a whole, there were similar curves between flavonoids intervention group and alcohol control group on the indexes. However, to some extent, the supplement of flavonoid of ginkgo biloba can prohibit the rise of MDA level and the decline of GSH-Px, SOD, GSH which were induced by acute alcohol intakes. Flavonoid of ginkgo biloba have some protective effects on the damage of anti-oxidizing system of mice induced by acute alcohol adminstration.

Ethanol-Sensitive Pacemaker Neurons in the Mouse External Globus Pallidus

PubMed Central

Abrahao, Karina P; Chancey, Jessica H; Chan, C Savio; Lovinger, David M

2017-01-01

Although ethanol is one of the most widely used drugs, we still lack a full understanding of which neuronal subtypes are affected by this drug. Pacemaker neurons exert powerful control over brain circuit function, but little is known about ethanol effects on these types of neurons. Neurons in the external globus pallidus (GPe) generate pacemaker activity that controls basal ganglia, circuitry associated with habitual and compulsive drug use. We performed patch-clamp recordings from GPe neurons and found that bath application of ethanol dose-dependently decreased the firing rate of low-frequency GPe neurons, but did not alter the firing of high-frequency neurons. GABA or glutamate receptor antagonists did not block the ethanol effect. The GPe is comprised of a heterogeneous population of neurons. We used Lhx6-EGFP and Npas1-tdTm mice strains to identify low-frequency neurons. Lhx6 and Npas1 neurons exhibited decreased firing with ethanol, but only Npas1 neurons were sensitive to 10 mM ethanol. Large-conductance voltage and Ca2+-activated K+ (BK) channel have a key role in the ethanol effect on GPe neurons, as the application of BK channel inhibitors blocked the ethanol-induced firing decrease. Ethanol also increased BK channel open probability measured in single-channel recordings from Npas1-tdTm neurons. In addition, in vivo electrophysiological recordings from GPe showed that ethanol decreased the firing of a large subset of low-frequency neurons. These findings indicate how selectivity of ethanol effects on pacemaker neurons can occur, and enhance our understanding of the mechanisms contributing to acute ethanol effects on the basal ganglia. PMID:27827370

Sex Differences in Acute Ethanol Withdrawal Severity After Adrenalectomy and Gonadectomy in WSP and WSR Mice

PubMed Central

Strong, Moriah N.; Kaufman, Katherine R.; Crabbe, John C.; Finn, Deborah A.

2009-01-01

Recent findings suggest that the ability of ethanol (EtOH) to increase the levels of neurosteroids with potent γ-aminobutyric acid (GABA)ergic properties can influence measures of EtOH sensitivity. Earlier studies determined that removal of the adrenals and gonads diminished the steroidogenic effect of EtOH and significantly increased acute EtOH withdrawal severity in two inbred mouse strains that differed in withdrawal severity, suggesting the contribution of anticonvulsant GABAergic steroids to acute withdrawal in intact animals. Thus, the goal of the present studies was to investigate the consequence of steroid removal on acute EtOH withdrawal through excision of the adrenals and gonads, in another genetic animal model of EtOH withdrawal differences, the Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) selected lines. Male and female WSP and WSR mice underwent surgical removal of the adrenals and gonads or no organ removal (SHAM). One to two weeks later, baseline handling-induced convulsions (HICs) were assessed, mice were given a 4 g/kg dose of ethanol, and HICs were measured hourly for 12 hours and then at 24 hours. The combination surgery significantly increased EtOH withdrawal in WSP and WSR female mice, as measured by area under the curve (AUC) and peak HIC scores. AUC was significantly positively correlated with plasma corticosterone levels and significantly negatively correlated with progesterone levels. In contrast, surgical status did not alter withdrawal severity in male WSP and WSR mice. Overall, the increase in acute ethanol withdrawal severity in female WSP and WSR mice following adrenalectomy and gonadectomy corroborate our recent evidence that withdrawal from a high dose of EtOH can be modulated by anticonvulsant steroids produced in the periphery. PMID:19671463

The acute effects of ethanol on acetanilide disposition in normal subjects, and in patients with liver disease.

PubMed Central

McKay, J; Rawlings, M D; Cobden, I; James, O F

1982-01-01

1 The effects of single doses (25 g and 50 g) oral ethanol on the disposition of acetanilide (50 mg/kg metabolic active mass) has been studied in normal subjects, and in patients with chronic non-alcoholic liver disease. 2 In normal subjects, ethanol produced a dose-dependent increase in acetanilide half-life, and a decrease in acetenilide clearance. There was a significant correlation (rs = 0.71, P less than 0.01) between the 90 min blood ethanol concentration and the reduction in acetanilide clearance. 3 In patients with liver disease, ethanol produced a similar proportional change in acetanilide half-life and clearance, but these were less consistent. Moreover, liver disease itself was associated with an increase in acetenilide half-life, and a reduction in clearance. 4 It is concluded that single oral doses of ethanol, comparable to those consumed during social drinking, may inhibit some forms of microsomal oxidation and thus have important clinical implications. PMID:7138735

The acute effects of ethanol on acetanilide disposition in normal subjects, and in patients with liver disease.

PubMed

McKay, J; Rawlings, M D; Cobden, I; James, O F

1982-10-01

1 The effects of single doses (25 g and 50 g) oral ethanol on the disposition of acetanilide (50 mg/kg metabolic active mass) has been studied in normal subjects, and in patients with chronic non-alcoholic liver disease. 2 In normal subjects, ethanol produced a dose-dependent increase in acetanilide half-life, and a decrease in acetenilide clearance. There was a significant correlation (rs = 0.71, P less than 0.01) between the 90 min blood ethanol concentration and the reduction in acetanilide clearance. 3 In patients with liver disease, ethanol produced a similar proportional change in acetanilide half-life and clearance, but these were less consistent. Moreover, liver disease itself was associated with an increase in acetenilide half-life, and a reduction in clearance. 4 It is concluded that single oral doses of ethanol, comparable to those consumed during social drinking, may inhibit some forms of microsomal oxidation and thus have important clinical implications.

Quantification of ethanol in plasma by electrochemical detection with an unmodified screen printed carbon electrode

NASA Astrophysics Data System (ADS)

Tian, Gang; Zhang, Xiao-Qing; Zhu, Ming-Song; Zhang, Zhong; Shi, Zheng-Hu; Ding, Min

2016-03-01

Simple, rapid and accurate detection of ethanol concentration in blood is very crucial in the diagnosis and management of potential acute ethanol intoxication patients. A novel electrochemical detection method was developed for the quantification of ethanol in human plasma with disposable unmodified screen-printed carbon electrode (SPCE) without sample preparation procedure. Ethanol was detected indirectly by the reaction product of ethanol dehydrogenase (ADH) and cofactor nicotinamide adenine dinucleotide (NAD+). Method validation indicated good quantitation precisions with intra-day and inter-day relative standard deviations of ≤9.4% and 8.0%, respectively. Ethanol concentration in plasma is linear ranging from 0.10 to 3.20 mg/mL, and the detection limit is 40.0 μg/mL (S/N > 3). The method shows satisfactory correlation with the reference method of headspace gas chromatography in twenty human plasma samples (correlation coefficient 0.9311). The proposed method could be applied to diagnose acute ethanol toxicity or ethanol-related death.

Quantification of ethanol in plasma by electrochemical detection with an unmodified screen printed carbon electrode

PubMed Central

Tian, Gang; Zhang, Xiao-Qing; Zhu, Ming-Song; Zhang, Zhong; Shi, Zheng-Hu; Ding, Min

2016-01-01

Simple, rapid and accurate detection of ethanol concentration in blood is very crucial in the diagnosis and management of potential acute ethanol intoxication patients. A novel electrochemical detection method was developed for the quantification of ethanol in human plasma with disposable unmodified screen-printed carbon electrode (SPCE) without sample preparation procedure. Ethanol was detected indirectly by the reaction product of ethanol dehydrogenase (ADH) and cofactor nicotinamide adenine dinucleotide (NAD+). Method validation indicated good quantitation precisions with intra-day and inter-day relative standard deviations of ≤9.4% and 8.0%, respectively. Ethanol concentration in plasma is linear ranging from 0.10 to 3.20 mg/mL, and the detection limit is 40.0 μg/mL (S/N > 3). The method shows satisfactory correlation with the reference method of headspace gas chromatography in twenty human plasma samples (correlation coefficient 0.9311). The proposed method could be applied to diagnose acute ethanol toxicity or ethanol-related death. PMID:27006081

A case of methylene chloride poisoning due to ingestion of home-distilled alcohol and potential new treatment with ethanol infusion.

PubMed

Vetro, Joseph; Koutsogiannis, Zeff; Jones, Daryl A; Canestra, Jane

2012-03-01

We describe a case of a 51-year-old man who ingested methylene chloride and presented with the classical clinical features. He developed an acute abdomen that required repeated laparotomy. The effect of an ethanol infusion on carboxyhaemoglobin concentrations in this case was also of interest and could potentially be a new treatment modality.

Acute Ethanol Has Biphasic Effects on Short- and Long-Term Memory in Both Foreground and Background Contextual Fear Conditioning in C57BL/6 Mice

PubMed Central

Gulick, Danielle; Gould, Thomas J.

2009-01-01

Background Ethanol is a frequently abused, addictive drug that impairs cognitive function. Ethanol may disrupt cognitive processes by altering attention, short-term memory, and/ or long-term memory. Interestingly, some research suggests that ethanol may enhance cognitive processes at lower doses. The current research examined the dose-dependent effects of ethanol on contextual and cued fear conditioning. In addition, the present studies assessed the importance of stimulus salience in the effects of ethanol and directly compared the effects of ethanol on short-term and long-term memory. Methods This study employed both foreground and background fear conditioning, which differ in the salience of contextual stimuli, and tested conditioning at 4 hours, 24 hours, and 1 week in order to assess the effects of ethanol on short-term and long-term memory. Foreground conditioning consisted of 2 presentations of a foot shock unconditioned stimulus (US) (2 seconds, 0.57 mA). Background conditioning consisted of 2 auditory conditioned stimulus (30 seconds, 85 dB white noise)–foot shock (US; 2 seconds, 0.57 mA) pairings. Results For both foreground and background conditioning, ethanol enhanced short-term and long-term memory for contextual and cued conditioning at a low dose (0.25 g/kg) and impaired short-term and long-term memory for contextual and cued conditioning at a high dose (1.0 g/kg). Conclusions These results suggest that ethanol has long-lasting, biphasic effects on short-term and long-term memory for contextual and cued conditioning. Furthermore, the effects of ethanol on contextual fear conditioning are independent of the salience of the context. PMID:17760787

Differential Sensitivity to Ethanol-Induced Circadian Rhythm Disruption in Adolescent and Adult Mice

PubMed Central

Ruby, Christina L.; Palmer, Kaitlyn N.; Zhang, Jiawen; Risinger, Megan O.; Butkowski, Melissa A.; Swartzwelder, H. Scott

2016-01-01

Background Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether ethanol has similar effects on circadian regulation during adolescence. Methods General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12 h light, 12 h dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of ethanol (1.5 g/kg, i.p.) or equal volume saline 15 min prior to a 30-min light pulse at Zeitgeber Time 14 (2 h into the dark phase), then were released into constant darkness (DD) for ~2 weeks to assess phase-resetting responses. Control mice of each age group received injections but no light pulse prior to DD. Results While adults showed the expected decrease in photic phase-delays induced by acute ethanol, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude. Conclusions Collectively, our results indicate that adolescent mice are less sensitive to the effect of ethanol on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults. PMID:27997028

Hydroethanolic extract of Baccharis trimera promotes gastroprotection and healing of acute and chronic gastric ulcers induced by ethanol and acetic acid.

PubMed

Dos Reis Lívero, Francislaine Aparecida; da Silva, Luisa Mota; Ferreira, Daniele Maria; Galuppo, Larissa Favaretto; Borato, Debora Gasparin; Prando, Thiago Bruno Lima; Lourenço, Emerson Luiz Botelho; Strapasson, Regiane Lauriano Batista; Stefanello, Maria Élida Alves; Werner, Maria Fernanda de Paula; Acco, Alexandra

2016-09-01

Ethanol is a psychoactive substance highly consumed around the world whose health problems include gastric lesions. Baccharis trimera is used in folk medicine for the treatment of gastrointestinal disorders. However, few studies have evaluated its biological and toxic effects. To validate the popular use of B. trimera and elucidate its possible antiulcerogenic and cytotoxic mechanisms, a hydroethanolic extract of B. trimera (HEBT) was evaluated in models of gastric lesions. Rats and mice were used to evaluate the protective and antiulcerogenic effects of HEBT on gastric lesions induced by ethanol, acetic acid, and chronic ethanol consumption. The effects of HEBT were also evaluated in a pylorus ligature model and on gastrointestinal motility. The LD50 of HEBT in mice was additionally estimated. HEBT was analyzed by nuclear magnetic resonance, and a high-performance liquid chromatography fingerprint analysis was performed. Oral HEBT administration significantly reduced the lesion area and the oxidative stress induced by acute and chronic ethanol consumption. However, HEBT did not protect against gastric wall mucus depletion and did not alter gastric secretory volume, pH, or total acidity in the pylorus ligature model. Histologically, HEBT accelerated the healing of chronic gastric ulcers in rats, reflected by contractions of the ulcer base. Flavonoids and caffeoylquinic acids were detected in HEBT, which likely contributed to the therapeutic efficacy of HEBT, preventing or reversing ethanol- and acetic acid-induced ulcers, respectively. HEBT antiulcerogenic activity may be partially attributable to the inhibition of free radical generation and subsequent prevention of lipid peroxidation. Our results indicate that HEBT has both gastroprotective and curative activity in animal models, with no toxicity.

Effects of ethanol on social avoidance induced by chronic social defeat stress in mice.

PubMed

Favoretto, Cristiane A; Macedo, Giovana C; Quadros, Isabel M H

2017-01-01

In rodents, chronic social defeat stress promotes deficits in social interest and social interaction. We further explored these antisocial effects by comparing the consequences of two different defeat stress protocols (episodic vs. continuous stress) in a social investigation test. We expected that continuous, but not episodic, stress would induce social deficits in this model. Furthermore, we tested whether a potentially anxiolytic dose of ethanol reverses social deficits induced by defeat stress. Male Swiss mice were exposed to a 10-day social defeat protocol, using daily confrontations with an aggressive resident mouse. Episodic stress consisted of brief defeat episodes, after which the defeated mouse was returned to its home cage, until the next defeat 24 h later (n = 7-11/group). For continuous stress, similar defeat episodes were followed by cohabitation with the aggressive resident for 24 h, separated by a perforated divider, until the following defeat (n = 8-14/group). Eight days after stress termination, defeated and control mice were assessed in a social investigation test, after treatment with ethanol (1.0 g/kg, i.p.) or 0.9% saline. Considering the time spent investigating a social target, mice exposed to episodic or continuous social stress showed less social investigation than controls (p < .05). Deficits in social interest were not reversed by acute ethanol treatment. However, ethanol reduced time spent in social interaction in one control group (p < .05). Locomotor activity was not affected by social stress or ethanol. Thus, a history of social defeat stress, whether episodic or continuous, promotes deficits in social investigation that were not reversed by acute treatment with ethanol.

Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis.

PubMed

Zhou, Richard; Lin, Jianjun; Wu, Defeng

2014-01-01

The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase-1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol-induced fatty liver in mice. The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study. © 2013.

The acute effects of MDMA and ethanol administration on electrophysiological correlates of performance monitoring in healthy volunteers.

PubMed

Spronk, D B; Dumont, G J H; Verkes, R J; De Bruijn, E R A

2014-07-01

Knowing how commonly used drugs affect performance monitoring is of great importance, because drug use is often associated with compromised behavioral control. Two of the most commonly used recreational drugs in the western world, 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and ethanol (alcohol), are also often used in combination. The error-related negativity (ERN), correct-related negativity (CRN), and N2 are electrophysiological indices of performance monitoring. The present study aimed to investigate how ethanol, MDMA, and their co-administration affect performance monitoring as indexed by the electrophysiological correlates. Behavioral and EEG data were obtained from 14 healthy volunteers during execution of a speeded choice-reaction-time task after administration of ethanol, MDMA, and combined ethanol and MDMA, in a double-blind, placebo-controlled, randomized crossover design. Ethanol significantly reduced ERN amplitudes, while administration of MDMA did not affect the ERN. Co-administration of MDMA and ethanol did not further impair nor ameliorate the effect of ethanol alone. No drug effects on CRN nor N2 were observed. A decreased ERN following ethanol administration is in line with previous work and offers further support for the impairing effects of alcohol intoxication on performance monitoring. This impairment may underlie maladaptive behavior in people who are under influence. Moreover, these data demonstrate for the first time that MDMA does not affect performance monitoring nor does it interact with ethanol in this process. These findings corroborate the notion that MDMA leaves central executive functions relatively unaffected.

Ethanol-induced dopamine elevation in the rat--modulatory effects by subchronic treatment with nicotinic drugs.

PubMed

Löf, Elin; Chau, Pei Pei; Stomberg, Rosita; Söderpalm, Bo

2007-01-26

Chronic nicotine administration is associated with increased ethanol consumption in laboratory animals and in humans. Some smokers report less sedation during acute ethanol intoxication after nicotine administration and the sedative effects from ethanol are mediated by inhibitory GABA(A)-receptors. In a series of in vivo microdialysis experiments we investigated whether subchronic pre-treatment with nicotinic drugs known to enhance ethanol consumption in the rat (nicotine or the peripheral nicotinic antagonist hexamethonium) could modulate the alterations in extracellular dopamine observed in response to administration of ethanol or the sedative GABA(A)-agonist diazepam. In the nucleus accumbens and the dorsal striatum, systemic and/or local ethanol administration resulted in transient increases in extracellular dopamine levels that returned to baseline before the local levels of ethanol started to decline. In hexamethonium pre-treated rats, however, the nucleus accumbens dopamine levels were time-locked to the ethanol levels in the same area after systemic or local ethanol administration. Perfusion of diazepam into the nucleus accumbens produced a significant reduction in nucleus accumbens dopamine in controls. Prior subchronic treatment with nicotine or hexamethonium abolished this effect. The present results suggest that subchronic treatment with the nicotinic acetylcholine receptor antagonist hexamethonium reduces a GABA(A)-R mediated counteraction of the nucleus accumbens dopamine response to ethanol. Additionally, we demonstrate that modulation of nicotinic receptors may reduce the sensitivity of GABA(A) receptors to benzodiazepines. These phenomena may offer a novel explanation to why nicotine and alcohol are often co-abused.

Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons

PubMed Central

Roberto, Marisa; Madamba, Samuel G.; Moore, Scott D.; Tallent, Melanie K.; Siggins, George R.

2003-01-01

We examined the interaction of ethanol with the γ-aminobutyric acid (GABA)ergic system in neurons of slices of the rat central amygdala nucleus (CeA), a brain region thought to be critical for the reinforcing effects of ethanol. Brief superfusion of 11–66 mM ethanol significantly increased GABA type A (GABAA) receptor-mediated inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in most CeA neurons, with a low apparent EC50 of 20 mM. Acute superfusion of 44 mM ethanol increased the amplitude of evoked GABAA IPSPs and IPSCs in 70% of CeA neurons. The ethanol enhancement of IPSPs and IPSCs occurred to a similar extent in the presence of the GABA type B (GABAB) receptor antagonist CGP 55845A, suggesting that this receptor is not involved in the ethanol effect on CeA neurons. Ethanol superfusion also decreased paired-pulse facilitation of evoked GABAA IPSPs and IPSCs and always increased the frequency and sometimes the amplitude of spontaneous miniature GABAA IPSCs as well as responses to local GABA application, indicating both presynaptic and postsynaptic sites of action for ethanol. Thus, the CeA is the first brain region to reveal, without conditional treatments such as GABAB antagonists, consistent, low-dose ethanol enhancement of GABAergic transmission at both pre- and postsynaptic sites. These findings add further support to the contention that the ethanol–GABA interaction in CeA plays an important role in the reinforcing effects of ethanol. PMID:12566570

GM1 ganglioside reduces the motor incoordination and loss of righting reflex caused by acute ethanol in C57BL/6J mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wallis, C.; Rezazadeh, S.M.; Forster, M.J.

1992-02-26

Ethanol produces its intoxicating effects by modifying neuronal membranes. Gangliosides stabilize neuronal membranes and promote their recovery from a variety of insults. In this experiment, the efficacy of GM1(i.p.) to reverse ethanol intoxication was evaluated in male mice trained to run on a constantly accelerating rotorod. When mice were tested 15-min following saline or ethanol GM1 pre-treatment reduced rotorod performance by 15% but was ineffective in modifying the ethanol-impaired performance. However, when mice were tested at 15, 35, 55, 75, and 95 min intervals following ethanol, GM1 pre-treatments dose-dependently reduced the efficacy and duration of ethanol in producing motor incoordination.more » Further, GM1 given prior to ethanol significantly prolonged the time to onset of the loss of righting reflex from 1.4 to 1.9 min, and reduced the duration of the righting-reflex loss from 94 to 77 min. This GM1 effect was seen at 24 h, but not at 48 or 72 h after its administration. The blood ethanol concentration at awakening was significantly higher in 24h GM1-treated animals than in controls suggesting that the GM1 effect was not due to an alteration in ethanol clearance. These findings support the hypothesis that GM1 promotes recovery from ethanol intoxication via a neuroprotective mechanism.« less

Differential sensitivity of ethanol-elicited ERK phosphorylation in nucleus accumbens of Sardinian alcohol-preferring and -non preferring rats.

PubMed

Rosas, Michela; Zaru, Alessandro; Sabariego, Marta; Giugliano, Valentina; Carboni, Ezio; Colombo, Giancarlo; Acquas, Elio

2014-08-01

Sardinian alcohol-preferring (sP) and -non preferring (sNP) rats have been selectively bred for opposite ethanol preference and consumption; sP rats represent a validated experimental tool to model several aspects of excessive ethanol drinking in humans. Phosphorylated Extracellular signal-Regulated Kinase (pERK) in dopamine-rich terminal areas plays a critical role in several psychopharmacological effects of addictive drugs, including ethanol. This study was aimed at investigating whether ethanol-elicited ERK activation may differ in key brain areas of ethanol-naïve sP and sNP rats. To this end, the effects of ethanol (0, 0.5, 1, and 2 g/kg, administered intra-gastrically [i.g.]) on ERK phosphorylation were assessed by pERK immunohistochemistry in the shell (AcbSh) and core (AcbC) of the nucleus accumbens (Acb) as well as in the prelimbic (PrL) and infralimbic (IL) prefrontal cortex (PFCx), in the bed nucleus of stria terminalis (BSTL) and in the central nucleus of the amygdala (CeA). Ethanol (1 g/kg) significantly increased pERK immunoreactivity in AcbSh and AcbC of sP but not sNP rats. Conversely, ethanol failed to affect pERK expression in PrL and IL PFCx as well as in BSTL and CeA of both sP and sNP rats. These results suggest that selective breeding of these rat lines results in differential effects of acute ethanol on ERK phosphorylation in brain regions critical for the psychopharmacological effects of ethanol. Copyright © 2014 Elsevier Inc. All rights reserved.

An overview of exposure to ethanol-containing substances and ethanol intoxication in children based on three illustrated cases.

PubMed

Hon, Kam Lun; Leung, Alexander Kc; Cheung, Eddie; Lee, Bryan; Tsang, Michelle Mc; Torres, Alcy R

2018-01-01

Alcohol addiction and intoxication are major health problems worldwide. Acute alcohol intoxication is well reported in adults and adolescents but less frequently reported in children of younger ages. We report three anonymized cases of pediatric ethanol exposure and illustrate the different mechanisms of intoxication. In all cases, a focused history is the key to prompt diagnosis and timely management. Physicians should be aware of this potential poison in children presented with acute confusional or encephalopathic state. In contrast, neonates with ethanol intoxication may present with nonspecific gastrointestinal symptomatology. Urgent exclusion of sepsis, electrolyte imbalance, drug intoxication, and surgical abdominal condition is critical. Using these illustrated cases, we performed a narrative literature review on issues of exposure to ethanol-containing substances and ethanol intoxication in children. In conclusion, a high level of suspicion and interrogation on ethanol or substance use are essential particularly in the lactating mother for an accurate and timely diagnosis of ethanol intoxication to be made.

An overview of exposure to ethanol-containing substances and ethanol intoxication in children based on three illustrated cases

PubMed Central

Hon, Kam Lun; Leung, Alexander KC; Cheung, Eddie; Lee, Bryan; Tsang, Michelle MC; Torres, Alcy R

2018-01-01

Alcohol addiction and intoxication are major health problems worldwide. Acute alcohol intoxication is well reported in adults and adolescents but less frequently reported in children of younger ages. We report three anonymized cases of pediatric ethanol exposure and illustrate the different mechanisms of intoxication. In all cases, a focused history is the key to prompt diagnosis and timely management. Physicians should be aware of this potential poison in children presented with acute confusional or encephalopathic state. In contrast, neonates with ethanol intoxication may present with nonspecific gastrointestinal symptomatology. Urgent exclusion of sepsis, electrolyte imbalance, drug intoxication, and surgical abdominal condition is critical. Using these illustrated cases, we performed a narrative literature review on issues of exposure to ethanol-containing substances and ethanol intoxication in children. In conclusion, a high level of suspicion and interrogation on ethanol or substance use are essential particularly in the lactating mother for an accurate and timely diagnosis of ethanol intoxication to be made. PMID:29344053

Effects of Topical Anesthetics on Behavior, Plasma Corticosterone, and Blood Glucose Levels after Tail Biopsy of C57BL/6NHSD Mice (Mus musculus)

PubMed Central

Dudley, Emily S; Johnson, Robert A; French, DeAnne C; Boivin, Gregory P

2016-01-01

Tail biopsy is a common procedure that is performed to obtain genetic material for determining genotype of transgenic mice. The use of anesthetics or analgesics is recommended, although identifying safe and effective drugs for this purpose has been challenging. We evaluated the effects of topical 2.5% lidocaine–2.5% prilocaine cream applied to the distal tail tip at 5 or 60 min before biopsy, immersion of the tail tip for 10 seconds in ice-cold 70% ethanol just prior to biopsy, and immersion of the tail tip in 0.5% bupivacaine for 30 s after biopsy. Mice were 7, 11, or 15 d old at the time of tail biopsy. Acute behavioral responses, plasma corticosterone, and blood glucose were measured after biopsy, and body weight and performance in elevated plus maze and open-field tests after weaning. Ice-cold ethanol prior to biopsy prevented acute behavioral responses to biopsy, and both ice-cold ethanol and bupivacaine prevented elevations in corticosterone and blood glucose after biopsy. Tail biopsy with or without anesthesia did not affect body weight or performance on elevated plus maze or open-field tests. We recommend the use of ice-cold ethanol for topical anesthesia prior to tail biopsy in mice 7 to 15 d old. PMID:27423152

Effects of Topical Anesthetics on Behavior, Plasma Corticosterone, and Blood Glucose Levels after Tail Biopsy of C57BL/6NHSD Mice (Mus musculus).

PubMed

Dudley, Emily S; Johnson, Robert A; French, DeAnne C; Boivin, Gregory P

2016-01-01

Tail biopsy is a common procedure that is performed to obtain genetic material for determining genotype of transgenic mice. The use of anesthetics or analgesics is recommended, although identifying safe and effective drugs for this purpose has been challenging. We evaluated the effects of topical 2.5% lidocaine-2.5% prilocaine cream applied to the distal tail tip at 5 or 60 min before biopsy, immersion of the tail tip for 10 seconds in ice-cold 70% ethanol just prior to biopsy, and immersion of the tail tip in 0.5% bupivacaine for 30 s after biopsy. Mice were 7, 11, or 15 d old at the time of tail biopsy. Acute behavioral responses, plasma corticosterone, and blood glucose were measured after biopsy, and body weight and performance in elevated plus maze and open-field tests after weaning. Ice-cold ethanol prior to biopsy prevented acute behavioral responses to biopsy, and both ice-cold ethanol and bupivacaine prevented elevations in corticosterone and blood glucose after biopsy. Tail biopsy with or without anesthesia did not affect body weight or performance on elevated plus maze or open-field tests. We recommend the use of ice-cold ethanol for topical anesthesia prior to tail biopsy in mice 7 to 15 d old.

The novel gene tank, a tumor suppressor homolog, regulates ethanol sensitivity in Drosophila.

PubMed

Devineni, Anita V; Eddison, Mark; Heberlein, Ulrike

2013-05-08

In both mammalian and insect models of ethanol intoxication, high doses of ethanol induce motor impairment and eventually sedation. Sensitivity to the sedative effects of ethanol is inversely correlated with risk for alcoholism. However, the genes regulating ethanol sensitivity are largely unknown. Based on a previous genetic screen in Drosophila for ethanol sedation mutants, we identified a novel gene, tank (CG15626), the homolog of the mammalian tumor suppressor EI24/PIG8, which has a strong role in regulating ethanol sedation sensitivity. Genetic and behavioral analyses revealed that tank acts in the adult nervous system to promote ethanol sensitivity. We localized the function of tank in regulating ethanol sensitivity to neurons within the pars intercerebralis that have not been implicated previously in ethanol responses. We show that acutely manipulating the activity of all tank-expressing neurons, or of pars intercerebralis neurons in particular, alters ethanol sensitivity in a sexually dimorphic manner, since neuronal activation enhanced ethanol sedation in males, but not females. Finally, we provide anatomical evidence that tank-expressing neurons form likely synaptic connections with neurons expressing the neural sex determination factor fruitless (fru), which have been implicated recently in the regulation of ethanol sensitivity. We suggest that a functional interaction with fru neurons, many of which are sexually dimorphic, may account for the sex-specific effect induced by activating tank neurons. Overall, we have characterized a novel gene and corresponding set of neurons that regulate ethanol sensitivity in Drosophila.

The Novel Gene tank, a Tumor Suppressor Homolog, Regulates Ethanol Sensitivity in Drosophila

PubMed Central

Eddison, Mark; Heberlein, Ulrike

2013-01-01

In both mammalian and insect models of ethanol intoxication, high doses of ethanol induce motor impairment and eventually sedation. Sensitivity to the sedative effects of ethanol is inversely correlated with risk for alcoholism. However, the genes regulating ethanol sensitivity are largely unknown. Based on a previous genetic screen in Drosophila for ethanol sedation mutants, we identified a novel gene, tank (CG15626), the homolog of the mammalian tumor suppressor EI24/PIG8, which has a strong role in regulating ethanol sedation sensitivity. Genetic and behavioral analyses revealed that tank acts in the adult nervous system to promote ethanol sensitivity. We localized the function of tank in regulating ethanol sensitivity to neurons within the pars intercerebralis that have not been implicated previously in ethanol responses. We show that acutely manipulating the activity of all tank-expressing neurons, or of pars intercerebralis neurons in particular, alters ethanol sensitivity in a sexually dimorphic manner, since neuronal activation enhanced ethanol sedation in males, but not females. Finally, we provide anatomical evidence that tank-expressing neurons form likely synaptic connections with neurons expressing the neural sex determination factor fruitless (fru), which have been implicated recently in the regulation of ethanol sensitivity. We suggest that a functional interaction with fru neurons, many of which are sexually dimorphic, may account for the sex-specific effect induced by activating tank neurons. Overall, we have characterized a novel gene and corresponding set of neurons that regulate ethanol sensitivity in Drosophila. PMID:23658154

Ethanol exposure during the early first trimester equivalent impairs reflexive motor activity and heightens fearfulness in an avian model.

PubMed

Smith, Susan M; Flentke, George R; Kragtorp, Katherine A; Tessmer, Laura

2011-02-01

Prenatal alcohol exposure is a leading cause of childhood neurodevelopmental disability. The adverse behavioral effects of alcohol exposure during the second and third trimester are well documented; less clear is whether early first trimester-equivalent exposures also alter behavior. We investigated this question using an established chick model of alcohol exposure. In ovo embryos experienced a single, acute ethanol exposure that spanned gastrulation through neuroectoderm induction and early brain patterning (19-22h incubation). At 7 days posthatch, the chicks were evaluated for reflexive motor function (wingflap extension, righting reflex), fearfulness (tonic immobility [TI]), and fear/social reinstatement (open-field behavior). Chicks exposed to a peak ethanol level of 0.23-0.28% were compared against untreated and saline-treated controls. Birds receiving early ethanol exposure had a normal righting reflex and a significantly reduced wingflap extension in response to a sudden descent. The ethanol-treated chicks also displayed heightened fearfulness, reflected in increased frequency of TI, and they required significantly fewer trials for its induction. In an open-field test, ethanol treatment did not affect latency to move, steps taken, vocalizations, defecations, or escape attempts. The current findings demonstrate that early ethanol exposure can increase fearfulness and impair aspects of motor function. Importantly, the observed dysfunctions resulted from an acute ethanol exposure during the period when the major brain components are induced and patterned. The equivalent period in human development is 3-4 weeks postconception. The current findings emphasize that ethanol exposure during the early first trimester equivalent can produce neurodevelopmental disability in the offspring. Copyright © 2011 Elsevier Inc. All rights reserved.

Ethanol-nicotine interactions in long-sleep and short-sleep mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

de Fiebre, C.M.; Marks, M.J.; Collins, A.C.

The possibility that common genetic factors regulate initial sensitivities to ethanol and nicotine as well as the development of cross-tolerance between these agents was explored using the long-sleep (LS) and short-sleep (SS) mice. The LS mice proved to be more sensitive to an acute challenge with nicotine than were the SS mice. Segregation analysis (F1, F2, backcross) indicated that ethanol sensitivity and nicotine sensitivity segregate together. Acute pretreatment with nicotine did not significantly affect sensitivity to ethanol, but ethanol pretreatment altered nicotine responsiveness. The LS mice develop more tolerance to nicotine and ethanol than do the SS and they alsomore » develop more cross-tolerance. These genetically determined differences in initial sensitivities, and tolerance and cross-tolerance development are not readily explained by differences in brain nicotinic receptor numbers.« less

Evaluation of acute toxicity, genotoxicity and inhibitory effect on acute inflammation of an ethanol extract of Morus alba L. (Moraceae) in mice.

PubMed

Oliveira, Alisson Macário de; Nascimento, Matheus Ferreira do; Ferreira, Magda Rhayanny Assunção; Moura, Danielle Feijó de; Souza, Talita Giselly Dos Santos; Silva, Gabriela Cavalcante da; Ramos, Eduardo Henrique da Silva; Paiva, Patrícia Maria Guedes; Medeiros, Paloma Lys de; Silva, Teresinha Gonçalves da; Soares, Luiz Alberto Lira; Chagas, Cristiano Aparecido; Souza, Ivone Antônia de; Napoleão, Thiago Henrique

2016-12-24

Morus alba L. (white mulberry) is used in traditional medicine worldwide, including Brazil. The leaves of this plant are used to treat inflammatory disorders. Universal interest in this plant necessitates studies on the toxicological safety and scientific substantiation of the medicinal properties of M. alba. In previous work, we investigated the acute toxicity of orally administered M. alba ethanol extract in mice. This work was designed to investigate the ethanol extract obtained from M. alba leaves for acute toxicity when intraperitoneally administered, in vivo genotoxicity, and potential to reduce acute inflammation. In order to further investigate the constituents of the extract, we also obtained the high-performance liquid chromatography (HPLC) fingerprint of the extract. Phytochemical analysis by thin layer chromatography (TLC) was performed and the results were used to obtain the HPLC fingerprint. Acute toxicity of 300 and 2000mg/kg b.w. i.p. doses administered to mice for 14 days was evaluated. Genotoxicity was evaluated by counting the number of micronucleated polychromatic erythrocytes in the blood of mice that either received or did not receive the extract at 75, 150 and 300mg/kg b.w. per os. The anti-inflammatory effect of the same doses administered per os was investigated using the carrageenan air pouch model. The TLC analysis of the extract revealed the presence of a remarkable amount of flavonoids and cinnamic acids. The HPLC fingerprint showed the presence of one major peak corresponding to chlorogenic acid and two smaller peaks corresponding to flavonoids. In the toxicity assays, there were no deaths or deviations in behavior of treated mice as compared to the control at any dose. However, biochemical, hematological, and histological analyses showed that intraperitoneal injection caused several forms of damage to the mice, which were not observed in case of oral administration, studied in our previous work. Oral administration of the extract did not result in genotoxicity and considerably reduced (58.6-65.6% inhibition) leukocyte migration in all doses evaluated, in comparison with the negative control. The ethanol extract from M. alba leaves administered intraperitoneally possesses a greater degree of toxicity in mice when compared to per os administration. The extract was not genotoxic when ingested by mice and exhibited a highly inhibitory effect against acute inflammation, which is probably linked to the presence of chlorogenic acid and flavonoids in the composition. This work contributes to the determination of safety of the medicinal use of M. alba leaves. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of the Acute and Chronic Ethanol Intoxication on Acetate Metabolism and Kinetics in the Rat Brain.

PubMed

Hsieh, Ya-Ju; Wu, Liang-Chih; Ke, Chien-Chih; Chang, Chi-Wei; Kuo, Jung-Wen; Huang, Wen-Sheng; Chen, Fu-Du; Yang, Bang-Hung; Tai, Hsiao-Ting; Chen, Sharon Chia-Ju; Liu, Ren-Shyan

2018-02-01

Ethanol (EtOH) intoxication inhibits glucose transport and decreases overall brain glucose metabolism; however, humans with long-term EtOH consumption were found to have a significant increase in [1- 11 C]-acetate uptake in the brain. The relationship between the cause and effect of [1- 11 C]-acetate kinetics and acute/chronic EtOH intoxication, however, is still unclear. [1- 11 C]-acetate positron emission tomography (PET) with dynamic measurement of K 1 and k 2 rate constants was used to investigate the changes in acetate metabolism in different brain regions of rats with acute or chronic EtOH intoxication. PET imaging demonstrated decreased [1- 11 C]-acetate uptake in rat brain with acute EtOH intoxication, but this increased with chronic EtOH intoxication. Tracer uptake rate constant K 1 and clearance rate constant k 2 were decreased in acutely intoxicated rats. No significant change was noted in K 1 and k 2 in chronic EtOH intoxication, although 6 of 7 brain regions showed slightly higher k 2 than baseline. These results indicate that acute EtOH intoxication accelerated acetate transport and metabolism in the rat brain, whereas chronic EtOH intoxication status showed no significant effect. In vivo PET study confirmed the modulatory role of EtOH, administered acutely or chronically, in [1- 11 C]-acetate kinetics and metabolism in the rat brain. Acute EtOH intoxication may inhibit the transport and metabolism of acetate in the brain, whereas chronic EtOH exposure may lead to the adaptation of the rat brain to EtOH in acetate utilization. [1- 11 C]-acetate PET imaging is a feasible approach to study the effect of EtOH on acetate metabolism in rat brain. Copyright © 2017 by the Research Society on Alcoholism.

Transgenic over expression of nicotinic receptor alpha 5, alpha 3, and beta 4 subunit genes reduces ethanol intake in mice.

PubMed

Gallego, Xavier; Ruiz-Medina, Jessica; Valverde, Olga; Molas, Susanna; Robles, Noemí; Sabrià, Josefa; Crabbe, John C; Dierssen, Mara

2012-05-01

Abuse of alcohol and smoking are extensively co-morbid. Some studies suggest partial commonality of action of alcohol and nicotine mediated through nicotinic acetylcholine receptors (nAChRs). We tested mice with transgenic over expression of the alpha 5, alpha 3, beta 4 receptor subunit genes, which lie in a cluster on human chromosome 15, that were previously shown to have increased nicotine self-administration, for several responses to ethanol. Transgenic and wild-type mice did not differ in sensitivity to several acute behavioral responses to ethanol. However, transgenic mice drank less ethanol than wild-type in a two-bottle (ethanol vs. water) preference test. These results suggest a complex role for this receptor subunit gene cluster in the modulation of ethanol's as well as nicotine's effects. Copyright © 2012. Published by Elsevier Inc.

Action of ethanol low doses on heart rate variability following intravenous administration in rabbits.

PubMed

Khvedelidze, M; Chitanava, E; Nadareishvili, D; Jiqia, G; Gvasalia, M

2007-05-01

Effects of low ethanol doses on the vagosympathetic mechanisms of heart rate regulation were studied in rabbits. Analysis of heart rate variability showed that single intravenous administration of 0.5 mg/kg ethanol caused a higher probability of heart electrophysiological instability in sympathicotonics in contrast to vagotonics. This was associated with activation of the whole complex of regulatory mechanisms. In vagotonics, perturbations in power spectrum indicated on rapidly shunting of regulatory activity from lower to high levels of regulatory mechanisms to realize a "first class" undifferentiated response on stress induction. Sympathicotonics were unready to ethanol intravenous administration that resulted in reduction of all spectral component. Intravenous administration of ethanol caused a higher probability of heart electrophysiological instability in sympathicotonics then in vagotonics. It is important to consider these differences for therapeutic application of ethanol to some acute poisoning (methyl alcohol, ethylene glycol).

Refeeding after acute food restriction: differential reduction in preference for ethanol and ethanol-paired flavors in selectively bred rats.

PubMed

Dess, Nancy K; Chapman, Clinton D; Cousins, Laura A; Monroe, Derek C; Nguyen, Phuong

2013-01-17

Rats' voluntary ethanol intake varies with dispositional factors and energy status. The joint influences of these were of interest here. We previously reported that rats selectively bred for high voluntary saccharin intake (HiS) consume more ethanol and express more robust conditioning of preference for flavors paired with voluntarily consumed ethanol than do low-saccharin consuming counterparts (LoS). Three new experiments examined the effect of refeeding after an episode of food restriction on ethanol intake and on preference for ethanol-paired flavors in HiS and LoS rats. A 48-h episode of food restriction with wheel running reduced intake of and preference for 4% ethanol (Exp. 1a) and preference for an ethanol-paired flavor (Exp. 1b) during refeeding. Food restriction alone was sufficient to reduce the flavor preference (Exp. 2). Adding fat to the refeeding diet or extending the food restriction period exacerbated the effect (Exp. 3), yielding a frank aversion to ethanol-paired flavors in LoS rats. These studies indicate that rebound from negative energy balance shifts responses to ethanol-associated cues from preference toward aversion. Analyses of bodyweight changes and caloric intake during refeeding support this conclusion and further suggest that lower metabolic efficiency may be a marker for enhanced preference mutability. Copyright © 2012 Elsevier Inc. All rights reserved.

Galanin knockout mice show disturbances in ethanol consumption and expression of hypothalamic peptides that stimulate ethanol intake

PubMed Central

Karatayev, Olga; Baylan, Jessica; Weed, Valerie; Chang, Siyi; Wynick, David; Leibowitz, Sarah F.

2009-01-01

Background There is growing evidence suggesting that hypothalamic galanin (GAL), which is known to stimulate intake of a fat-rich diet, has a role in promoting the consumption of ethanol. The present study further examined this possibility in GAL knockout (GALKO) mice. Methods Two groups of female and male GALKO mice, compared to wild-type (WT) controls, were trained to voluntarily drink increasing concentrations of ethanol, while maintained on lab chow and water. They were examined in terms of their daily ethanol intake and preference, acute consumption of a high-fat diet, preference for flavored solutions, and expression of different peptides shown to stimulate ethanol intake. Results In the GALKO mice compared to WT, the results revealed: 1) a 35-45% decrease in ethanol intake and preference, which was evident only at the highest (15%) ethanol concentration, was stronger in female than in male mice, and was seen with comparisons to littermate as well as non-littermate WT mice; 2) a 48% decrease in acute intake of a fat-rich diet, again stronger in female than male mice; 3) no difference in consumption of sucrose or quinine solutions in preference tests; 4) a total loss of GAL mRNA in the hypothalamic paraventricular nucleus (PVN) of female and male mice; and 5) a gender-specific change in mRNA levels of peptides in the perifornical lateral hypothalamus (PFLH), orexin and melanin-concentrating hormone, which are known to stimulate ethanol and food intake and were markedly decreased in females while increased in males Conclusions These results provide strong support for a physiological role of PVN GAL in stimulating the consumption of ethanol, as well as a fat-rich diet. Ablation of the GAL gene produced a behavioral phenotype, particularly in females, which may reflect the functional relationship of galanin to ovarian steroids. It also altered the peptides in the PFLH, with their reduced expression contributing to the larger behavioral effects observed in females and their increased expression attenuating these effects in males. PMID:19860804

Systemic blockade of LPA1/3 lysophosphatidic acid receptors by ki16425 modulates the effects of ethanol on the brain and behavior.

PubMed

Sánchez-Marín, Laura; Ladrón de Guevara-Miranda, David; Mañas-Padilla, M Carmen; Alén, Francisco; Moreno-Fernández, Román D; Díaz-Navarro, Caridad; Pérez-Del Palacio, José; García-Fernández, María; Pedraza, Carmen; Pavón, Francisco J; Rodríguez de Fonseca, Fernando; Santín, Luis J; Serrano, Antonia; Castilla-Ortega, Estela

2018-05-01

The systemic administration of lysophosphatidic acid (LPA) LPA 1/3 receptor antagonists is a promising clinical tool for cancer, sclerosis and fibrosis-related diseases. Since LPA 1 receptor-null mice engage in increased ethanol consumption, we evaluated the effects of systemic administration of an LPA 1/3 receptor antagonist (intraperitoneal ki16425, 20 mg/kg) on ethanol-related behaviors as well as on brain and plasma correlates. Acute administration of ki16425 reduced motivation for ethanol but not for saccharine in ethanol self-administering Wistar rats. Mouse experiments were conducted in two different strains. In Swiss mice, ki16425 treatment reduced both ethanol-induced sedation (loss of righting reflex, LORR) and ethanol reward (escalation in ethanol consumption and ethanol-induced conditioned place preference, CPP). Furthermore, in the CPP-trained Swiss mice, ki16425 prevented the effects of ethanol on basal c-Fos expression in the medial prefrontal cortex and on adult neurogenesis in the hippocampus. In the c57BL6/J mouse strain, however, no effects of ki16425 on LORR or voluntary drinking were observed. The c57BL6/J mouse strain was then evaluated for ethanol withdrawal symptoms, which were attenuated when ethanol was preceded by ki16425 administration. In these animals, ki16425 modulated the expression of glutamate-related genes in brain limbic regions after ethanol exposure; and peripheral LPA signaling was dysregulated by either ki16425 or ethanol. Overall, these results suggest that LPA 1/3 receptor antagonists might be a potential new class of drugs that are suitable for treating or preventing alcohol use disorders. A pharmacokinetic study revealed that systemic ki16425 showed poor brain penetration, suggesting the involvement of peripheral events to explain its effects. Copyright © 2018 Elsevier Ltd. All rights reserved.

The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice.

PubMed

Blagaic, Alenka Boban; Blagaic, Vladimir; Romic, Zeljko; Sikiric, Predrag

2004-09-24

The stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W.1419), which was promising in inflammatory bowel disease (PL-10, PLD-116, PL-14736, Pliva) trials, protects against both acute and chronic alcohol-induced lesions in stomach and liver, but also, given peripherally, affects various centrally mediated disturbances. Now, in male NMRI mice BPC 157 (10 pg intraperitoneally, 10 ng and 10 microg, intraperitoneally or intragastrically) (i) strongly opposed acute alcohol (4 g/kg intraperitoneally) intoxication (i.e., quickly produced and sustained anesthesia, hypothermia, increased ethanol blood values, 25% fatality, 90-min assessment period) given before or after ethanol, and (ii) when given after abrupt cessation of ethanol (at 0 or 3 or 7 h withdrawal time), attenuated withdrawal (assessed through 24 hours) after 20%-alcohol drinking (7.6 g/kg) through 13 days, with provocation on the 14th day.

Alcohol Alters the Activation of ERK1/2, a Functional Regulator of Binge Alcohol Drinking in Adult C57BL/6J Mice

PubMed Central

Agoglia, Abigail E.; Sharko, Amanda C.; Psilos, Kelly E.; Holstein, Sarah E.; Reid, Grant T.; Hodge, Clyde W.

2014-01-01

Background Binge alcohol drinking is a particularly risky pattern of alcohol consumption that often precedes alcohol dependence and addiction. The transition from binge alcohol drinking to alcohol addiction likely involves mechanisms of synaptic plasticity and learning in the brain. The mitogen-activated protein kinase (MAPK) signaling cascades have been shown to be involved in learning and memory, as well as the response to drugs of abuse, but their role in binge alcohol drinking remains unclear. The present experiments were designed to determine the effects of acute alcohol on extracellular signaling related kinases (ERK1/2) expression and activity, and to determine whether ERK1/2 activity functionally regulates binge-like alcohol drinking. Methods Adult male C57BL/6J mice were injected with ethanol (3.0 mg/kg, IP) 10, 30 or 90 minutes prior to brain tissue collection. Next, mice that were brought to freely consume unsweetened ethanol in a binge-like access procedure were pretreated with the MEK1/2 inhibitor SL327 or the p38 MAP kinase inhibitor SB239063. Results Acute ethanol increased pERK1/2 immunoreactivity relative to vehicle in brain regions known to be involved in drug reward and addiction, including the central amygdala and prefrontal cortex. However, ethanol decreased pERK1/2 immunoreactivity relative to vehicle in the nucleus accumbens core. SB239063 pretreatment significantly decreased ethanol consumption only at doses that also produced nonspecific locomotor effects. SL327 pretreatment significantly increased ethanol, but not sucrose, consumption without inducing generalized locomotor effects. Conclusions These findings indicate that ERK1/2MAPK signaling regulates binge-like alcohol drinking. Since alcohol increased pERK1/2 immunoreactivity relative to vehicle in brain regions known to regulate drug self-administration, SL327 may have blocked this direct pharmacological effect of alcohol and thereby inhibited the termination of binge-like drinking. PMID:25703719

Characteristics of ethanol-induced behavioral sensitization in rats: Molecular mediators and cross-sensitization between ethanol and cocaine.

PubMed

Xu, Shijie; Kang, Ung Gu

2017-09-01

Repeated exposure to drugs of abuse can induce a progressive increase in locomotor activity, known as behavioral sensitization. However, little is known about behavioral sensitization to ethanol. We examined whether ethanol could induce behavioral sensitization and investigated several molecular changes accompanying sensitization. We also assessed whether "cross-sensitization" occurred between ethanol and cocaine, another abused drug. Ethanol-induced sensitization was examined in rats after ethanol treatment (0.5 or 2g/kg) for 15days. The biochemical effects of low- or high-dose ethanol were examined in terms of N-methyl-d-aspartate (NMDA) receptor subunit phosphorylation or expression. Neuronal activity after ethanol treatment was assessed by measuring the level of early growth response (Egr-1) expression. Ethanol-induced behavioral sensitization was observed at the low dose (0.5g/kg) but not the high dose (2g/kg). Although acute treatment with the sensitizing dose of ethanol robustly increased Egr-1 protein and mRNA levels, the expression and phosphorylation of NMDA receptor subunits were not affected. The biochemical responses to ethanol seemed to be enhanced in ethanol-sensitized animals. Cross-sensitization between ethanol and cocaine was observed, which supports the hypothesis that there are commonalities among substances in the pathophysiology of substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

Ethanol Forensic Toxicology.

PubMed

Perry, Paul J; Doroudgar, Shadi; Van Dyke, Priscilla

2017-12-01

Ethanol abuse can lead to negative consequences that oftentimes result in criminal charges and civil lawsuits. When an individual is suspected of driving under the influence, law enforcement agents can determine the extent of intoxication by measuring the blood alcohol concentration (BAC) and performing a standardized field sobriety test. The BAC is dependent on rates of absorption, distribution, and elimination, which are influenced mostly by the dose of ethanol ingested and rate of consumption. Other factors contributing to BAC are gender, body mass and composition, food effects, type of alcohol, and chronic alcohol exposure. Because of individual variability in ethanol pharmacology and toxicology, careful extrapolation and interpretation of the BAC is needed, to justify an arrest and assignment of criminal liability. This review provides a summary of the pharmacokinetic properties of ethanol and the clinical effects of acute intoxication as they relate to common forensic questions. Concerns regarding the extrapolation of BAC and the implications of impaired memory caused by alcohol-induced blackouts are discussed. © 2017 American Academy of Psychiatry and the Law.

Real-time monitoring of intracellular cAMP during acute ethanol exposure

PubMed Central

Gupta, Ratna; Qualls-Creekmore, Emily; Yoshimura, Masami

2013-01-01

Background In previous studies we have shown that ethanol enhances the activity of Gs-stimulated membrane-bound adenylyl cyclase (AC). The effect is AC isoform specific and the type 7 AC (AC7) is most responsive to ethanol. In this study, we employed a fluorescence resonance energy transfer (FRET) based cAMP sensor, Epac1-camps, to examine real-time temporal dynamics of ethanol effects on cAMP concentrations. To our knowledge, this is the first report on real-time detection of the ethanol effect on intracellular cAMP. Methods Hela cells were transfected with Epac1-camps, dopamine D1A receptor, and one isoform of AC (AC7 or AC3). Fluorescent images were captured using a specific filter set for cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), and FRET, respectively and FRET intensity was calculated on a pixel-by-pixel basis to examine changes in cAMP. Results During 2-minute stimulation with dopamine (DA), the cytoplasmic cAMP level quickly increased, then decreased to a plateau, where the cAMP level was higher than the level prior to stimulation with DA. Ethanol concentration dependently increased cytoplasmic cAMP in cells transfected with AC7, while ethanol did not have effect on cells transfected with AC3. Similar trends were observed for cAMP at the plasma membrane and in the nucleus during 2-minute stimulation with DA. Unexpectedly, when cells expressing AC7 were stimulated with DA or other Gs protein-coupled receptor’s ligand plus ethanol for 5 seconds, ethanol reduced cAMP concentration. Conclusion These results suggest that ethanol has two opposing effects on the cAMP generating system in an AC isoform specific manner, the enhancing effect on AC activity and the short lived inhibitory effect. Thus, ethanol may have a different effect on cAMP depending on not only AC isoform but also the duration of exposure. PMID:23731206

Transgenic Over Expression of Nicotinic Receptor Alpha 5, Alpha 3, and Beta 4 Subunit Genes Reduces Ethanol Intake in Mice

PubMed Central

Gallego, Xavier; Ruiz, Jessica; Valverde, Olga; Molas, Susanna; Robles, Noemí; Sabrià, Josefa; Crabbe, John C.; Dierssen, Mara

2012-01-01

Abuse of alcohol and smoking are extensively co-morbid. Some studies suggest partial commonality of action of alcohol and nicotine mediated through nicotinic acetylcholine receptors (nAChRs). We tested mice with transgenic over expression of the alpha 5, alpha 3, beta 4 receptor subunit genes, which lie in a cluster on human chromosome 15, that were previously shown to have increased nicotine self-administration, for several responses to ethanol. Transgenic and wild-type mice did not differ in sensitivity to several acute behavioral responses to ethanol. However, transgenic mice drank less ethanol than wild-type in a two-bottle (ethanol vs. water) preference test. These results suggest a complex role for this receptor subunit gene cluster in the modulation of ethanol’s as well as nicotine’s effects. PMID:22459873

A preliminary study on the effects of acute ethanol ingestion on default mode network and temporal fractal properties of the brain.

PubMed

Weber, Alexander M; Soreni, Noam; Noseworthy, Michael D

2014-08-01

To study the effect of acute alcohol intoxication on the functional connectivity of the default mode network (DMN) and temporal fractal properties of the healthy adult brain. Eleven healthy male volunteers were asked to drink 0.59 g/kg of ethanol. Resting state blood oxygen level dependent (rsBOLD) MRI scans were obtained before consumption, 60 min post-consumption and 90 min post-consumption. Before each rsBOLD scan, pointed-resolved spectroscopy (PRESS) (1)H-MRS (magnetic resonance spectroscopy) scans were acquired to measure ethanol levels in the right basal ganglia. Significant changes in DMN connectivity were found following alcohol consumption (p < 0.01). Both increased and decreased regional connectivity were found after 60 min, whereas mostly decreased connectivity was found after 90 min. The fractal behaviour of the rsBOLD signal, which is believed to help reveal complexity of small-scale neuronal circuitry, became more ordered after both 60 and 90 min of alcohol consumption (p < 0.01). The DMN has been linked to personal identity and social behavior. As such, our preliminary findings may provide insight into the neuro-functional underpinnings of the cognitive and behavioral changes observed during acute alcohol intoxication. The reduced fractal dimension implies a change in function of small-scale neural networks towards less complex signaling.

Molecular Genetic Analysis of Ethanol Intoxication in Drosophila melanogaster.

PubMed

Heberlein, Ulrike; Wolf, Fred W; Rothenfluh, Adrian; Guarnieri, Douglas J

2004-08-01

Recently, the fruit fly Drosophila melanogaster has been introduced as a model system to study the molecular bases of a variety of ethanol-induced behaviors. It became immediately apparent that the behavioral changes elicited by acute ethanol exposure are remarkably similar in flies and mammals. Flies show signs of acute intoxication, which range from locomotor stimulation at low doses to complete sedation at higher doses and they develop tolerance upon intermittent ethanol exposure. Genetic screens for mutants with altered responsiveness to ethanol have been carried out and a few of the disrupted genes have been identified. This analysis, while still in its early stages, has already revealed some surprising molecular parallels with mammals. The availability of powerful tools for genetic manipulation in Drosophila, together with the high degree of conservation at the genomic level, make Drosophila a promising model organism to study the mechanism by which ethanol regulates behavior and the mechanisms underlying the organism's adaptation to long-term ethanol exposure.

The role of social isolation in ethanol effects on the preweanling rat

PubMed Central

Kozlov, Andrey P.; Nizhnikov, Michael; Varlinskaya, Elena I.; Spear, Norman E.

2011-01-01

The present experiments investigated the effects of acute ethanol exposure on voluntary intake of 0.1% saccharin or water as well as behavioral and nociceptive reactivity in twelve–day-old (P12) rats exposed to differing levels of isolation. The effects of ethanol emerged only during short-term social isolation (STSI) with different patterns observed in males and females and in pups exposed to saccharin or water. The 0.5 g/kg ethanol dose selectively increased saccharin intake in females, decreased rearing activity in males and attenuated isolation-induced analgesia (IIA) in all water-exposed pups. Ingestion of saccharin decreased IIA, and the 0.5 g/kg ethanol dose further reduced IIA. The 1.0 g/kg ethanol dose, administered either intragastrically or intraparentionally, also decreased IIA in P12 females, but not in P9 pups. A significant correlation between voluntary saccharin intake and baseline nociceptive reactivity was revealed in saline injected animals, saccharin intake was inversely correlated with behavioral activation and latency of reaction to noxious heat after 0.5 g/kg ethanol in females. The 0.5 g/kg ethanol dose did not affect plasma corticosterone (CORT) measured 5 hours after maternal separation or 20 minutes after ethanol injection. Female pups CORT level was inversely correlated with magnitude of IIA that accompanied the first episode of STSI (pretest isolation) 1.5–2 hours before CORT measurement. The present findings suggest that the anxiolytic properties of ethanol are responsible for enhancement of saccharin intake during STSI. Furthermore, differential reactivity of P12 males and females to STSI plays an important role in ethanol effects observed at this age. PMID:22051944

Ethanol exerts dual effects on calcium homeostasis in CCK-8-stimulated mouse pancreatic acinar cells.

PubMed

Fernández-Sánchez, Marcela; del Castillo-Vaquero, Angel; Salido, Ginés M; González, Antonio

2009-10-30

A significant percentage of patients with pancreatitis often presents a history of excessive alcohol consumption. Nevertheless, the patho-physiological effect of ethanol on pancreatitis remains poorly understood. In the present study, we have investigated the early effects of acute ethanol exposure on CCK-8-evoked Ca2+ signals in mouse pancreatic acinar cells. Changes in [Ca2+]i and ROS production were analyzed employing fluorescence techniques after loading cells with fura-2 or CM-H2DCFDA, respectively. Ethanol, in the concentration range from 1 to 50 mM, evoked an oscillatory pattern in [Ca2+]i. In addition, ethanol evoked reactive oxygen species generation (ROS) production. Stimulation of cells with 1 nM or 20 pM CCK-8, respectively led to a transient change and oscillations in [Ca2+]i. In the presence of ethanol a transformation of 20 pM CCK-8-evoked physiological oscillations into a single transient increase in [Ca2+]i in the majority of cells was observed. Whereas, in response to 1 nM CCK-8, the total Ca2+ mobilization was significantly increased by ethanol pre-treatment. Preincubation of cells with 1 mM 4-MP, an inhibitor of alcohol dehydrogenase, or 10 microM of the antioxidant cinnamtannin B-1, reverted the effect of ethanol on total Ca2+ mobilization evoked by 1 nM CCK-8. Cinnamtannin B-1 blocked ethanol-evoked ROS production. ethanol may lead, either directly or through ROS generation, to an over stimulation of pancreatic acinar cells in response to CCK-8, resulting in a higher Ca2+ mobilization compared to normal conditions. The actions of ethanol on CCK-8-stimulation of cells create a situation potentially leading to Ca2+ overload, which is a common pathological precursor that mediates pancreatitis.

Differential effects of ethanol on glycine uptake mediated by the recombinant GLYT1 and GLYT2 glycine transporters

PubMed Central

Núñez, Enrique; López-Corcuera, Beatriz; Martínez-Maza, Rodrigo; Aragón, Carmen

2000-01-01

The effects of ethanol on the function of recombinant glycine transporter 1 (GLYT1) and glycine transporter 2 (GLYT2) have been investigated. GLYT1b and GLYT2a isoforms stably expressed in human embryonic kidney 293 (HEK 293) cells showed a differential behaviour in the presence of ethanol; only the GLYT2a isoform was acutely inhibited. The ‘cut-off' (alcohols with four carbons) displayed by the n-alkanols on GLYT2a indicates that a specific binding site for ethanol exists on GLYT2a or on a GLYT2a-interacting protein. The non-competitive inhibition of GLYT2a indicates an allosteric modulation by ethanol of GLYT2a activity. Chronic treatment with ethanol caused differential adaptive responses on the activity and the membrane expression levels of these transporters. The neuronal GLYT2a isoform decreased in activity and surface expression and the mainly glial GLYT1b isoform slightly increased in function and surface density. These changes may be involved in some of the modifications of glycinergic or glutamatergic neurotransmitter systems produced by ethanol intoxication. PMID:10683205

Chronic intracerebroventricular infusion of nociceptin/orphanin FQ increases food and ethanol intake in alcohol-preferring rats.

PubMed

Cifani, Carlo; Guerrini, Remo; Massi, Maurizio; Polidori, Carlo

2006-11-01

Central administration of low doses of nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, have been shown to reduce ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behavior in alcohol preferring rats. The present study evaluated the effect of continuous (7 days) lateral brain ventricle infusions of N/OFQ (0, 0.25, 1, 4, and 8 microg/h), by means of osmotic mini-pumps, on 10% ethanol intake in Marchigian-Sardinian alcohol-preferring (msP) rats provided 2h or 24h access to it. N/OFQ dose-dependently increased food intake in msP rats. On the other hand, in contrast to previous studies with acute injections, continuous lateral brain ventricle infusion of high doses of N/OFQ increased ethanol consumption when the ethanol solution was available for 24h/day or 2h/day. The present study demonstrates that continuous activation of the opioidergic N/OFQ receptor does not blunt the reinforcing effects of ethanol. Moreover, the data suggest that continuous activation of the opioidergic N/OFQ receptor is not a suitable way to reduce alcohol abuse.

Sulforaphane Induces Nrf2 and Protects Against CYP2E1-dependent Binge Alcohol –induced Liver Steatosis

PubMed Central

Zhou, Richard; Lin, Jianjun; Wu, Defeng

2013-01-01

Background The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. Method The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. Results The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase -1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-Nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. Conclusions Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol–induced fatty liver in mice. General significance The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study. PMID:24060752

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

PubMed Central

Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J; Woodward, John J

2016-01-01

Alcoholism is associated with changes in brain reward and control systems, including the prefrontal cortex. In prefrontal areas, the orbitofrontal cortex (OFC) has been suggested to have an important role in the development of alcohol-abuse disorders and studies from this laboratory demonstrate that OFC-mediated behaviors are impaired in alcohol-dependent animals. However, it is not known whether chronic alcohol (ethanol) exposure alters the fundamental properties of OFC neurons. In this study, mice were exposed to repeated cycles of chronic intermittent ethanol (CIE) exposure to induce dependence and whole-cell patch-clamp electrophysiology was used to examine the effects of CIE treatment on lateral OFC (lOFC) neuron excitability, synaptic transmission, and plasticity. Repeated cycles of CIE exposure and withdrawal enhanced current-evoked action potential (AP) spiking and this was accompanied by a reduction in the after-hyperpolarization and a decrease in the functional activity of SK channels. CIE mice also showed an increase in the AMPA/NMDA ratio, and this was associated with an increase in GluA1/GluA2 AMPA receptor expression and a decrease in GluN2B NMDA receptor subunits. Following CIE treatment, lOFC neurons displayed a persistent long-term potentiation of glutamatergic synaptic transmission following a spike-timing-dependent protocol. Lastly, CIE treatment diminished the inhibitory effect of acute ethanol on AP spiking of lOFC neurons and reduced expression of the GlyT1 transporter. Taken together, these results suggest that chronic exposure to ethanol leads to enhanced intrinsic excitability and glutamatergic synaptic signaling of lOFC neurons. These alterations may contribute to the impairment of OFC-dependent behaviors in alcohol-dependent individuals. PMID:26286839

Understanding behavioral and physiological phenotypes of stress and anxiety in zebrafish.

PubMed

Egan, Rupert J; Bergner, Carisa L; Hart, Peter C; Cachat, Jonathan M; Canavello, Peter R; Elegante, Marco F; Elkhayat, Salem I; Bartels, Brett K; Tien, Anna K; Tien, David H; Mohnot, Sopan; Beeson, Esther; Glasgow, Eric; Amri, Hakima; Zukowska, Zofia; Kalueff, Allan V

2009-12-14

The zebrafish (Danio rerio) is emerging as a promising model organism for experimental studies of stress and anxiety. Here we further validate zebrafish models of stress by analyzing how environmental and pharmacological manipulations affect their behavioral and physiological phenotypes. Experimental manipulations included exposure to alarm pheromone, chronic exposure to fluoxetine, acute exposure to caffeine, as well as acute and chronic exposure to ethanol. Acute (but not chronic) alarm pheromone and acute caffeine produced robust anxiogenic effects, including reduced exploration, increased erratic movements and freezing behavior in zebrafish tested in the novel tank diving test. In contrast, ethanol and fluoxetine had robust anxiolytic effects, including increased exploration and reduced erratic movements. The behavior of several zebrafish strains was also quantified to ascertain differences in their behavioral profiles, revealing high-anxiety (leopard, albino) and low-anxiety (wild type) strains. We also used LocoScan (CleverSys Inc.) video-tracking tool to quantify anxiety-related behaviors in zebrafish, and dissect anxiety-related phenotypes from locomotor activity. Finally, we developed a simple and effective method of measuring zebrafish physiological stress responses (based on a human salivary cortisol assay), and showed that alterations in whole-body cortisol levels in zebrafish parallel behavioral indices of anxiety. Collectively, our results confirm zebrafish as a valid, reliable, and high-throughput model of stress and affective disorders.

Antitumor activity of ethanol extract from Hippophae rhamnoides L. leaves towards human acute myeloid leukemia cells in vitro.

PubMed

Zhamanbaeva, G T; Murzakhmetova, M K; Tuleukhanov, S T; Danilenko, M P

2014-12-01

We studied the effects of ethanol extract from Hippophae rhamnoides L. leaves on the growth and differentiation of human acute myeloid leukemia cells (KG-1a, HL60, and U937). The extract of Hippophae rhamnoides L. leaves inhibited cell growth depending on the cell strain and extract dose. In a high concentration (100 μg/ml), the extract also exhibited a cytotoxic effect on HL60 cells. Hippophae rhamnoides L. leaves extract did not affect cell differentiation and did not modify the differentiating effect of calcitriol, active vitamin D metabolite. Inhibition of cell proliferation was paralleled by paradoxical accumulation of phase S cells (synthetic phase) with a reciprocal decrease in the count of G1 cells (presynthetic phase). The extract in a concentration of 100 μg/ml induced the appearance of cells with a subdiploid DNA content (sub-G1 phase cells), which indicated induction of apoptosis. The antiproliferative effect of Hippophae rhamnoides L. extract on acute myeloid leukemia cells was at least partially determined by activation of the S phase checkpoint, which probably led to deceleration of the cell cycle and apoptosis induction.

Acute exposure to ethanol on gestational day 15 affects social motivation of female offspring.

PubMed

Varlinskaya, Elena I; Mooney, Sandra M

2014-03-15

Alterations in social behavior are a hallmark of many neurodevelopmental disorders in humans. In rodents, social behavior is affected by prenatal insults. The outcomes are dependent on the timing of the insult as well as the sex and age of the animal tested. The limbic system is particularly important for social behavior, and a peak of neurogenesis within this system occurs on gestational day (G)15. Neurons appear particularly vulnerable to ethanol insult around the time they become post-mitotic. We tested the hypothesis that acute exposure to ethanol on G15 would result in significant social behavior deficits. Accordingly, Long Evans pregnant females were injected with ethanol (2.9 g/kg) or an equivalent volume of saline on G15. Offspring were assessed in a modified social interaction test on postnatal day (P) 28, P42, or P75, i.e., during early adolescence, late adolescence, or young adulthood. Prenatal ethanol exposure decreased social investigation in P28 females and transformed social preference into social avoidance in 75-day-old females. Contact behavior, play fighting, and locomotor activity differed as a function of age, but were not significantly affected by ethanol exposure. Males demonstrated significantly more contact behavior and play fighting at P42 than at P28 or P70, whereas there were no age-related changes in females. Adult females showed more locomotor activity than adult males. Overall, prenatal ethanol exposure on G15 enhanced social anxiety in females, with these effects seen in adulthood only. Copyright © 2013 Elsevier B.V. All rights reserved.

GABAA Receptors Containing ρ1 Subunits Contribute to In Vivo Effects of Ethanol in Mice

PubMed Central

Blednov, Yuri A.; Benavidez, Jillian M.; Black, Mendy; Leiter, Courtney R.; Osterndorff-Kahanek, Elizabeth; Johnson, David; Borghese, Cecilia M.; Hanrahan, Jane R.; Johnston, Graham A. R.; Chebib, Mary; Harris, R. Adron

2014-01-01

GABAA receptors consisting of ρ1, ρ2, or ρ3 subunits in homo- or hetero-pentamers have been studied mainly in retina but are detected in many brain regions. Receptors formed from ρ1 are inhibited by low ethanol concentrations, and family-based association analyses have linked ρ subunit genes with alcohol dependence. We determined if genetic deletion of ρ1 in mice altered in vivo ethanol effects. Null mutant male mice showed reduced ethanol consumption and preference in a two-bottle choice test with no differences in preference for saccharin or quinine. Null mutant mice of both sexes demonstrated longer duration of ethanol-induced loss of righting reflex (LORR), and males were more sensitive to ethanol-induced motor sedation. In contrast, ρ1 null mice showed faster recovery from acute motor incoordination produced by ethanol. Null mutant females were less sensitive to ethanol-induced development of conditioned taste aversion. Measurement of mRNA levels in cerebellum showed that deletion of ρ1 did not change expression of ρ2, α2, or α6 GABAA receptor subunits. (S)-4-amino-cyclopent-1-enyl butylphosphinic acid (“ρ1” antagonist), when administered to wild type mice, mimicked the changes that ethanol induced in ρ1 null mice (LORR and rotarod tests), but the ρ1 antagonist did not produce these effects in ρ1 null mice. In contrast, (R)-4-amino-cyclopent-1-enyl butylphosphinic acid (“ρ2” antagonist) did not change ethanol actions in wild type but produced effects in mice lacking ρ1 that were opposite of the effects of deleting (or inhibiting) ρ1. These results suggest that ρ1 has a predominant role in two in vivo effects of ethanol, and a role for ρ2 may be revealed when ρ1 is deleted. We also found that ethanol produces similar inhibition of function of recombinant ρ1 and ρ2 receptors. These data indicate that ethanol action on GABAA receptors containing ρ1/ρ2 subunits may be important for specific effects of ethanol in vivo. PMID:24454882

Red wine induced modulation of vascular function: separating the role of polyphenols, ethanol, and urates.

PubMed

Boban, Mladen; Modun, Darko; Music, Ivana; Vukovic, Jonatan; Brizic, Ivica; Salamunic, Ilza; Obad, Ante; Palada, Ivan; Dujic, Zeljko

2006-05-01

By using red wine (RW), dealcoholized red wine (DARW), polyphenols-stripped red wine (PSRW), ethanol-water solution (ET), and water (W), the role of wine polyphenols, ethanol, and urate on vascular function was examined in humans (n = 9 per beverage) and on isolated rat aortic rings (n = 9). Healthy males randomly consumed each beverage in a cross-over design. Plasma ethanol, catechin, and urate concentrations were measured before and 30, 60 and 120 minutes after beverage intake. Endothelial function was assessed before and 60 minutes after beverage consumption by normalized flow-mediated dilation (FMD). RW and DARW induced similar vasodilatation in the isolated vessels whereas PSRW, ET, and W did not. All ethanol-containing beverages induced similar basal vasodilatation of brachial artery. Only intake of RW resulted in enhancement of endothelial response, despite similar plasma catechin concentration after DARW. The borderline effect of RW on FMD (P = 0.0531) became significant after FMD normalization (P = 0.0043) that neutralized blunting effect of ethanol-induced basal vasodilatation. Effects of PSRW and ET did not differ although plasma urate increased after PSRW and not after ET, indicating lack of urate influence on endothelial response. Acute vascular effects of RW, mediated by polyphenols, cannot be predicted by plasma catechin concentration only.

Gastroprotective actions of Taraxacum coreanum Nakai water extracts in ethanol-induced rat models of acute and chronic gastritis.

PubMed

Yang, Hye Jeong; Kim, Min Jung; Kwon, Dae Young; Kang, Eun Seon; Kang, Suna; Park, Sunmin

2017-08-17

Taraxacum coreanum Nakai has been traditionally used for treating inflammatory diseases including gastrointestinal diseases. We studied whether water extracts of Taraxacum coreanum Nakai (TCN) had a protective effect on acute and chronic gastritis induced by ethanol/HCl in an animal model of gastritis and its mechanism was also explored. In the acute study, rats were orally administered 0.15g/mL dextrin (normal-control), 0.15g/mL dextrin (control), 0.05g/mL TCN (TCN-L), 0.15g/mL TCN (TCN-H), or 0.01g/mL omeprazole (orally; positive-control), followed by oral administration of 1mL of 60% ethanol plus 150mM HCl (inducer). In the chronic study, rats were administered 10% diluted inducer in drinking water, and 0.6% dextrin, 0.2% or 0.6% TCN, and 0.05% omeprazole were administered in chow for 4 weeks. Acid content, gastric structure, oxidative stress, and markers of inflammation in the stomach tissue were measured at the end of experiment. Acute and chronic ethanol/HCl administration caused the inner layer of the stomach to redden, hemorrhage, and edema in the control group; TCN-H reduced these symptoms more effectively than did the omeprazole positive-control. Acid production and total acidity in the stomach increased in the control group, which was markedly suppressed by omeprazole. TCN also reduced the acid production and acidity, but not to the same degree as omeprazole. H-E and PAS staining revealed that in the inner layer of the stomach, cellular structure was disrupted, with an increased nuclear size and thickness, disarrangement, and decreased mucin in the control group. TCN prevented the cellular disruption in the inner layer, and TCN-H was more effective than the positive-control. This was associated with oxidative stress and inflammation. TCN dose-dependently reduced the infiltration of mast cells and TNF-α expression in the inner layer of the stomach, and decreased lipid peroxides by increasing superoxide dismutase and glutathione peroxidase expression. TCN-H acutely and chronically protected against gastritis and gastric ulcer by reducing oxidative stress and inflammation, not by completely suppressing gastric acid production. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

[Involvement of distal fragment of chromosome 13 in the regulation of sensitivity to ethanol in mice].

PubMed

Bazovkina, D V; Kulikov, A V

2015-01-01

The role of the fragment 57-65 cM of mouse chromosome 13 was studied in the regulation of ethanol action on locomotor activity, anxiety and sensitivity to hypnotic and hypothermic effects of ethanol. We used male mice of recombinant lines AKR/J and AKR.CBA-D13Mit76C, differing only in this fragment. After acute administration of ethanol only AKR mice showed the increase in the length of traveled distance in the open-field test (p < 0.05), only the AKR.CBA-D13Mit76C mice demonstrated the increase the time spent in the center of open-field arena (p < 0.05). Intact animals of both lines did not differ in sleep duration and intensity of hypothermia induced by injections of high doses of ethanol. At the same time, long-term alcohol treatment led to the weakening of the hypnotic effect of ethanol in the males of both lines compared to intact animals (p < 0.01 for the AKR, p < 0.001 for AKR.CBA-D13Mit76C). Chronic alcoholization led to increased ethanol-induced hypothermia in AKR males compared to intact animals (p < 0.01) and did not affect the intensity of ethanol hypothermic effect in AKR.CBA-D13Mit76C mice. The results suggest the involvement of the distal fragment 57-65 cM of chromosome 13 in the mechanisms of ethanol action in mice.

The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala

PubMed Central

Roberto, Marisa; Cruz, Maureen; Bajo, Michal; Siggins, George R; Parsons, Loren H; Schweitzer, Paul

2010-01-01

The central amygdala (CeA) has a major role in alcohol dependence and reinforcement, and behavioral and neurochemical evidence suggests a role for the endocannabinoid (eCB) system in ethanol binging and dependence. We used a slice preparation to investigate the physiological role of cannabinoids and their interaction with ethanol on inhibitory synaptic transmission in CeA. Superfusion of the cannabinoid receptor (CB1) agonist WIN55212-2 (WIN2) onto CeA neurons decreased evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the CB1 antagonists Rimonabant (SR141716, SR1) and AM251. SR1 or AM251 applied alone augmented IPSPs, revealing a tonic eCB activity that decreased inhibitory transmission in CeA. Paired-pulse analysis suggested a presynaptic CB1 mechanism. Intracellular BAPTA abolished the ability of AM251 to augment IPSPs, demonstrating the eCB-driven nature and postsynaptic origin of the tonic CB1-dependent control of GABA release. Superfusion of ethanol increased IPSPs and addition of WIN2 reversed the ethanol effect. Similarly, previous superfusion of WIN2 prevented subsequent ethanol effects on GABAergic transmission. The ethanol-induced augmentation of IPSPs was additive to CB1 blockade, ruling out a participation of CB1 in the action of acute ethanol. Our study points to an important role of CB1 in CeA in which the eCBs tonically regulate neuronal activity, and suggests a potent mechanism for modulating CeA tone during challenge with ethanol. PMID:20463657

Drosophila melanogaster, a genetic model system for alcohol research.

PubMed

Guarnieri, Douglas J; Heberlein, Ulrike

2003-01-01

In its natural environment, which consists of fermenting plant materials, the fruit fly Drosophila melanogaster encounters high levels of ethanol. Flies are well equipped to deal with the toxic effects of ethanol; they use it as an energy source and for lipid biosynthesis. The primary ethanol-metabolizing pathway in flies involves the enzymes alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH); their role in adaptation to ethanol-rich environments has been studied extensively. The similarity between Drosophila and mammals is not restricted to the manner in which they metabolize ethanol; behaviors elicited by ethanol exposure are also remarkably similar in these organisms. Flies show signs of acute intoxication, which range from locomotor stimulation at low doses to complete sedation at higher doses, they develop tolerance upon intermittent ethanol exposure, and they appear to like ethanol, showing preference for ethanol-containing media. Molecular genetic analysis of ethanol-induced behaviors in Drosophila, while still in its early stages, has already revealed some surprising parallels with mammals. The availability of powerful tools for genetic manipulation in Drosophila, together with the high degree of conservation at the genomic level, make Drosophila a promising model organism to study the mechanism by which ethanol regulates behavior and the mechanisms underlying the organism's adaptation to long-term ethanol exposure.

[A case of favourable outcome of the treatment of extremely severe acute poisoning with methanol].

PubMed

Batotsyrenov, B V; Livanov, G A; Vasil'ev, S A; Fedorov, A V; Antrianov, A Iu

2013-01-01

A case of favourable outcome of the treatment of extremely severe acute poisoning after prolonged exposure to lethal doses of methanol is reported. The complex treatment included urgent and effective elimination of the poison (multiple gastric lavage, hemodialysis), antidote therapy (administration of ethanol), correction of decompensated metabolic acidosis (alkali therapy and infusion therapy with reamberin). These measures had beneficial effect on the clinical course of poisoning and ensured its favourable outcome.

Protective activity of salidroside against ethanol-induced gastric ulcer via the MAPK/NF-κB pathway in vivo and in vitro.

PubMed

Chang, Xiayun; Luo, Fen; Jiang, Wenjiao; Zhu, Lingpeng; Gao, Jin; He, He; Wei, Tingting; Gong, Shilin; Yan, Tianhua

2015-09-01

Salidroside (Sal) is a traditional Chinese medicine with various pharmacological effects. The present study aimed to investigate the protective effect of Sal on ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage. 0.2 ml ethanol and 400 μM H2O2 were applied to establish a gastric ulcer model in vivo and in vitro respectively. The production of interleukin (IL)-6, interleukin (IL)-1β and tumor necrosis factor (TNF)-α was analyzed, as well as myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD). MTT assay was used to detect cell viability. In addition, MAPK/NF-κB signal pathway-related proteins p-ERK, p-JNK, p-p38, p-IκBα and p-NF-κBp65 were analyzed to determine the underlying protective mechanism. Downstream genes such as cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and leukotrienes B4 (LTB4) were also measured. Obtained data indicated that Sal inhibited the overproduction of pro-inflammatory cytokines and enhanced antioxidant activity. Collectively, it is assumed that Sal could alleviate ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage through the MAPK/NF-κB pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Gastroprotective activity of Zanthoxylum rhoifolium Lam. in animal models.

PubMed

Freitas, F F B P; Fernandes, H B; Piauilino, C A; Pereira, S S; Carvalho, K I M; Chaves, M H; Soares, P M G; Miura, L M C V; Leite, J R S A; Oliveira, R C M; Oliveira, F A

2011-09-01

The stem barks of Zanthoxylum rhoifolium Lam. (Rutaceae), locally known as "mamica de cadela", are popularly used in dyspepsies, stomachic, tonic, antitumoral, antipyretic and are used in treating flatulence and colic. The objective of this study was to evaluate the gastroprotective effect of the ethanolic extract of Zanthoxylum rhoifolium (EEZR) stem barks in acute gastric lesion models, investigating their possible mechanisms. Mice were used for the evaluation of the acute toxicity, and mice and rats to study the gastroprotective activity. The gastroprotective action of EEZR was analyzed in the absolute ethanol, HCl/ethanol and indomethacin-induced gastric lesion models in mice, hypothermic-restraint stress, and ischemia/reperfusion in rats. In the investigation of the gastroprotective mechanisms of EEZR, the participation of the NO-synthase pathway, ATP-sensitive potassium channels (K(ATP)), the levels of the non-protein sulfhydril groups (NP-SH) and the catalase activity using the ethanol-induced gastric mucosa lesion model and the quantification of the gastric mucus and the antisecretory activity through pylorus ligature model in rats were analyzed. The animals did not present any signs of acute toxicity for the EEZR (up to the 4 g/kg dose, po), and it was not possible to calculate the DL(50). EEZR (125-500 mg/kg) exhibited a significant gastroprotective effect in absolute ethanol, HCl/ethanol, hypothermic-restraint stress, and ischemia/reperfusion-induced gastric lesion models. EEZR (250 and 500 mg/kg) exhibited still a gastroprotective activity in the indomethacin-induced ulcer model. Gastroprotection of EEZR was significantly decreased in pre-treated mice with l-NAME or glibenclamide, the respective nitric oxide synthase and K(ATP) channels inhibitors. Our studies revealed that EEZR (500 mg/kg) prevented the decrease of the non-protein sulfhydril groups (NP-SH) and increased the catalase levels in ethanol-treated animals. Furthermore, the extract (500 mg/kg) significantly increased the mucus production, however, the gastric secretion parameters (volume, [H(+)], pH) did not show any alteration. Our results indicate that the ethanolic extract of Zanthoxylum rhoifolium exhibits a significant gastroprotection, because it inhibits the formation of gastric lesions using different models. The release of the nitric oxide, the opening of the K(ATP) channels, the participation of the non-protein sulfhydril groups (NP-SH), catalase and the increase of mucous secretion seem to be involved in the gastroprotection activity of the EEZR. Nevertheless, this activity does not seem to be related to antisecretory mechanisms. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure

PubMed Central

Gano, Anny; Doremus-Fitzwater, Tamara L.; Deak, Terrence

2016-01-01

Acute ethanol intoxication is associated with Rapid Alterations in Neuroimmune Gene expression (RANGE), including increased Interleukin (IL)-6 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), and suppressed IL-1β and Tumor necrosis factor (TNF) α, yet little is known about adaptations in cytokines across the first few ethanol exposures. Thus, the present studies examined central cytokines during intoxication (3 h post-ethanol) following 2, 4 or 6 intragastric ethanol challenges (4 g/kg) delivered either daily or every-other-day (EOD). Subsequent analyses of blood ethanol concentrations (BECs) and corticosterone were performed to determine whether the schedule of ethanol delivery would alter the pharmacokinetics of, or general sensitivity to, subacute ethanol exposure. As expected, ethanol led to robust increases in IL-6 and IκBα gene expression in hippocampus, amygdala and bed nucleus of the stria terminalis (BNST), whereas IL-1β and TNFα were suppressed, thereby replicating our prior work. Ethanol-dependent increases in IL-6 and IκBα remained significant in all structures—even after 6 days of ethanol. When these doses were administered EOD, modest IL-6 increases in BNST were observed, with TNFα and IL-1β suppressed exclusively in the hippocampus. Analysis of BECs revealed a small but significant reduction in ethanol after 4 EOD exposures — an effect which was not observed when ethanol was delivered after 6 daily intubations. These findings suggest that ethanol-induced RANGE effects are not simply a function of ethanol load per se, and underscore the critical role that ethanol dosing interval plays in determining the neuroimmune consequences of alcohol. PMID:27208497

Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment

PubMed Central

Ignacio, Cherry; Mooney, Sandra M.; Middleton, Frank A.

2014-01-01

Fetal alcohol spectrum disorders (FASDs) are associated with abnormal social behavior. These behavioral changes may resemble those seen in autism. Rats acutely exposed to ethanol on gestational day 12 show decreased social motivation at postnatal day 42. We previously showed that housing these ethanol-exposed rats with non-exposed controls normalized this deficit. The amygdala is critical for social behavior and regulates it, in part, through connections with the basal ganglia, particularly the ventral striatum. MicroRNAs (miRNAs) are short, hairpin-derived RNAs that repress mRNA expression. Many brain disorders, including FASD, show dysregulation of miRNAs. In this study, we tested if miRNA and mRNA networks are altered in the amygdala and ventral striatum as a consequence of prenatal ethanol exposure and show any evidence of reversal as a result of social enrichment. RNA samples from two different brain regions in 72 male and female adolescent rats were analyzed by RNA-Seq and microarray analysis. Several miRNAs showed significant changes due to prenatal ethanol exposure and/or social enrichment in one or both brain regions. The top predicted gene targets of these miRNAs were mapped and subjected to pathway enrichment analysis. Several miRNA changes caused by ethanol were reversed by social enrichment, including mir-204, mir-299a, miR-384-5p, miR-222-3p, miR-301b-3p, and mir-6239. Moreover, enriched gene networks incorporating the targets of these miRNAs also showed reversal. We also extended our previously published mRNA expression analysis by directly examining all annotated brain-related canonical pathways. The additional pathways that were most strongly affected at the mRNA level included p53, CREB, glutamate, and GABA signaling. Together, our data suggest a number of novel epigenetic mechanisms for social enrichment to reverse the effects of ethanol exposure through widespread influences on gene expression. PMID:25309888

The effect of prior alcohol consumption on the ataxic response to alcohol in high-alcohol preferring mice

PubMed Central

Fritz, Brandon M.; Boehm, Stephen L.

2014-01-01

We have previously shown that ethanol-naïve high-alcohol preferring (HAP) mice, genetically predis-posed to consume large quantities of alcohol, exhibited heightened sensitivity and more rapid acute functional tolerance (AFT) to alcohol-induced ataxia compared to low-alcohol preferring mice. The goal of the present study was to evaluate the effect of prior alcohol self-administration on these responses in HAP mice. Naïve male and female adult HAP mice from the second replicate of selection (HAP2) underwent 18 days of 24-h, 2-bottle choice drinking for 10% ethanol vs. water, or water only. After 18 days of fluid access, mice were tested for ataxic sensitivity and rapid AFT following a 1.75 g/kg injection of ethanol on a static dowel apparatus in Experiment 1. In Experiment 2, a separate group of mice was tested for more protracted AFT development using a dual-injection approach where a second, larger (2.0 g/kg) injection of ethanol was given following the initial recovery of performance on the task. HAP2 mice that had prior access to alcohol exhibited a blunted ataxic response to the acute alcohol challenge, but this pre-exposure did not alter rapid within-session AFT capacity in Experiment 1 or more protracted AFT capacity in Experiment 2. These findings suggest that the typically observed increase in alcohol consumption in these mice may be influenced by ataxic functional tolerance development, but is not mediated by a greater capacity for ethanol exposure to positively influence within-session ataxic tolerance. PMID:25454537

Taste responses to monosodium glutamate after alcohol exposure.

PubMed

Wrobel, Elzbieta; Skrok-Wolska, Dominika; Ziolkowski, Marcin; Korkosz, Agnieszka; Habrat, Boguslaw; Woronowicz, Bohdan; Kukwa, Andrzej; Kostowski, Wojciech; Bienkowski, Przemyslaw; Scinska, Anna

2005-01-01

The aim of the present study was to evaluate the effects of acute and chronic exposure to alcohol on taste responses to a prototypic umami substance, monosodium glutamate (MSG). The rated intensity and pleasantness of MSG taste (0.03-10.0%) was compared in chronic male alcoholics (n = 35) and control subjects (n = 25). In a separate experiment, the effects of acute exposure of the oral mucosa to ethanol rinse (0.5-4.0%) on MSG taste (0.3-3.0%) were studied in 10 social drinkers. The alcoholic and control group did not differ in terms of the rated intensity and pleasantness of MSG taste. Electrogustometric thresholds were significantly (P < 0.01) higher, i.e. worse, in the alcohol-dependent subjects. The difference remained significant after controlling for between-group differences in cigarette smoking and coffee drinking. Rinsing with ethanol did not alter either intensity or pleasantness of MSG taste in social drinkers. The present results suggest that: (i) neither acute nor chronic alcohol exposure modifies taste responses to MSG; (ii) alcohol dependence may be associated with deficit in threshold taste reactivity, as assessed by electrogustometry.

Deletion of vanilloid receptor (TRPV1) in mice alters behavioral effects of ethanol

PubMed Central

Blednov, Y.A.; Harris, R.A.

2009-01-01

The vanilloid receptor TRPV1 is activated by ethanol and this may be important for some of the central and peripheral actions of ethanol. To determine if this receptor has a role in ethanol-mediated behaviors, we studied null mutant mice in which the Trpv1 gene was deleted. Mice lacking this gene showed significantly higher preference for ethanol and consumed more ethanol in a two-bottle choice test as compared with wild type littermates. Null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol (2 g/kg). However, there were no differences between null mutant and wild type mice in severity of ethanol-induced acute withdrawal (4 g/kg) or conditioned taste aversion to ethanol (2.5 g/kg). Two behavioral phenotypes (decreased sensitivity to ethanol-induced sedation and faster recovery from ethanol-induced motor incoordination) seen in null mutant mice were reproduced in wild type mice by injection of a TRPV1 antagonist, capsazepine (10 mg/kg). These two ethanol behaviors were changed in the opposite direction after injection of capsaicin, a selective TRPV1 agonist, in wild type mice. The studies provide the first evidence that TRPV1 is important for specific behavioral actions of ethanol. PMID:19705551

The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice. The effect of N(G)-nitro-L-arginine methyl ester and L-arginine.

PubMed

Boban-Blagaic, Alenka; Blagaic, Vladimir; Romic, Zeljko; Jelovac, Nikola; Dodig, Goran; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Seiwerth, Sven; Sikiric, Predrag

2006-01-01

Alcohol disturbances, NO stimulation (by the NO-precursor L-arginine), and/or NO-synthesis blockade (by N(G)-nitro-L-arginine methyl ester, i.e. L-NAME) were challenged with stable gastric pentadecapeptide BPC 157, which inhibits both acute alcohol intoxication and alcohol withdrawal symptoms. Mice received intraperitoneally (i.p.) BPC 157 (10 microg/kg), L-NAME (10 mg/kg), and L-arginine (400 mg/kg), alone or in combination, 5 minutes before or after acute ethanol (4 g/kg i.p.) intoxication or after 0, 3, or 7 hours of withdrawal after drinking 20% alcohol for 13 days. BPC 157 rapidly opposes the strongest disturbance presentations in acute intoxication (sustained ethanol anesthesia, complete loss of righting reflex, no reaction to external stimuli, hypothermia, 25% mortality) and withdrawal (prominent seizures). NO-agents: Aggravation of acute alcohol intoxication and opposition to withdrawal are common, but the later intervals affected by L-arginine and the action throughout the experiment by L-NAME are distinctive. Given together, L-arginine and L-NAME counteract each other, while either the "L-NAME presentation" (acute intoxication) or the "L-arginine presentation" (withdrawal) predominates. BPC157+NO-agent: In acute intoxication (L-NAME predominating in NO-system functioning to aggravate intoxication), both BPC157+L-NAME and BPC157+L-arginine follow the presentation of L-NAME, but without worsened mortality. In withdrawal (L-arginine predominating in NO-system functioning to oppose disturbance symptoms), BPC157+L-NAME follows the presentation of L-NAME, while BPC 157+L-arginine imitates that of L-arginine. The relationships among pentadecapeptide BPC 157, the NO-system, acute alcohol intoxication, and opposed withdrawal may be important, presenting pentadecapeptide BPC 157 as a suitable alcohol antagonist.

Protective Effect of Hericium erinaceus on Alcohol Induced Hepatotoxicity in Mice

PubMed Central

Hao, Lijun; Xie, Yuxi; Wu, Guikai; Cheng, Aibin; Liu, Xiaogang; Zheng, Rongjuan; Huo, Hong; Zhang, Junwei

2015-01-01

We investigated the effects of Hericium erinaceus (HEM) on liver injury induced by acute alcohol administration in mice. Mice received ethanol (5 g/kg BW) by gavage every 12 hrs for a total of 3 doses. HEM (200 mg/kg BW) was gavage before ethanol administration. Subsequent serum alanine aminotransferase (ALT) level, aspartate aminotransaminase (AST) level, Maleic dialdehyde (MDA) level, hepatic total antioxidant status (TAOS), and activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were determined by ELISA and immunohistochemistry, respectively. HEM administration markedly (P < 0.05) decreased serum ALT, AST, and MDA levels. The hepatic histopathological observations showed that HEM had a relatively significant role in mice model, which had alcoholic liver damage. In conclusion, we observed that HEM (200 mg/kg BW) supplementation could restrain the hepatic damage caused by acute alcohol exposure. PMID:25960751

Protective Effect of Hericium erinaceus on Alcohol Induced Hepatotoxicity in Mice.

PubMed

Hao, Lijun; Xie, Yuxi; Wu, Guikai; Cheng, Aibin; Liu, Xiaogang; Zheng, Rongjuan; Huo, Hong; Zhang, Junwei

2015-01-01

We investigated the effects of Hericium erinaceus (HEM) on liver injury induced by acute alcohol administration in mice. Mice received ethanol (5 g/kg BW) by gavage every 12 hrs for a total of 3 doses. HEM (200 mg/kg BW) was gavage before ethanol administration. Subsequent serum alanine aminotransferase (ALT) level, aspartate aminotransaminase (AST) level, Maleic dialdehyde (MDA) level, hepatic total antioxidant status (TAOS), and activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were determined by ELISA and immunohistochemistry, respectively. HEM administration markedly (P < 0.05) decreased serum ALT, AST, and MDA levels. The hepatic histopathological observations showed that HEM had a relatively significant role in mice model, which had alcoholic liver damage. In conclusion, we observed that HEM (200 mg/kg BW) supplementation could restrain the hepatic damage caused by acute alcohol exposure.

Transient Exposure to Ethanol during Zebrafish Embryogenesis Results in Defects in Neuronal Differentiation: An Alternative Model System to Study FASD

PubMed Central

Joya, Xavier; Garcia-Algar, Oscar; Vall, Oriol; Pujades, Cristina

2014-01-01

Background The exposure of the human embryo to ethanol results in a spectrum of disorders involving multiple organ systems, including the impairment of the development of the central nervous system (CNS). In spite of the importance for human health, the molecular basis of prenatal ethanol exposure remains poorly understood, mainly to the difficulty of sample collection. Zebrafish is now emerging as a powerful organism for the modeling and the study of human diseases. In this work, we have assessed the sensitivity of specific subsets of neurons to ethanol exposure during embryogenesis and we have visualized the sensitive embryonic developmental periods for specific neuronal groups by the use of different transgenic zebrafish lines. Methodology/Principal Findings In order to evaluate the teratogenic effects of acute ethanol exposure, we exposed zebrafish embryos to ethanol in a given time window and analyzed the effects in neurogenesis, neuronal differentiation and brain patterning. Zebrafish larvae exposed to ethanol displayed small eyes and/or a reduction of the body length, phenotypical features similar to the observed in children with prenatal exposure to ethanol. When neuronal populations were analyzed, we observed a clear reduction in the number of differentiated neurons in the spinal cord upon ethanol exposure. There was a decrease in the population of sensory neurons mainly due to a decrease in cell proliferation and subsequent apoptosis during neuronal differentiation, with no effect in motoneuron specification. Conclusion Our investigation highlights that transient exposure to ethanol during early embryonic development affects neuronal differentiation although does not result in defects in early neurogenesis. These results establish the use of zebrafish embryos as an alternative research model to elucidate the molecular mechanism(s) of ethanol-induced developmental toxicity at very early stages of embryonic development. PMID:25383948

LINKING GABAA RECEPTOR SUBUNITS TO ALCOHOL-INDUCED CONDITIONED TASTE AVERSION AND RECOVERY FROM ACUTE ALCOHOL INTOXICATION

PubMed Central

Blednov, Y.A.; Benavidez, J.M.; Black, M.; Chandra, D.; Homanics, G.E.; Rudolph, U.; Harris, R.A.

2012-01-01

GABA type A receptors (GABAA-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors. We studied null mutant mice for six different GABAA-R subunits (α1, α2, α3, α4, α5 and δ). Only mice lacking the α2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol. These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the α2-subunit (Blednov et al., 2011) and indicate this aversive property of ethanol is dependent on ethanol action on α2-containing GABAA-R. Deletion of the α2-subunit led to faster recovery whereas absence of the α3-subunit slowed recovery from ethanol-induced incoordination (rotarod). Deletion of the other four subunits did not affect this behavior. Similar changes in this behavior for the α2 and α3 null mutants were found for flurazepam motor-incoordination. However, no differences in recovery were found in motor-incoordinating effects of an α1-selective modulator (zolpidem) or an α4-selective agonist (gaboxadol). Therefore, recovery of rotarod incoordination is under control of two GABAA-R subunits: α2 and α3. For motor activity, α3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both α2 and α3 (-/-) knockout mice were less sensitive to ethanol-induced reduction of motor activity (1.5 g/kg). These studies demonstrate that the effects of ethanol at GABAergic synapses containing α2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the α2 subunit with human alcoholism. PMID:23147414

Autophagy Constitutes a Protective Mechanism against Ethanol Toxicity in Mouse Astrocytes and Neurons.

PubMed

Pla, Antoni; Pascual, María; Guerri, Consuelo

2016-01-01

Ethanol induces brain damage and neurodegeneration by triggering inflammatory processes in glial cells through activation of Toll-like receptor 4 (TLR4) signaling. Recent evidence indicates the role of protein degradation pathways in neurodegeneration and alcoholic liver disease, but how these processes affect the brain remains elusive. We have demonstrated that chronic ethanol consumption impairs proteolytic pathways in mouse brain, and the immune response mediated by TLR4 receptors participates in these dysfunctions. We evaluate the in vitro effects of an acute ethanol dose on the autophagy-lysosome pathway (ALP) on WT and TLR4-/- mouse astrocytes and neurons in primary culture, and how these changes affect cell survival. Our results show that ethanol induces overexpression of several autophagy markers (ATG12, LC3-II, CTSB), and increases the number of lysosomes in WT astrocytes, effects accompanied by a basification of lysosomal pH and by lowered phosphorylation levels of autophagy inhibitor mTOR, along with activation of complexes beclin-1 and ULK1. Notably, we found only minor changes between control and ethanol-treated TLR4-/- mouse astroglial cells. Ethanol also triggers the expression of the inflammatory mediators iNOS and COX-2, but induces astroglial death only slightly. Blocking autophagy by using specific inhibitors increases both inflammation and cell death. Conversely, in neurons, ethanol down-regulates the autophagy pathway and triggers cell death, which is partially recovered by using autophagy enhancers. These results support the protective role of the ALP against ethanol-induced astroglial cell damage in a TLR4-dependent manner, and provide new insight into the mechanisms that underlie ethanol-induced brain damage and are neuronal sensitive to the ethanol effects.

Studies on the antimicrobial effects of Spondias mombin and Baphia nittida on dental caries organism.

PubMed

Amadi, E S; Oyeka, A; Onyeagba, R A; Okoli, I; Ugbogu, O C

2007-02-01

The antimicrobial effect of cold water, hot water and ethanolic extracts of Spondias mombin and Baphia nittida on cariogenic streptococci isolated from dental caries patients attending the Ebonyi State University Teaching hospital dental clinic Abakaliki was investigated using the agar well diffusion technique. The cold water and ethanolic extracts of Baphia nittida showed inhibition zone diameter (IZD) of 10 and 12 mm respectively at 400 mg mL(-1), while the hot water showed no inhibitory effect. All extracts of Spondias mombin did not inhibit the test organism. The cold water and ethanolic extracts of Baphia nittida showed Minimum Inhibitory Concentration (MIC) of 100 and 50 mg mL(-1) respectively. The combination of the cold water extracts of the two herbs showed enhanced activity of 13 mm. Phytochemical analysis of Baphia nittida revealed the presence of flavonoids, glycosides, proteins saponins, tannins, carbohydrate and steroidal aglycone. Acute toxicity testing of Baphia nittida at a range of 250-5000 mg kg(-1) bw using mice showed no clinical signs of acute toxicity. No chemical toxicity was observed amongst rats given Baphia nittida extracts 500 and 1000 mg kg(-1) bw after 30 days. Baphia nittida may be a potential source of an antimicrobial agent for the treatment and management of dental caries.

Gastroprotective Effects of Lion's Mane Mushroom Hericium erinaceus (Bull.:Fr.) Pers. (Aphyllophoromycetideae) Extract against Ethanol-Induced Ulcer in Rats

PubMed Central

Wong, Jing-Yang; Raman, Jegadeesh; Kuppusamy, Umah Rani; Sabaratnam, Vikineswary

2013-01-01

Hericium erinaceus is a famous tonic in oriental medicine. The gastroprotective effects of aqueous extract of H. erinaceus against ethanol-induced ulcers in Sprague Dawley rats were investigated. The possible involvements of lipid peroxidation, superoxide dismutase, and catalase were also investigated. Acute toxicity study was performed. The effects of aqueous extract of H. erinaceus on the ulcer areas, ulcer inhibition, gastric wall mucus, gross and histological gastric lesions, antioxidant levels, and malondialdehyde (MDA) contents were evaluated in ethanol-induced ulcer in vivo. In acute toxicity study, a high dose of 5 g/kg did not manifest any toxicological signs in rats. The extract promoted ulcer protection as ascertained by a significant reduction of the ulcer area. Furthermore, it exhibited a significant protection activity against gastric mucosal injury by preventing the depletion of antioxidant enzymes. The level of MDA was also limited in rat stomach tissues when compared with the ulcer control group. Immunohistochemistry showed upregulation of HSP70 protein and downregulation of BAX protein in rats pretreated with the extract. The aqueous extract of H. erinaceus protected gastric mucosa in our in vivo model. It is speculated that the bioactive compounds present in the extract may play a major role in gastroprotective activity. PMID:24302966

Concomitant stress potentiates the preference for, and consumption of, ethanol induced by chronic pre-exposure to ethanol.

PubMed

Morais-Silva, G; Fernandes-Santos, J; Moreira-Silva, D; Marin, M T

2016-01-01

Ethanol abuse is linked to several acute and chronic injuries that can lead to health problems. Ethanol addiction is one of the most severe diseases linked to the abuse of this drug. Symptoms of ethanol addiction include compulsive substance intake and withdrawal syndrome. Stress exposure has an important role in addictive behavior for many drugs of abuse (including ethanol), but the consequences of stress and ethanol in the organism when these factors are concomitant results in a complex interaction. We investigated the effects of concomitant, chronic administration of ethanol and stress exposure on the withdrawal and consumption of, as well as the preference for, ethanol in mice. Male Swiss mice (30-35 g, 8-10 per group) were exposed to an ethanol liquid diet as the only source of food for 15 days. In the final 5 days, they were exposed to forced swimming stress. Twelve hours after removal of the ethanol liquid diet, animals were evaluated for ethanol withdrawal by measuring anxiety-related behaviors and locomotor activity. Twenty-four hours after evaluation of ethanol withdrawal, they were evaluated for voluntary consumption of ethanol in a "three-bottle choice" paradigm. Mice exposed to chronic consumption of ethanol had decreased locomotor activity during withdrawal. Contrary to our expectations, a concomitant forced swimming stress did not aggravate ethanol withdrawal. Nevertheless, simultaneous ethanol administration and stress exposure increased voluntary consumption of ethanol, mainly solutions containing high concentrations of ethanol. These results showed that stressful situations during ethanol intake may aggravate specific addiction-related behaviors.

Analysis of Surgical Success in Preventing Recurrent Acute Exacerbations in Chronic Pancreatitis

PubMed Central

Nealon, William H.; Matin, Sina

2001-01-01

Objective To determine whether surgical intervention prevents recurrent acute exacerbations in chronic pancreatitis (CP). Summary Background Data The primary goal of surgical intervention in the treatment of CP has been relief of chronic unrelenting abdominal pain. A subset of patients with CP have intermittent acute exacerbations, often with increasing frequency and often unrelated to ongoing ethanol abuse. Little data exist regarding the effectiveness of surgery to prevent acute attacks. Methods From 1985 to 1999, all patients identified with a diagnosis of CP were recruited to participate in an ongoing program of serial clinic visits and functional and clinical evaluations. Patients were offered surgery using standard criteria. Data were gathered regarding ethanol abuse, pain, narcotic use, and recurrent acute exacerbations requiring hospital admission before and after surgery. Patients were broadly categorized as having severe unrelenting pain alone (group 1), severe pain with intermittent acute exacerbations (group 2), and intermittent acute exacerbations only (group 3). Results Two hundred fifty-nine patients were recruited. One hundred eighty-five patients underwent 199 surgical procedures (124 modified Puestow procedure [LPJ], 29 distal pancreatectomies [DP], and 46 pancreatic head resections [PHR; 14 performed after failure of LPJ]). There were no deaths. The complication rate was 4% for LPJ, 15% for DP, and 27% for PHR. Ethanol abuse was causative in 238 patients (92%). Mean follow-up was 81 months. There were 104 patients in group 1 (86 who underwent surgery), 71 patients in group 2 (64 who underwent surgery), and 84 in group 3 (49 who underwent surgery). No patient without surgery had spontaneous resolution of symptoms. Postoperative pain relief (freedom from narcotic analgesics) was achieved in 153 of 185 patients (83%) overall: 106 of 124 (86%) for LPJ, 19 of 29 (67%) for DP, and 42 of 46 (91%) for PHR. The mean rate of acute exacerbations was 6.3 ± 2.1 events per year before surgery in group 2 and 7.8 ± 1.8 events per year in group 3. After surgery, no acute exacerbations occurred in 42 of 64 (66%) group 2 patients and in 40 of 49 (82%) group 3 patients. The mean number of episodes of acute exacerbation after surgery was 1.6 ± 2.3 events in group 2 and 1.1 ± 1.9 events in group 3. Only four patients in group 2 and one patient in group 3 had an equal or increased frequency of attacks after surgery. Preventing attacks was most effective with LPJ (58/64, 91%) and least effective for DP (6/18, 33%). Conclusions Surgical intervention prevents recurrent acute exacerbations. The overall frequency of events was reduced in nearly all patients. Therefore, surgical intervention is indicated in patients with CP whose disease is characterized by recurrent acute exacerbations. PMID:11371738

Analysis of surgical success in preventing recurrent acute exacerbations in chronic pancreatitis.

PubMed

Nealon, W H; Matin, S

2001-06-01

To determine whether surgical intervention prevents recurrent acute exacerbations in chronic pancreatitis (CP). The primary goal of surgical intervention in the treatment of CP has been relief of chronic unrelenting abdominal pain. A subset of patients with CP have intermittent acute exacerbations, often with increasing frequency and often unrelated to ongoing ethanol abuse. Little data exist regarding the effectiveness of surgery to prevent acute attacks. From 1985 to 1999, all patients identified with a diagnosis of CP were recruited to participate in an ongoing program of serial clinic visits and functional and clinical evaluations. Patients were offered surgery using standard criteria. Data were gathered regarding ethanol abuse, pain, narcotic use, and recurrent acute exacerbations requiring hospital admission before and after surgery. Patients were broadly categorized as having severe unrelenting pain alone (group 1), severe pain with intermittent acute exacerbations (group 2), and intermittent acute exacerbations only (group 3). Two hundred fifty-nine patients were recruited. One hundred eighty-five patients underwent 199 surgical procedures (124 modified Puestow procedure [LPJ], 29 distal pancreatectomies [DP], and 46 pancreatic head resections [PHR; 14 performed after failure of LPJ]). There were no deaths. The complication rate was 4% for LPJ, 15% for DP, and 27% for PHR. Ethanol abuse was causative in 238 patients (92%). Mean follow-up was 81 months. There were 104 patients in group 1 (86 who underwent surgery), 71 patients in group 2 (64 who underwent surgery), and 84 in group 3 (49 who underwent surgery). No patient without surgery had spontaneous resolution of symptoms. Postoperative pain relief (freedom from narcotic analgesics) was achieved in 153 of 185 patients (83%) overall: 106 of 124 (86%) for LPJ, 19 of 29 (67%) for DP, and 42 of 46 (91%) for PHR. The mean rate of acute exacerbations was 6.3 +/- 2.1 events per year before surgery in group 2 and 7.8 +/- 1.8 events per year in group 3. After surgery, no acute exacerbations occurred in 42 of 64 (66%) group 2 patients and in 40 of 49 (82%) group 3 patients. The mean number of episodes of acute exacerbation after surgery was 1.6 +/- 2.3 events in group 2 and 1.1 +/- 1.9 events in group 3. Only four patients in group 2 and one patient in group 3 had an equal or increased frequency of attacks after surgery. Preventing attacks was most effective with LPJ (58/64, 91%) and least effective for DP (6/18, 33%). Surgical intervention prevents recurrent acute exacerbations. The overall frequency of events was reduced in nearly all patients. Therefore, surgical intervention is indicated in patients with CP whose disease is characterized by recurrent acute exacerbations.

Gas chromatography-mass spectrometry of ethyl palmitate calibration and resolution with ethyl oleate as biomarker ethanol sub acute in urine application study

NASA Astrophysics Data System (ADS)

Suaniti, Ni Made; Manurung, Manuntun

2016-03-01

Gas Chromatography-Mass Spectrometry is used to separate two and more compounds and identify fragment ion specific of biomarker ethanol such as palmitic acid ethyl ester (PAEE), as one of the fatty acid ethyl esters as early detection through conyugated reaction. This study aims to calibrate ethyl palmitate and develop analysis with oleate acid. This methode can be used analysis ethanol and its chemistry biomarker in ethanol sub-acute consumption as analytical forensic toxicology. The result show that ethanol level in urine rats Wistar were 9.21 and decreased 6.59 ppm after 48 hours consumption. Calibration curve of ethyl palmitate was y = 0.2035 x + 1.0465 and R2 = 0.9886. Resolution between ethyl palmitate and oleate were >1.5 as good separation with fragment ion specific was 88 and the retention time was 18 minutes.

Effects of ethanolic extract and naphthoquinones obtained from the bulbs of Cipura paludosa on short-term and long-term memory: involvement of adenosine A₁ and A₂A receptors.

PubMed

Lucena, Greice M R S; Matheus, Filipe C; Ferreira, Vania M; Tessele, Priscila B; Azevedo, Mariangela S; Cechinel-Filho, Valdir; Prediger, Rui D

2013-04-01

Previous studies from our group have indicated important biological properties of the ethanolic extract and isolated compounds from the bulbs of Cipura paludosa (Iridaceae), a native plant widely distributed in northern Brazil, including antioxidant, neuroprotective and anti-nociceptive activities. In the present study, the effects of the ethanolic extract and its two naphthoquinones (eleutherine and isoeleutherine) on the short- and long-term memory of adult rodents were assessed in social recognition and inhibitory avoidance tasks. Acute pre-training oral administration of the ethanolic extract improved the short-term social memory in rats as well as facilitated the step-down inhibitory avoidance short- and long-term memory in mice. Moreover, the co-administration of 'non-effective' doses of the extract of Cipura paludosa and the adenosine receptor antagonists caffeine (non-selective), DPCPX (adenosine A1 receptor antagonist) and ZM241385 (adenosine A2A receptor antagonist) improved the social recognition memory of rats. In the inhibitory avoidance task, the co-administration of sub-effective doses of the extract with caffeine or ZM241385, but not with DPCPX, improved the short- and long-term memory of mice. Finally, the acute oral administration of eleutherine and isoeleutherine facilitated the inhibitory avoidance short- and long-term memory in mice. These results demonstrate for the first time the cognitive-enhancing properties of the extract and isolated compounds from the bulbs of Cipura paludosa in rodents and suggest a possible involvement of adenosine A1 and A2A receptors in these effects. © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.

Neuromotor effects of acute ethanol inhalation exposure in humans: a preliminary study.

PubMed

Nadeau, Véronique; Lamoureux, Daniel; Beuter, Anne; Charbonneau, Michel; Tardif, Robert

2003-07-01

Ethanol (ETOH) is added to unleaded gasoline to decrease environmental levels of carbon monoxide from automobiles emissions. Therefore, addition of ETOH in reformulated fuel will most likely increase and the involuntarily human exposure to this chemical will also increase. This preliminary study was undertaken to evaluate the possible neuromotor effects resulting from acute ETOH exposure by inhalation in humans. Five healthy non-smoking adult males, with no history of alcohol abuse, were exposed by inhalation, in a dynamic, controlled-environment exposure chamber, to various concentrations of ETOH (0, 250, 500 and 1,000 ppm in air) for six hours. Reaction time, body sway, hand tremor and rapid alternating movements were measured before and after each exposure session by using the CATSYS 7.0 system and a diadochokinesimeter. The concentrations of ETOH in blood and in alveolar air were also measured. ETOH was not detected in blood nor in alveolar air when volunteers were exposed to 250 and 500 ppm, but at the end of exposure to 1,000 ppm, blood and alveolar air concentrations were 0.443 mg/100ml and 253.1 ppm, respectively. The neuromotor tests did not show conclusively significant differences between the exposed and non-exposed conditions. In conclusion, this study suggests that acute exposure to ethanol at 1,000 ppm or lower or to concentrations that could be encountered upon refueling is not likely to cause any significant neuromotor alterations in healthy males.

Adolescent alcohol exposure and persistence of adolescent-typical phenotypes into adulthood: a mini-review

PubMed Central

Spear, Linda Patia; Swartzwelder, H. Scott

2014-01-01

Alcohol use is typically initiated during adolescence, which, along with young adulthood, is a vulnerable period for the onset of high-risk drinking and alcohol abuse. Given across-species commonalities in certain fundamental neurobehavioral characteristics of adolescence, studies in laboratory animals such as the rat have proved useful to assess persisting consequences of repeated alcohol exposure. Despite limited research to date, reports of long-lasting effects of adolescent ethanol exposure are emerging, along with certain common themes. One repeated finding is that adolescent exposure to ethanol sometimes results in the persistence of adolescent-typical phenotypes into adulthood. Instances of adolescent -like persistence have been seen in terms of baseline behavioral, cognitive, electrophysiological and neuroanatomical characteristics, along with the retention of adolescent-typical sensitivities to acute ethanol challenge. These effects are generally not observed after comparable ethanol exposure in adulthood. Persistence of adolescent-typical phenotypes is not always evident, and may be related to regionally-specific ethanol influences on the interplay between CNS excitation and inhibition critical for the timing of neuroplasticity. PMID:24813805

Glutamatergic transmission in the central nucleus of the amygdala is selectively altered in Marchigian Sardinian alcohol-preferring rats: alcohol and CRF effects

PubMed Central

Herman, Melissa A.; Varodayan, Florence P.; Oleata, Christopher S.; Luu, George; Kirson, Dean; Heilig, Markus; Ciccocioppo, Roberto; Roberto, Marisa

2015-01-01

The CRF system of the central nucleus of the amygdala (CeA) is important for the processing of anxiety, stress, and effects of acute and chronic ethanol. We previously reported that ethanol decreases evoked glutamate transmission in the CeA of Sprague Dawley rats and that ethanol dependence alters glutamate release in the CeA. Here, we examined the effects of ethanol, CRF and a CRF1 receptor antagonist on spontaneous and evoked glutamatergic transmission in CeA neurons from Wistar and Marchigian Sardinian Preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and characterized by heightened activity of the CRF1 system. Basal spontaneous and evoked glutamate transmission in CeA neurons from msP rats was increased compared to Wistar rats. Ethanol had divergent effects, either increasing or decreasing spontaneous glutamate release in the CeA of Wistar rats. This bidirectional effect was retained in msP rats, but the magnitude of the ethanol-induced increase in glutamate release was significantly smaller. The inhibitory effect of ethanol on evoked glutamatergic transmission was similar in both strains. CRF also either increased or decreased spontaneous glutamate release in CeA neurons of Wistar rats, however, in msP rats CRF only increased glutamate release. The inhibitory effect of CRF on evoked glutamatergic transmission was also lost in neurons from msP rats. A CRF1 antagonist produced only minor effects on spontaneous glutamate transmission, which were consistent across strains, and no effects on evoked glutamate transmission. These results demonstrate that the genetically altered CRF system of msP rats results in alterations in spontaneous and stimulated glutamate signaling in the CeA that may contribute to both the anxiety and drinking behavioral phenotypes. PMID:26519902

Low and moderate prenatal ethanol exposures of mice during gastrulation or neurulation delays neurobehavioral development.

PubMed

Schambra, Uta B; Goldsmith, Jeff; Nunley, Kevin; Liu, Yali; Harirforoosh, Sam; Schambra, Heidi M

2015-01-01

Human and animal studies show significant delays in neurobehavioral development in offspring after prolonged prenatal exposure to moderate and high ethanol doses resulting in high blood alcohol concentration (BECs). However, none have investigated the effects of lower ethanol doses given acutely during specific developmental time periods. Here, we sought to create a mouse model for modest and circumscribed human drinking during the 3rd and 4th weeks of pregnancy. We acutely treated mice during embryo gastrulation on gestational day (GD) 7 or neurulation on GD8 with a low or moderate ethanol dose given via gavage that resulted in BECs of 107 and 177 mg/dl, respectively. We assessed neonatal physical development (pinnae unfolding, and eye opening); weight gain from postnatal day (PD) 3-65; and neurobehavioral maturation (pivoting, walking, cliff aversion, surface righting, vertical screen grasp, and rope balance) from PD3 to 17. We used a multiple linear regression model to determine the effects of dose, sex, day of treatment and birth in animals dosed during gastrulation or neurulation, relative to their vehicle controls. We found that ethanol exposure during both time points (GD7 and GD8) resulted in some delays of physical development and significant sensorimotor delays of pivoting, walking, and thick rope balance, as well as additional significant delays in cliff aversion and surface righting after GD8 treatment. We also found that treatment with the low ethanol dose more frequently affected neurobehavioral development of the surviving pups than treatment with the moderate ethanol dose, possibly due to a loss of severely affected offspring. Finally, mice born prematurely were delayed in their physical and sensorimotor development. Importantly, we showed that brief exposure to low dose ethanol, if administered during vulnerable periods of neuroanatomical development, results in significant neurobehavioral delays in neonatal mice. We thus expand concerns about alcohol consumption during the 3rd and 4th weeks of human pregnancy to include occasional light to moderate drinking. Copyright © 2015 Elsevier Inc. All rights reserved.

Ethanol increases HSP70 concentrations in honeybee (Apis mellifera L.) brain tissue.

PubMed

Hranitz, John M; Abramson, Charles I; Carter, Richard P

2010-05-01

Previous research on the honeybee ethanol model established how acute ethanol exposure altered function at different levels of organization: behavior and learning, ecology, and physiology. The purpose of this study was to evaluate whether ethanol doses that affect honeybee behavior also induce a significant stress response, measured by heat shock protein 70 (HSP70) concentrations, in honeybee brain tissues. Experiment 1 examined how pretreatment handling influenced brain HSP70 concentrations in three pretreatment groups of bees; immediately after being collected, after being harnessed and fed, and after 22-24h in a harness. HSP70 concentrations did not differ among pretreatment groups within replicates, although we observed significantly different HSP70 concentrations between the two replicates. Experiment 2 investigated the relationship between ethanol dose and brain HSP70 concentrations. Bees were placed in seven experimental groups, the three pretreatment groups as in Experiment 1 and four ethanol-fed groups. Bees in ethanol treatments were fed 1.5M sucrose (control) and 1.5M sucrose-ethanol solutions containing 2.5, 5, and 10% ethanol, allowed to sit for 4h, and dissected brains were assayed for HSP70. We observed ethanol-induced increases in honeybee brain HSP70 concentrations from the control group through the 5% ethanol group. Only bees in the 5% ethanol group had HSP70 concentrations significantly higher than the control group. The inverted U-shaped ethanol dose-HSP70 concentration response curve indicated that ingestion of 2.5% ethanol and 5% ethanol stimulated the stress response, whereas ingestion of 10% ethanol inhibited the stress response. Doses that show maximum HSP70 concentration (5% ethanol) or HSP70 inhibition (10% ethanol) correspond to those (> or =5% ethanol) that also impaired honeybees in previous studies. We conclude that acute ethanol intoxication by solutions containing > or =5% ethanol causes significant ethanol-induced stress in brain tissue that impairs honeybee behavior and associative learning. 2010 Elsevier Inc. All rights reserved.

Effects of an ethanol extract and the diterpene, xylopic acid, of Xylopia aethiopica fruits in murine models of musculoskeletal pain.

PubMed

Woode, Eric; Ameyaw, Elvis Ofori; Boakye-Gyasi, Eric; Abotsi, Wonder Kofi Mensah; Oppong Kyekyeku, James; Adosraku, Reimmel; Biney, Robert Peter

2016-12-01

Fruits of Xylopia aethiopica (Dunal) A. Rich. (Annonaceae) are used traditionally to manage arthritis, headache and other pain disorders. The analgesic properties of the X. aethiopica ethanol fruit extract (XAE) and xylopic acid (XA) were evaluated in musculoskeletal pain models. Acute muscle pain was induced in gastrocnemius muscle of Sprague-Dawley rats with 3% carrageenan (i.m.). Rats received XAE (30-300 mg/kg), XA (10-100 mg/kg) or morphine (1-10 mg/kg) after 12 h. Effects of XAE and XA on muscle pain were assessed by measuring post-treatment grip strength of the rats. Chronic muscle pain was similarly induced, but drug treatment was on the eighth day and effects of XAE and XA assessed with Randall-Selitto test for hyperlagesia. Acute-skeletal pain was induced in knee joints of rats with 3% carrageenan-kaolin mixture and effects determined 12-h later. Similar induction protocol was used for chronic knee pain with treatment and measurement as done for chronic muscle pain. XAE and XA significantly and dose-dependently ameliorated both acute muscle (ED 50 mg/kg: XAE = 22.9; XA = 6.2) and skeletal hyperalgesia (XAE = 39.9; XA = 17.7) induced by 3% carrageenan. Similarly, chronic skeletal hyperalgesia was reduced by XAE and XA treatment similar to morphine (ED 50 : XAE = 13.0; XA = 4.6). This reduction was also seen in chronic muscle hyperalgesia (ED 50 : XAE = 79.1; XA = 42.7). XAE and XA significantly reduced the spread of hyperalgesia to contralateral limbs in both models of chronic hyperalgesia. These findings establish analgesic properties of the ethanol fruit extract of X. aethiopica and xylopic acid in musculoskeletal pain.

Inhibitory effects of physalin B and physalin F on various human leukemia cells in vitro.

PubMed

Chiang, H C; Jaw, S M; Chen, P M

1992-01-01

Physalins B and F were isolated and characterized from the ethanolic extract of the whole plant of Physalis angulata L. (Solanaceae). Both physalin B and physalin F inhibited the growth of several human leukemia cells: K562 (erythroleukemia), APM1840 (acute T lymphoid leukemia), HL-60 (acute promyelocytic leukemia), KG-1 (acute myeloid leukemia), CTV1 (acute monocytic leukemia) and B cell (acute B lymphoid leukemia). Physalin F showed a stronger activity against these leukemia cells than physalin B, especially against acute myeloid leukemia (KG-1) and acute B lymphoid leukemia (B cell). From the structural features, the active site seems to be the functional epoxy group for physalin F and the double bond for physalin B located at carbon 5 and 6; the former is much more active than the latter as regards anti-leukemic effects.

Effects of an alkaloid-rich extract from Mitragyna speciosa leaves and fluoxetine on sleep profiles, EEG spectral frequency and ethanol withdrawal symptoms in rats.

PubMed

Cheaha, Dania; Keawpradub, Niwat; Sawangjaroen, Kitja; Phukpattaranont, Pimpimol; Kumarnsit, Ekkasit

2015-10-15

Many antidepressants are effective in alleviating ethanol withdrawal symptoms. However, most of them suppress rapid eye movement (REM) sleep. Thus, development of antidepressants without undesirable side effects would be preferable. Previously, crude alkaloid extract from Mitragyna speciosa (MS) Korth was found to produce antidepressant activities. It was hypothesized that the alkaloid extract from MS may attenuate ethanol withdrawal without REM sleep disturbance. Adult male Wistar rats implanted with electrodes over the frontal and parietal cortices were used for two separated studies. For an acute study, 10 mg/kg fluoxetine or 60 mg/kg alkaloid extract from MS were administered intragastrically. Electroencephalographic (EEG) signals were recorded for 3 h to examine sleep profiles and EEG fingerprints. Another set of animal was used for an ethanol withdrawal study. They were rendered dependent on ethanol via a modified liquid diet (MLD) containing ethanol ad libitum for 28 days. On day 29, fluoxetine (10 mg/kg) or alkaloid extract from MS (60 mg/kg) were administered 15 min before the ethanol-containing MLD was replaced with an isocaloric ethanol-free MLD to induced ethanol withdrawal symptoms. The sleep analysis revealed that alkaloid extract from MS did not change any REM parameters which included average duration of each REM episode, total REM time, number of REM episode and REM latency whereas fluoxetine significantly suppressed all REM parameters and delayed REM latency. However, power spectral analysis revealed similar fingerprints for fluoxetine and alkaloid extract from MS characterized by decreasing powers in the slow frequency range in frontal and parietal cortical EEG. Neither treatment affected spontaneous motor activity. Finally, both alkaloid extract from MS and fluoxetine were found to significantly attenuate ethanol withdrawal-induced hyperexcitability (increases gamma activity) in both cortices and to reduce locomotor activity. The present study demonstrated that the alkaloid extract from MS alleviates ethanol withdrawal severity with no side effect on REM sleep. In addition, these data suggest that suppressive effects on slow frequency powers but not REM sleep may be hallmarks of effective antidepressants for ethanol withdrawal treatment. Copyright © 2015 Elsevier GmbH. All rights reserved.

Preliminary studies on antihepatotoxic effect of Physalis peruviana Linn. (Solanaceae) against carbon tetrachloride induced acute liver injury in rats.

PubMed

Arun, M; Asha, V V

2007-04-20

Physalis peruviana is a medicinal herb used by Muthuvan tribes and Tamilian native who reside in the shola forest regions of Kerala, India against jaundice. It was evaluated for its antihepatotoxic, phytochemical analysis and the acute toxicity of the most promising extract in rats. Water, ethanol and hexane extracts of Physalis peruviana (500mg/kg body weight) showed antihepatotoxic activities against CCl(4) induced hepatotoxicity. The ethanol and hexane extracts showed moderate activity compared to water extract, which showed activity at a low dose of 125mg/kg. The results were judged from the serum marker enzymes. Histopathological changes induced by CCl(4) were also significantly reduced by the extract. Further, the extract administration to rats resulted in an increase in hepatic GSH and decrease in MDA. Preliminary phytochemical analysis revealed the presence of various components in the crude aqueous extract. The extract was found to be devoid of any conspicuous acute toxicity in rats.

Conditioned effects of ethanol on the immune system.

PubMed

Gano, Anny; Pautassi, Ricardo Marcos; Doremus-Fitzwater, Tamara L; Deak, Terrence

2017-04-01

Several studies indicate that the immune system can be subjected to classical conditioning. Acute ethanol intoxication significantly modulates several pro-inflammatory cytokines (e.g. interleukins-1 and 6 [IL-1β and IL-6, respectively] and tumor necrosis factor alpha [TNFα])) in several brain areas, including amygdala (AMG), paraventricular nucleus (PVN), and hippocampus (HPC). It is unknown, however, whether cues associated with ethanol can elicit conditioned alterations in cytokine expression. The present study analyzed, in male Sprague-Dawley rats, whether ethanol-induced changes in the central cytokine response may be amenable to conditioning. In Experiments 1 and 2, the rats were given one or two pairings between a distinctive odor (conditional stimulus, CS) and the post-absorptive effects of a high (3.0 or 4.0 g/kg, Experiments 1 and 2, respectively) ethanol dose. Neither of these experiments revealed conditioning of IL-6, IL-1β, or TNFα, as measured via mRNA levels. Yet, re-exposure to the lemon-odor CS in Experiment 1 significantly increased C-Fos levels in the PVN. In Experiment 3, the rats were given four pairings between an odor CS and a moderate ethanol dose (2.0 g/kg), delivered intraperitoneally (i.p.) or intragastrically (i.g.). Re-exposure to the odor CS significantly increased IL-6 levels in HPC and AMG, an effect only evident in paired rats administered ethanol i.p. Overall, this study suggests that ethanol exposure can regulate the levels of IL-6 at HPC and AMG via classical conditioning mechanisms. These ethanol-induced, conditioned alterations in cytokine levels may ultimately affect the intake and motivational effects of ethanol. Impact statement This study examines, across three experiments, whether odor cues associated with ethanol exposure can condition changes in cytokine expression. The analysis of ethanol-induced conditioning of immune responses is a novel niche that can help understand the transition from social drinking to alcohol abuse and dependence. Ethanol-induced conditioning of the immune system could likely exacerbate neuroinflammation and drug-related toxicity, which in turn may facilitate further engagement in ethanol intake. The main new finding of the present study was that, after four pairings of ethanol's unconditioned effects and a distinctive odor, the latter CS increased IL-6 levels in HPC and AMG. This suggests that ethanol's effects upon IL-6 in HPC and AMG may come under conditioned control, particularly after repeated pairings between distinctive odor cues and ethanol's effects. This article advances our knowledge of conditioned increases in cytokine responses, which should help understand the mechanisms underlying alcohol use, abuse, and relapse.

Effect of guava (Psidium guajava Linn.) leaf soluble solids on glucose metabolism in type 2 diabetic rats.

PubMed

Shen, Szu-Chuan; Cheng, Fang-Chi; Wu, Ning-Jung

2008-11-01

This study investigated the effect of aqueous and ethanol soluble solid extracts of guava (Psidium guajava Linn.) leaves on hypoglycemia and glucose metabolism in type 2 diabetic rats. Low-dose streptozotocin (STZ) and nicotinamide were injected into Sprague-Dawley (SD) rats to induce type 2 diabetes. Acute and long-term feeding tests were carried out, and an oral glucose tolerance test (OGTT) to follow the changes in plasma glucose and insulin levels was performed to evaluate the antihyperglycemic effect of guava leaf extracts in diabetic rats.The results of acute and long-term feeding tests showed a significant reduction in the blood sugar level in diabetic rats fed with either the aqueous or ethanol extract of guava leaves (p < 0.05). Long-term administration of guava leaf extracts increased the plasma insulin level and glucose utilization in diabetic rats. The results also indicated that the activities of hepatic hexokinase, phosphofructokinase and glucose-6-phosphate dehydrogenase in diabetic rats fed with aqueous extracts were higher than in the normal diabetic group (p < 0.05). On the other hand, diabetic rats treated with the ethanol extract raised the activities of hepatic hexokinase and glucose-6-phosphate dehydrogenase (p < 0.05) only. The experiments provided evidence to support the antihyperglycemic effect of guava leaf extract and the health function of guava leaves against type 2 diabetes.

Repeated Binge-Like Ethanol Drinking Alters Ethanol Drinking Patterns and Depresses Striatal GABAergic Transmission

PubMed Central

Wilcox, Mark V; Carlson, Verginia C Cuzon; Sherazee, Nyssa; Sprow, Gretchen M; Bock, Roland; Thiele, Todd E; Lovinger, David M; Alvarez, Veronica A

2014-01-01

Repeated cycles of binge alcohol drinking and abstinence are key components in the development of dependence. However, the precise behavioral mechanisms underlying binge-like drinking and its consequences on striatal synaptic physiology remain unclear. In the present study, ethanol and water drinking patterns were recorded with high temporal resolution over 6 weeks of binge-like ethanol drinking using the ‘drinking in the dark' (DID) protocol. The bottle exchange occurring at the beginning of each session prompted a transient increase in the drinking rate that might facilitate the acquisition of ethanol binge-like drinking. Ethanol drinking mice also displayed a ‘front-loading' behavior, in which the highest rate of drinking was recorded during the first 15 min. This rate increased over weeks and paralleled the mild escalation of blood ethanol concentrations. GABAergic and glutamatergic transmission in the dorsal striatum were examined following DID. Spontaneous glutamatergic transmission and the density of dendritic spines were unchanged after ethanol drinking. However, the frequency of GABAA receptor-mediated inhibitory postsynaptic currents was depressed in medium spiny neurons of ethanol drinking mice. A history of ethanol drinking also increased ethanol preference and altered the acute ethanol effects on GABAergic transmission differentially in dorsolateral and dorsomedial striatum. Together, the study shows that the bottle exchange during DID promotes fast, voluntary ethanol drinking and that this intermittent pattern of ethanol drinking causes a depression of GABAergic transmission in the dorsal striatum. PMID:23995582

The Role of GABAA Receptors in the Development of Alcoholism

PubMed Central

Enoch, Mary-Anne

2008-01-01

Alcoholism is a common, heritable, chronic relapsing disorder. GABAA receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABAA receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABAA receptors: tolerance is associated with generally decreased GABAA receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABAA receptors may be implicated in the switch from heavy drinking to dependence. GABAA receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABAA receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABAA receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review. PMID:18440057

The role of GABA(A) receptors in the development of alcoholism.

PubMed

Enoch, Mary-Anne

2008-07-01

Alcoholism is a common, heritable, chronic relapsing disorder. GABA(A) receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA(A) receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA(A) receptors: tolerance is associated with generally decreased GABA(A) receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA(A) receptors may be implicated in the switch from heavy drinking to dependence. GABA(A) receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA(A) receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA(A) receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

Inflammatory PAF Receptor Signaling Initiates Hedgehog Signaling and Kidney Fibrogenesis During Ethanol Consumption

PubMed Central

Latchoumycandane, Calivarathan; Hanouneh, Mohamad; Nagy, Laura E.; McIntyre, Thomas M.

2015-01-01

Acute inflammation either resolves or proceeds to fibrotic repair that replaces functional tissue. Pro-fibrotic hedgehog signaling and induction of its Gli transcription factor in pericytes induces fibrosis in kidney, but molecular instructions connecting inflammation to fibrosis are opaque. We show acute kidney inflammation resulting from chronic ingestion of the common xenobiotic ethanol initiates Gli1 transcription and hedgehog synthesis in kidney pericytes, and promotes renal fibrosis. Ethanol ingestion stimulated transcription of TGF-ß, collagens I and IV, and alpha-smooth muscle actin with accumulation of these proteins. This was accompanied by deposition of extracellular fibrils. Ethanol catabolism by CYP2E1 in kidney generates local reactive oxygen species that oxidize cellular phospholipids to phospholipid products that activate the Platelet-activating Factor receptor (PTAFR) for inflammatory phospholipids. Genetically deleting this ptafr locus abolished accumulation of mRNA for TGF-ß, collagen IV, and α-smooth muscle actin. Loss of PTAFR also abolished ethanol-stimulated Sonic (Shh) and Indian hedgehog (Ihh) expression, and abolished transcription and accumulation of Gli1. Shh induced in pericytes and Ihh in tubules escaped to urine of ethanol-fed mice. Neutrophil myeloperoxidase (MPO) is required for ethanol-induced kidney inflammation, and Shh was not present in kidney or urine of mpo -/- mice. Shh also was present in urine of patients with acute kidney injury, but not in normal individuals or those with fibrotic liver cirrhosis We conclude neither endogenous PTAFR signaling nor CYP2E1-generated radicals alone are sufficient to initiate hedgehog signaling, but instead PTAFR-dependent neutrophil infiltration with myeloperoxidase activation is necessary to initiate ethanol-induced fibrosis in kidney. We also show fibrogenic mediators escape to urine, defining a new class of urinary mechanistic biomarkers of fibrogenesis for an organ not commonly biopsied. PMID:26720402

[Acute ethanol intoxication among children and adolescents. A retrospective analysis of 173 patients admitted to a university children hospital].

PubMed

Schöberl, S; Nickel, P; Schmutzer, G; Siekmeyer, W; Kiess, W

2008-01-01

In the last time the alcohol consumption among children and adolescents is a big theme in all kind of media. The ethanol consumption among children and adolescents has risen during the last years, but also new hazardous drinking patterns like "binge-drinking" are increasing. These drinking episodes are responsible for many hospital presentations of children and adolescents with acute ethanol intoxication. This study is a retrospective analysis of 173 patients admitted to the university children hospital of Leipzig due to acute ethanol intoxication during the period 1998-2004. Investigated parameters were: socio-demographic factors, clinical presentation and management as well as quantity and type of alcohol. During the years 1998-2004 the rate of alcohol intoxicated patients in this study increased, from 1998-2003 at about 171.4%. Totally 173 patients with an average age of 14.5 years were admitted to the university children hospital. There were significantly more boys than girls. The mean blood alcohol concentration of these patients was 1.77%. Some of the patients had severe symptoms. 62 were unconscious, 2 were in coma and at least 3 patients had to be ventilated. A difference between socioeconomic groups could be observed by comparing the different school types. 44.8% of the patients went to the middle school. Furthermore 17 patients of this study had mental disorders or psychosocial problems and were therefore in psychological or psychiatric treatment. In this study a significant influence of social classes or psychosocial problems on alcohol consumption such as binge-drinking leading to acute ethanol intoxication could not be found. Alarming is the increasing number of ethanol intoxicated patients, the young age, the high measured blood ethanol concentrations and the severe symptoms of these patients. This is the reason why early and intensive prevention strategies are required.

Effects of prolonged ethanol vapor exposure on forced swim behavior, and neuropeptide Y and corticotropin-releasing factor levels in rat brains.

PubMed

Walker, Brendan M; Drimmer, David A; Walker, Jennifer L; Liu, Tianmin; Mathé, Aleksander A; Ehlers, Cindy L

2010-09-01

Depressive symptoms in alcohol-dependent individuals are well-recognized and clinically relevant phenomena. The etiology has not been elucidated although it is clear that the depressive symptoms may be alcohol independent or alcohol induced. To contribute to the understanding of the neurobiology of chronic ethanol use, we investigated the effects of chronic intermittent ethanol vapor exposure on behaviors in the forced swim test (FST) and neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) levels in specific brain regions. Adult male Wistar rats were subjected to intermittent ethanol vapor (14 h on/10 h off) or air exposure for 2 weeks and were then tested at three time points corresponding to acute withdrawal (8-12 h into withdrawal) and protracted withdrawal (30 and 60 days of withdrawal) in the FST. The behaviors that were measured in the five-min FST consisted of latency to immobility, swim time, immobility time, and climbing time. The FST results showed that the vapor-exposed animals displayed depressive-like behaviors; for instance, decreased latency to immobility in acute withdrawal and decreased latency to immobility, decreased swim time and increased immobility time in protracted withdrawal, with differences between air- and vapor-exposed animals becoming more pronounced over the 60-day withdrawal period. NPY levels in the frontal cortex of the vapor-exposed animals were decreased compared with the control animals, and CRF levels in the amygdala were correlated with increased immobility time. Thus, extended ethanol vapor exposure produced long-lasting changes in FST behavior and NPY levels in the brain. Copyright © 2010 Elsevier Inc. All rights reserved.

Protective effect of chelerythrine against ethanol-induced gastric ulcer in mice.

PubMed

Li, Wei-Feng; Hao, Ding-Jun; Fan, Ting; Huang, Hui-Min; Yao, Huan; Niu, Xiao-Feng

2014-02-05

The quaternary benzo[c]phenanthridine alkaloid, chelerythrine (CHE), is of great practical and research interest because of its pronounced, widespread physiological effects, primarily antimicrobial and anti-inflammatory, arising from its ability to interact with proteins and DNA. Although CHE was originally shown to possess anti-inflammatory properties, its effects on acute gastric ulcer have not been previously explored. The aim of the present study is to evaluate the protective effect of CHE on ethanol induced gastric ulcer in mice. Administration of CHE at doses of 1, 5 and 10mg/kg bodyweight prior to ethanol ingestion dose-dependently inhibited gastric ulcer. The gastric mucosal lesion was assessed by ulcer area, gastric juice acidity, myeloperoxidase (MPO) activities, macroscopic and histopathological examinations. CHE significantly reduced the gastric ulcer index, myeloperoxidase activities, macroscopic and histological score in a dose-dependent manner. In addition, CHE also significantly inhibited nitric oxide (NO) concentration, pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level in serum and gastric mucosal in the mice exposed to ethanol induced ulceration in a dose-dependent manner. In addition, immunohistochemical analysis revealed that CHE markedly attenuated the overexpression of nuclear factor-κB in gastric mucosa of mice. It was concluded that CHE represents a potential therapeutic option to reduce the risk of gastric ulceration. In addition, acute toxicity study revealed no abnormal sign to the mice treated with CHE (15mg/kg). These findings suggest that the gastroprotective activity of CHE might contribute in adjusting the inflammatory cytokine by regulating the NF-κB signalling pathway. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Acute and subacute toxicity evaluation of ethanolic extract from fruits of Schinus molle in rats.

PubMed

Ferrero, Adriana; Minetti, Alejandra; Bras, Cristina; Zanetti, Noelia

2007-09-25

Ethanolic and hexanic extracts from fruits and leaves of Schinus molle showed ability to control several insect pests. Potential vertebrate toxicity associated with insecticidal plants requires investigation before institutional promotion. The aim of the present study was to evaluate the acute and subacute toxicity of ethanolic extracts from fruits of Schinus molle in rats. The plant extract was added to the diet at 2g/kg body weight/day during 1 day to evaluate acute toxicity and at 1g/kg body weight/day during 14 days to evaluate subacute toxicity. At the end of the exposure and after 7 days, behavioral and functional parameters in a functional observational battery and motor activity in an open field were assessed. Finally, histopathological examinations were conducted on several organs. In both exposures, an increase in the arousal level was observed in experimental groups. Also, the landing foot splay parameter increased in the experimental group after acute exposure. Only the subacute exposure produced a significant increase in the motor activity in the open field. All these changes disappeared after 7 days. None of the exposures affected the different organs evaluated. Our results suggest that ethanolic extracts from fruits and leaves of Schinus molle should be relatively safe to use as insecticide.

[Ethanol changes sensitivity of Kupffer cells to endotoxin].

PubMed

Yamashina, Shunhei; Ikejima, Kenichi; Enomoto, Nobuyuki; Takei, Yoshiyuki; Sato, Nobuhiro

2003-10-01

Gut-derived endotoxin plays an important role in alcoholic liver injury. Intestinal sterilization with antibiotics (polymyxin B and neomycin) or inactivation of Kupffer cells with gadolinium chloride can prevent early alcohol-induced liver injury in the Tsukamoto-French model. Although short-term administration of alcohol enhances endotoxin hepatotoxicity, a majority of studies report that short-term ethanol inactivates Kupffer cells. It is therefore paradoxical that Kupffer cells are involved in alcoholic liver injury based on in vivo data with gadolinium chloride and antibiotics, yet ethanol blunts activation of isolated Kupffer cells. Accordingly, this review focuses on understanding this paradox by studying the temporal effect of ethanol in vivo on the response of subsequently isolated Kupffer cells. Mice were given ethanol intragastrically, and LPS was injected later. One hour after ethanol treatment, serum transaminases after LPS were 60% of control, while ethanol increased these parameters about 3-fold 21 hours after ethanol. Pretreatment with antibiotics blocked these effects of ethanol. Two hours after ethanol administration, the LPS-induced increases in intracellular calcium concentration and TNF alpha release by Kupffer cells was diminished by 50% of control, and these parameters were reciprocally enhanced two-fold at 24 hours. Sterilization of the gut with antibiotics blocked both effects of ethanol on intracellular calcium concentration and TNF alpha release. Twenty-four hours after ethanol, CD14 in Kupffer cells was elevated to about five-fold. In Kupffer cells from mice treated with ethanol 1 hour earlier, IRAK expression and activity and NF kappa B were decreased to 50-60% of control. In contrast, in Kupffer cells from mice treated with ethanol 21 hours earlier, LPS-induced TNF alpha production, expression and activity of IRAK were increased 1.5-fold over controls, while NF kappa B activation was elevated 3-fold. Kupffer cells isolated from rodents early after ethanol exhibited tolerance to LPS, whereas sensitization was observed later. In conclusion, acute ethanol alters the expression of endotoxin receptors and intracellular signaling molecules, and causes both tolerance and sensitization of Kupffer cells to endotoxin. It is postulated that tolerance of Kupffer cells contributes to the impairment of innate immune system in alcoholism, while sensitization to endotoxin enhances progression of alcoholic liver injury.

Proteinase-Activated Receptor-1 and Immunomodulatory Effects of a PAR1-Activating Peptide in a Mouse Model of Prostatitis

PubMed Central

Stanton, M. Mark; Nelson, Lisa K.; Benediktsson, Hallgrimur; Hollenberg, Morley D.; Buret, Andre G.; Ceri, Howard

2013-01-01

Background. Nonbacterial prostatitis has no established etiology. We hypothesized that proteinase-activated receptor-1 (PAR1) can play a role in prostatitis. We therefore investigated the effects of PAR1 stimulation in the context of a new model of murine nonbacterial prostatitis. Methods. Using a hapten (ethanol-dinitrobenzene sulfonic acid- (DNBS-)) induced prostatitis model with both wild-type and PAR1-null mice, we examined (1) the location of PAR1 in the mouse prostate and (2) the impact of a PAR1-activating peptide (TFLLR-NH2: PAR1-TF) on ethanol-DNBS-induced inflammation. Results. Ethanol-DNBS-induced inflammation was maximal at 2 days. In the tissue, PAR1 was expressed predominantly along the apical acini of prostatic epithelium. Although PAR1-TF on its own did not cause inflammation, its coadministration with ethanol-DNBS reduced all indices of acute prostatitis. Further, PAR1-TF administration doubled the prostatic production of interleukin-10 (IL-10) compared with ethanol-DNBS treatment alone. This enhanced IL-10 was not observed in PAR1-null mice and was not caused by the reverse-sequence receptor-inactive peptide, RLLFT-NH2. Surprisingly, PAR1-TF, also diminished ethanol-DNBS-induced inflammation in PAR1-null mice. Conclusions. PAR1 is expressed in the mouse prostate and its activation by PAR1-TF elicits immunomodulatory effects during ethanol-DNBS-induced prostatitis. However, PAR1-TF also diminishes ethanol-DNBS-induced inflammation via a non-PAR1 mechanism by activating an as-yet unknown receptor. PMID:24459330

Chronic effects of ethanol and/or darunavir/ritonavir on U937 monocytic cells: Regulation of cytochrome P450 and antioxidant enzymes, oxidative stress, and cytotoxicity

PubMed Central

Rao, P.S.S.; Kumar, Santosh

2015-01-01

Background Our recent study has shown that acute treatment with ethanol increases oxidative stress and cytotoxicity through cytochrome P450 2E1 (CYP2E1)-mediated pathway in U937 monocytic cells. U937 cells are derived from blood monocytes and are considered as the model system for HIV-related study. Since the prevalence of alcohol use in HIV-infected population is high, and HIV+ patients are on antiretroviral therapy (ART) soon after they are diagnosed, it is important to study the interactions between ethanol and ART in monocytes. Methods This study examined the chronic effects of ethanol and ART (darunavir/ritonavir), alone and in combination, on expression/levels of cytochrome P450 enzymes (CYPs), antioxidant enzymes (AOEs), reactive oxygen species (ROS), and cytotoxicity in U937 cells. The mRNA and protein levels were measured using quantitative RTPCR and Western blot, respectively. ROS and cytotoxicity were measured using flow cytometry and XTT assay, respectively. Results While chronic ART treatment increased CYP2E1 protein expression by 2-fold, ethanol and ethanol+ART increased CYP2E1 by ~5-fold. In contrast, ART and ethanol treatments decreased CYP3A4 protein expression by 38±17% and 74±15%, respectively, and the combination additively decreased CYP3A4 level by 90±8%. Expressions of superoxide dismutase (SOD1) and peroxiredoxin (PRDX6) were decreased by both ethanol and ART, however, the expressions of SOD2 and catalase were unaltered. These results suggested increased ethanol metabolism, increased ART accumulation, and decreased defense against ROS. Therefore, we determined the effects of ethanol and ART on ROS and cytotoxicity. While ART showed a slight increase, ethanol and ethanol+ART displayed significant increase in ROS and cytotoxicity. Moreover, the combination showed additive effects on ROS and cytotoxicity. Conclusions These results suggest that chronic ethanol, in the absence and presence of ART, increases ROS and cytotoxicity in monocytes, perhaps via CYPs and AOEs mediated pathways. This study has clinical implications in HIV+ alcohol users who are on ART. PMID:26727525

Acute ethanol exposure-induced autophagy-mediated cardiac injury via activation of the ROS-JNK-Bcl-2 pathway.

PubMed

Zhu, Zhongxin; Huang, Yewei; Lv, Lingchun; Tao, Youli; Shao, Minglong; Zhao, Congcong; Xue, Mei; Sun, Jia; Niu, Chao; Wang, Yang; Kim, Sunam; Cong, Weitao; Mao, Wei; Jin, Litai

2018-02-01

Binge drinking is associated with increased cardiac autophagy, and often triggers heart injury. Given the essential role of autophagy in various cardiac diseases, this study was designed to investigate the role of autophagy in ethanol-induced cardiac injury and the underlying mechanism. Our study showed that ethanol exposure enhanced the levels of LC3-II and LC3-II positive puncta and promoted cardiomyocyte apoptosis in vivo and in vitro. In addition, we found that ethanol induced autophagy and cardiac injury largely via the sequential triggering of reactive oxygen species (ROS) accumulation, activation of c-Jun NH2-terminal kinase (JNK), phosphorylation of Bcl-2, and dissociation of the Beclin 1/Bcl-2 complex. By contrast, inhibition of ethanol-induced autophagic flux with pharmacologic agents in the hearts of mice and cultured cells significantly alleviated ethanol-induced cardiomyocyte apoptosis and heart injury. Elimination of ROS with the antioxidant N-acetyl cysteine (NAC) or inhibition of JNK with the JNK inhibitor SP600125 reduced ethanol-induced autophagy and subsequent autophagy-mediated apoptosis. Moreover, metallothionein (MT), which can scavenge reactive oxygen and nitrogen species, also attenuated ethanol-induced autophagy and cell apoptosis in MT-TG mice. In conclusion, our findings suggest that acute ethanol exposure induced autophagy-mediated heart toxicity and injury mainly through the ROS-JNK-Bcl-2 signaling pathway. © 2017 Wiley Periodicals, Inc.

Chronic Nicotine Exposure Initiated in Adolescence and Unpaired to Behavioral Context Fails to Enhance Sweetened Ethanol Seeking

PubMed Central

Madayag, Aric C.; Czarnecki, Kyle S.; Wangler, Lynde M.; Robinson, Donita L.

2017-01-01

Nicotine use in adolescence is pervasive in the United States and, according to the Gateway Hypothesis, may lead to progression towards other addictive substances. Given the prevalence of nicotine and ethanol comorbidity, it is difficult to ascertain if nicotine is a gateway drug for ethanol. Our study investigated the relationship between adolescent exposure to nicotine and whether this exposure alters subsequent alcohol seeking behavior. We hypothesized that rats exposed to nicotine beginning in adolescence would exhibit greater alcohol seeking behavior than non-exposed siblings. To test our hypothesis, beginning at P28, female rats were initially exposed to once daily nicotine (0.4 mg/kg, SC) or saline for 5 days. Following these five initial injections, animals were trained to nose-poke for sucrose reinforcement (10%, w/v), gradually increasing to sweetened ethanol (10% sucrose; 10% ethanol, w/v) on an FR5 reinforcement schedule. Nicotine injections were administered after the behavioral sessions to minimize acute effects of nicotine on operant self-administration. We measured the effects of nicotine exposure on the following aspects of ethanol seeking: self-administration, naltrexone (NTX)-induced decreases, habit-directed behavior, motivation, extinction and reinstatement. Nicotine exposure did not alter self-administration or the effectiveness of NTX to reduce alcohol seeking. Nicotine exposure blocked habit-directed ethanol seeking. Finally, nicotine did not alter extinction learning or cue-induced reinstatement to sweetened ethanol seeking. Our findings suggest that nicotine exposure outside the behavioral context does not escalate ethanol seeking. Further, the Gateway Hypothesis likely applies to scenarios in which nicotine is either self-administered or physiologically active during the behavioral session. PMID:28860980

Chronic Intermittent Ethanol Inhalation Increases Ethanol Self-administration in both C57BL/6J and DBA/2J Mice

PubMed Central

McCool, Brian A.; Chappell, Ann M.

2015-01-01

Inbred mouse strains provide significant opportunities to understand the genetic mechanisms controlling ethanol-directed behaviors and neurobiology. They have been specifically employed to understand cellular mechanisms contributing to ethanol consumption, acute intoxication, and sensitivities to chronic effects. However, limited ethanol consumption by some strains has restricted our understanding of clinically relevant endpoints such as dependence-related ethanol intake. Previous work with a novel tastant-substitution procedure using monosodium glutamate (MSG or umami flavor) has shown that the procedure greatly enhances ethanol consumption by mouse strains that express limited drinking phenotypes using other methods. In the current study, we employ this MSG-substitution procedure to examine how ethanol dependence, induced with passive vapor inhalation, modifies ethanol drinking in C57BL/6J and DBA/2J mice. These strains represent ‘high’ and ‘low’ drinking phenotypes, respectively. We found that the MSG substitution greatly facilitates ethanol drinking in both strains, and likewise, ethanol dependence increased ethanol consumption regardless of strain. However, DBA/2J mice exhibited greater sensitivity dependence-enhanced drinking, as represented by consumption behaviors directed at lower ethanol concentrations and relative to baseline intake levels. DBA/2J mice also exhibited significant withdrawal-associated anxiety-like behavior while C57BL/6J mice did not. These findings suggest that the MSG-substitution procedure can be employed to examine dependence-enhanced ethanol consumption across a range of drinking phenotypes, and that C57BL/6J and DBA/2J mice may represent unique neurobehavioral pathways for developing dependence-enhanced ethanol consumption. PMID:25659650

Role of alcohol dehydrogenase activity and the acetaldehyde in ethanol- induced ethane and pentane production by isolated perfused rat liver.

PubMed Central

Müller, A; Sies, H

1982-01-01

The volatile hydrocarbons ethane and n-pentane are produced at increased rates by isolated perfused rat liver during the metabolism of acutely ethanol. The effect is half-maximal at 0.5 mM-ethanol, and its is not observed when inhibitors of alcohol dehydrogenase such as 4-methyl- or 4-propyl-pyrazole are also present. Propanol, another substrate for the dehydrogenase, is also active. Increased alkane production can be initiated by adding acetaldehyde in the presence of 4-methyl- or 4-propyl-pyrazole. An antioxidant, cyanidanol, suppresses the ethanol-induced alkane production. The data obtained with the isolated organ demonstrate that products known to arise from the peroxidation of polyunsaturated fatty acids are formed in the presence of ethanol and that the activity of alcohol dehydrogenase is required for the generation of the active radical species. The mere presence of ethanol, e.g. at binding sites of special form(s) of cytochrome P-450, it not sufficient to elicit an increased production of volatile hydrocarbons by rat liver. PMID:6751324

Anti-inflammatory activity of Albizia lebbeck Benth., an ethnomedicinal plant, in acute and chronic animal models of inflammation.

PubMed

Babu, N Prakash; Pandikumar, P; Ignacimuthu, S

2009-09-07

Albizia lebbeck Benth. is used both in Indian traditional system and folk medicine to treat several inflammatory pathologies such as asthma, arthritis and burns. The aim of the present study was to evaluate the scientific basis of anti-inflammatory activity of different organic solvent extracts of Albizia lebbeck. The anti-inflammatory activity of Albizia lebbeck was studied using the carrageenan, dextran, cotton pellet and Freund's complete adjuvant induced rat models. The extracts obtained using petroleum ether, chloroform and ethanol were administered at the concentrations of 100, 200 and 400mg/kg body weight. The petroleum ether and ethanol extracts at 400mg/kg, showed maximum inhibition of inflammation induced by carrageenan (petroleum ether-48.6%; ethanol-59.57%), dextran (petroleum ether-45.99%; ethanol-52.93%), cotton pellet (petroleum ether-34.46%; ethanol-53.57%) and Freund's adjuvant (petroleum ether-64.97%; ethanol-68.57%). The marked inhibitory effect on paw edema shows that Albizia lebbeck possesses remarkable anti-inflammatory activity, supporting the folkloric usage of the plant to treat various inflammatory diseases.

Effects of alcohol on body-sway patterns in human subjects.

PubMed

Nieschalk, M; Ortmann, C; West, A; Schmäl, F; Stoll, W; Fechner, G

1999-01-01

The vestibulospinal aspects of vestibular function are commonly neglected in the evaluation of alcohol-induced intoxication. Thus, in the present study the effect of an acute intoxication with a low or moderate quantity of alcohol was examined with respect to the equilibrium in 30 healthy subjects. The blood alcohol concentration (BAC) was measured 30 min after the ingestion of the last alcohol, ranging between 0.22 and 1.59 per thousand. Stability of stance was quantified by static platform posturography in Romberg-test conditions with eyes open and eyes closed. Among other parameters, the average body sway path (SP) and area of body sway (SA) were assessed. Posturography revealed a significant increase in body sway. There was a positive correlation between SA (or SP) and BAC both with eyes open and eyes closed. Multiple group comparisons revealed that the large-alcohol-dose group (BAC > or = 1.0 per thousand) could be clearly differentiated from test cases with BAC lower than 0.8 per thousand. Sway area was the most sensitive parameter for detecting increased body sway after alcohol ingestion. The area increase, present not only with eyes closed but with eyes open, revealed an inadequate compensation of the ethanol-induced ataxia by visual stabilization. The Romberg's quotient, which denotes eyes closed relative to eyes open, remained constant. The increase in sway path with eyes closed showed an omnidirectional sway. A comparison of the sway pattern of subjects after acute ethanol ingestion with the data of patients with permanent cerebellar lesions suggested that the acute effect of alcohol resembles that of a lesion of the spinocerebellum. This finding contrasts with earlier studies, which postulated an acute effect of ethanol resembling that in patients with an atrophy of the anterior lobe of the cerebellum due to chronic alcohol abuse. In seven cases of the lower dose group (BAC < or = 0.8 per thousand), a reduction in body sway after alcohol ingestion was observed. This finding may be consistent with a dose-related biphasic action of alcohol, which - besides its well-known depressant effects with high doses - also shows stimulatory action with small doses.

Evaluation of GABAergic neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats.

PubMed

Hirani, Khemraj; Sharma, Ajay N; Jain, Nishant S; Ugale, Rajesh R; Chopde, Chandrabhan T

2005-07-01

Acute systemic ethanol administration is known to elevate plasma and cerebral levels of neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha, 5alpha-THP; allopregnanolone) to a concentration sufficient to potentiate GABA(A) receptors. We have earlier demonstrated that 3alpha, 5alpha-THP mediates the antidepressant-like effect of ethanol in Porsolt forced swim test. The aim of the present study is to explain the relationship between endogenous GABAergic neurosteroids and anxiolytic effect of ethanol in Sprague-Dawley rats. The mediation of 3alpha, 5alpha-THP in the anti-anxiety effect of ethanol was assessed by pharmacological interactions of ethanol with various endogenous neurosteroidal modulators and using simulated physiological conditions of altered neurosteroid content in elevated plus maze (EPM) test. Pretreatment of 3alpha, 5alpha-THP (0.5-2.5 mug/rat, i.c.v.) or neurosteroidogenic agents such as 3alpha, 5alpha-THP precursor progesterone (5 or 10 mg/kg, i.p.), 11-beta hydroxylase inhibitor metyrapone (50 or 100 mg/kg, i.p.) or the GABA(A) receptor agonist muscimol (25 ng/rat, i.c.v.) significantly potentiated the anti-anxiety effect of ethanol (1 g/kg, i.p.). On the other hand, the GABAergic antagonistic neurosteroid dehydroepiandrosterone sulphate (DHEAS) (1 mg/kg, i.p.), the GABA(A) receptor blocker bicuculline (1 mg/kg, i.p.), the 5alpha-reductase inhibitor finasteride (50 x 2 mg/kg, s.c.) or the mitochondrial diazepam binding inhibitory receptor antagonist PK11195 (1 mg/kg, i.p.) reduced ethanol-induced preference of time spent and number of entries into open arms. Anti-anxiety effect of ethanol was abolished in adrenalectomized (ADX) rats as compared to sham-operated control. This ADX-induced blockade was restored by prior systemic injection of progesterone, signifying the contribution of peripheral steroidogenesis in ethanol anxiolysis. Socially isolated animals known to exhibit decreased brain 3alpha, 5alpha-THP and GABA(A) receptor functions displayed reduced sensitivity to the effects of ethanol and 3alpha, 5alpha-THP in EPM test. Our results demonstrated the contributory role of neuroactive steroid 3alpha, 5alpha-THP in the anti-anxiety effect of ethanol. It is speculated that ethanol-induced modulation of endogenous GABAergic neurosteroids, especially 3alpha, 5alpha-THP, might be crucial pertinent to the etiology of 'trait' anxiety (tension reduction) and ethanol abuse.

Evaluation of the acute dermal exposure of the ethanolic and hexanic extracts from leaves of Schinus molle var. areira L. in rats.

PubMed

Bras, Cristina; Gumilar, Fernanda; Gandini, Norberto; Minetti, Alejandra; Ferrero, Adriana

2011-10-11

Schinus molle var. areira L. (Anacardiaceae) is employed in herbal medicine for many conditions, including respiratory, urinary and menstrual disorders, and as a digestive stimulant, diuretic, astringent and antidepressant. It is also known for its topical use as wound healer, antiseptic, for skin disorders and as repellent and insecticide. In the present work, the acute dermal exposure to ethanolic and hexanic extracts from leaves of Schinus molle var. areira was studied in rats. A single dose of 2000 mg/kg of body weight of ethanolic and hexanic extracts from leaves was applied on the shaved skin of male and female rats. After 24h of exposure, the patch was removed and any sign of irritation was recorded. Behavioral and functional parameters in a functional observational battery and motor activity in an open field were assessed after the exposure to the extracts. Then, after 14 days of observation, animals were retested. Finally, histopathological studies were conducted on several organs. Slight signs of erythema and edema were observed in the skin site of exposure, but they disappeared after 48 h. The exposure to the hexanic extract produced an increase in parameters of activity, rearing and arousal assessed in the functional observational battery, which reversed after 14 days. On the other hand, the ethanolic extract caused an increase in locomotor activity, reflected in a higher number of rearings performed in the open field in the evaluation carried out on Day 14. No histopathological alterations were detected in the analyzed organs. The results show that the acute dermal exposure of the ethanolic and hexanic extracts from leaves of Schinus molle var. areira only causes a slight and reversible skin irritation, and a mild stimulatory effect in rats. All these indicate that the topical use of these extracts would be safe. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Behavioral and biochemical effects of ethanol withdrawal in zebrafish.

PubMed

da Silva Chaves, Suianny Nayara; Felício, Gabriel Rocha; Costa, Bruna Patrícia Dutra; de Oliveira, Witallo Etevaldo Araújo; Lima-Maximino, Monica Gomes; Siqueira Silva, Diógenes Henrique de; Maximino, Caio

2018-06-01

Chronic alcohol use induces adaptations and toxicity that can induce symptoms of anxiety, autonomic hyperarousal, and epileptic seizures when alcohol is removed (withdrawal syndrome). Zebrafish has recently gained wide attention as a behavioral model to study the neurobehavioral effects of acute and chronic alcohol use, including withdrawal. The literature, however, is very contradictory on findings regarding withdrawal effects, with some studies reporting increased anxiety, while others report no effect. A meta-analytic approach was taken to find the sources of this heterogeneity, and ethanol concentration during exposure and exposure duration were found to be the main sources of variation. A conceptual replication was also made using continuous exposure for 16 days in waterborne ethanol (0.5%) and assessing anxiety-like behavior in the light/dark test after 60 min withdrawal. Withdrawal was shown to reduce preference for darkness, consistent with decreased anxiety, but to increase risk assessment, consistent with increased anxiety. Animals were also subjected to the withdrawal protocol and injected with pilocarpine in a sub-convulsive dose to assess susceptibility to epileptic seizure-like behavior. The protocol was sufficient to increase susceptibility to epileptic seizure-like behavior in animals exposed to ethanol. Finally, withdrawal also decreased catalase activity in the brain, but not in the head kidney, suggesting mechanisms associated with the behavioral effects of ethanol withdrawal. Copyright © 2018 Elsevier Inc. All rights reserved.

Cue-Induced Ethanol Seeking in Drosophila melanogaster Is Dose-Dependent

PubMed Central

Nunez, Kavin M.; Azanchi, Reza; Kaun, Karla R.

2018-01-01

Alcohol use disorder generates devastating social, medical and economic burdens, making it a major global health issue. The persistent nature of memories associated with intoxication experiences often induces cravings and triggers relapse in recovering individuals. Despite recent advances, the neural and molecular mechanisms underlying these memories are complex and not well understood. This makes finding effective pharmacological targets challenging. The investigation of persistent alcohol-associated memories in the fruit fly, Drosophila melanogaster, presents a unique opportunity to gain a comprehensive understanding of the memories for ethanol reward at the level of genes, molecules, neurons and circuits. Here we characterize the dose-dependent nature of ethanol on the expression of memory for an intoxication experience. We report that the concentration of ethanol, number of ethanol exposures, length of ethanol exposures, and timing between ethanol exposures are critical in determining whether ethanol is perceived as aversive or appetitive, and in how long the memory for the intoxicating properties of ethanol last. Our study highlights that fruit flies display both acute and persistent memories for ethanol-conditioned odor cues, and that a combination of parameters that determine the intoxication state of the fly influence the seemingly complex retention and expression of memories associated with intoxication. Our thorough behavioral characterization provides the opportunity to interrogate the biological underpinnings of these observed preference differences in future studies. PMID:29740347

Study of acetylcholinesterase activity and apoptosis in SH-SY5Y cells and mice exposed to ethanol.

PubMed

Sun, Wenjun; Chen, Liangjing; Zheng, Wei; Wei, Xiaoan; Wu, Wenqi; Duysen, Ellen G; Jiang, Wei

2017-06-01

Ethanol is one of the most commonly abused psychotropic substances with deleterious effects on the central nervous system. Ethanol exposure during development results in the loss of neurons in brain regions and when exposed to ethanol cultured cells undergo apoptosis. To date no information is available on whether abnormally high AChE activity is characteristic of apoptosis in animals exposed to ethanol. The aims of the present study were to determine whether induction of AChE activity is associated with ethanol-induced apoptosis and to explore the mechanism of enhanced AChE activity induced by ethanol. For this purpose, in vitro and in vivo experiments were performed. AChE activity was quantified by spectrophotometry and apoptosis by flow cytometer in SH-SY5Y cells exposed to ethanol. The results showed that cells treated with 500mM ethanol for 24h had a 9-fold increase in apoptotic cells and a 6-fold increase in AChE activity compared with controls. Mice exposed acutely to 200μl of 20% ethanol daily on days 1-4 had elevated AChE activity in plasma on days 3-7. On day 4, plasma AChE activity was 2.4-fold higher than pretreatment activity. More apoptotic cells were found in the brains of treated mice compared to controls. Cells in brain sections that were positive in the TUNEL assay stained for AChE activity. In conclusion, AChE activity and apoptosis were induced in SH-SY5Y cells and mice treated with ethanol, which may indicate that increased AChE may related to apoptosis induced by ethanol. Unusually high AChE activity may be an effect marker of exposure to ethanol. The relationship between AChE and apoptosis might represent a novel mechanism of ethanol-associated neuronal injury. Copyright © 2017 Elsevier B.V. All rights reserved.

Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication.

PubMed

Blednov, Y A; Benavidez, J M; Black, M; Chandra, D; Homanics, G E; Rudolph, U; Harris, R A

2013-04-01

GABA type A receptors (GABA(A)-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors. We studied null mutant mice for six different GABA(A)-R subunits (α1, α2, α3, α4, α5 and δ). Only mice lacking the α2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol. These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the α2-subunit (Blednov et al., 2011). All together, they indicate that aversive property of ethanol is dependent on ethanol action on α2-containing GABA(A)-R. Deletion of the α2-subunit led to faster recovery whereas absence of the α3-subunit slowed recovery from ethanol-induced incoordination (rotarod). Deletion of the other four subunits did not affect this behavior. Similar changes in this behavior for the α2 and α3 null mutants were found for flurazepam motor incoordination. However, no differences in recovery were found in motor-incoordinating effects of an α1-selective modulator (zolpidem) or an α4-selective agonist (gaboxadol). Therefore, recovery of rotarod incoordination is under control of two GABA(A)-R subunits: α2 and α3. For motor activity, α3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both α2 (-/-) and α3 (-/Y) knockout mice were less sensitive to ethanol-induced reduction of motor activity (1.5 g/kg). These studies demonstrate that the effects of ethanol at GABAergic synapses containing α2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the α2 subunit with human alcoholism. Copyright © 2012 Elsevier Ltd. All rights reserved.

A combination of NMR and liquid chromatography to characterize the protective effects of Rhus tripartita extracts on ethanol-induced toxicity and inflammation on intestinal cells.

PubMed

Ben Barka, Zaineb; Grintzalis, Konstantinos; Polet, Madeleine; Heude, Clement; Sommer, Ulf; Ben Miled, Hanène; Ben Rhouma, Khémais; Mohsen, Sakly; Tebourbi, Olfa; Schneider, Yves-Jacques

2018-02-20

Consumption of ethanol may have severe effects on human organs and tissues and lead to acute and chronic inflammation of internal organs. The present study aims at investigating the potential protective effects of three different extracts prepared from the leaves, root, and stem of the sumac, Rhus tripartita, against ethanol-induced toxicity and inflammation using intestinal cells as a cell culture system, in vitro model of the intestinal mucosa. The results showed an induction of cytotoxicity by ethanol, which was partially reversed by co-administration of the plant extracts. As part of investigating the cellular response and the mechanism of toxicity, the role of reduced thiols and glutathione-S-transferases were assessed. In addition, intestinal cells were artificially imposed to an inflammation state and the anti-inflammatory effect of the extracts was estimated by determination of interleukin-8. Finally, a detailed characterization of the contents of the three plant extracts by high resolution Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry revealed significant differences in their chemical compositions. Copyright © 2017 Elsevier B.V. All rights reserved.

Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior.

PubMed

Wang, Jun; Ben Hamida, Sami; Darcq, Emmanuel; Zhu, Wenheng; Gibb, Stuart L; Lanfranco, Maria Fe; Carnicella, Sebastien; Ron, Dorit

2012-10-24

We found previously that acute ex vivo as well as repeated cycles of in vivo ethanol exposure and withdrawal, including excessive voluntary consumption of ethanol, produces a long-lasting increase in the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in the dorsomedial striatum (DMS) of rats (Wang et al., 2010a). Activation of NMDARs is required for the induction of long-term potentiation (LTP) of AMPA receptor (AMPAR)-mediated synaptic response. We therefore examined whether the ethanol-mediated upregulation of NMDAR activity alters the induction of LTP in the DMS. We found that ex vivo acute exposure of striatal slices to, and withdrawal from, ethanol facilitates the induction of LTP in DMS neurons, which is abolished by the inhibition of NR2B-NMDARs. We also report that repeated systemic administration of ethanol causes an NR2B-NMDAR-dependent facilitation of LTP in the DMS. LTP is mediated by the insertion of AMPAR subunits into the synaptic membrane, and we found that repeated systemic administration of ethanol, as well as cycles of excessive ethanol consumption and withdrawal, produced a long-lasting increase in synaptic localization of the GluR1 and GluR2 subunits of AMPARs in the DMS. Importantly, we report that inhibition of AMPARs in the DMS attenuates operant self-administration of ethanol, but not of sucrose. Together, our data suggest that aberrant synaptic plasticity in the DMS induced by repeated cycles of ethanol exposure and withdrawal contributes to the molecular mechanisms underlying the development and/or maintenance of excessive ethanol consumption.

Evaluation of the antiulcerogenic and analgesic activities of Cordia verbenacea DC. (Boraginaceae).

PubMed

Roldão, Erika de Freitas; Witaicenis, Aline; Seito, Leonardo Noboru; Hiruma-Lima, Clélia Akiko; Di Stasi, Luiz Claudio

2008-09-02

Cordia verbenacea is a medicinal plant popularly used in Brazil as anti-inflammatory, antiulcer and anti-rheumatic agent without detailed pharmacological and toxicological studies. The study was aimed to investigate the effects of Cordia verbenacea in antiulcer, analgesic and antioxidant assays, as well as to evaluate its toxic effects and phytochemical profile. Antiulcer activity of plant extract was evaluated using ethanol/HCl, ethanol and piroxican-induced gastric lesions methods. The pH, volume and total acid of gastric juice were determined by pylorus-ligated assay. Analgesic activity was evaluated by writhing, tail-flick and hot-plate tests. Antioxidant activity was determined by in vitro lipoperoxidation assay. Acute toxicity and number of deaths were evaluated by Hippocratic screening. The ethanol leaf extract shows a potent antiulcer activity in the ethanol/HCl and absolute ethanol-induced gastric lesions. The IC(50) value of plant extract on the lipid peroxidation was 76.11mug/ml. Preliminary phytochemical tests were positive for flavonoids, steroids, saponins, fixed acids, alkaloids and phenols. In the analgesic models the extract did not present any activity. Cordial verbenaceae showed a potent antiulcer activity at the dose of 125mg/kg and this effect may be associated with an improvement in stomach antioxidant mechanisms.

DIFFERENTIAL EFFECTS OF SINGLE VERSUS REPEATED ALCOHOL WITHDRAWAL ON THE EXPRESSION OF ENDOCANNABINOID SYSTEM-RELATED GENES IN THE RAT AMYGDALA

PubMed Central

Serrano, Antonia; Rivera, Patricia; Pavon, Francisco J.; Decara, Juan; Suárez, Juan; de Fonseca, Fernando Rodriguez; Parsons, Loren H.

2011-01-01

Background Endogenous cannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG) exert important regulatory influences on neuronal signaling, participate in short- and long-term forms of neuroplasticity, and modulate stress responses and affective behavior in part through the modulation of neurotransmission in the amygdala. Alcohol consumption alters brain endocannabinoid levels, and alcohol dependence is associated with dysregulated amygdalar function, stress responsivity and affective control. Methods The consequence of long-term alcohol consumption on the expression of genes related to endocannabinoid signaling was investigated using quantitative RT-PCR analyses of amygdala tissue. Two groups of ethanol-exposed rats were generated by maintenance on an ethanol liquid diet (10%): one group received continuous access to ethanol for 15 days, while the second group was given intermittent access to the ethanol diet (5 days/week for 3 weeks). Control subjects were maintained on an isocaloric ethanol-free liquid diet. To provide an initial profile of acute withdrawal amygdala tissue was harvested following either 6 or 24 hours of ethanol withdrawal. Results Acute ethanol withdrawal was associated with significant changes in mRNA expression for various components of the endogenous cannabinoid system in the amygdala. Specifically, reductions in mRNA expression for the primary clearance routes for anandamide and 2-AG (FAAH and MAGL, respectively) were evident, as were reductions in mRNA expression for CB1, CB2 and GPR55 receptors. Although similar alterations in FAAH mRNA were evident following either continuous or intermittent ethanol exposure, alterations in MAGL and cannabinoid receptor-related mRNA (e.g. CB1, CB2, GPR55) were more pronounced following intermittent exposure. In general, greater withdrawal-associated deficits in mRNA expression were evident following 24 versus 6 hours of withdrawal. No significant changes in mRNA expression for enzymes involved in 2-AG biosynthesis (e.g. DAGL-α/β) were found in any condition. Conclusions These findings suggest that ethanol dependence and withdrawal are associated with dysregulated endocannabinoid signaling in the amygdala. These alterations may contribute to withdrawal-related dysregulation of amygdalar neurotransmission. PMID:22141465

Reduced ultrafine particle levels in São Paulo's atmosphere during shifts from gasoline to ethanol use.

PubMed

Salvo, Alberto; Brito, Joel; Artaxo, Paulo; Geiger, Franz M

2017-07-18

Despite ethanol's penetration into urban transportation, observational evidence quantifying the consequence for the atmospheric particulate burden during actual, not hypothetical, fuel-fleet shifts, has been lacking. Here we analyze aerosol, meteorological, traffic, and consumer behavior data and find, empirically, that ambient number concentrations of 7-100-nm diameter particles rise by one-third during the morning commute when higher ethanol prices induce 2 million drivers in the real-world megacity of São Paulo to substitute to gasoline use (95% confidence intervals: +4,154 to +13,272 cm -3 ). Similarly, concentrations fall when consumers return to ethanol. Changes in larger particle concentrations, including US-regulated PM2.5, are statistically indistinguishable from zero. The prospect of increased biofuel use and mounting evidence on ultrafines' health effects make our result acutely policy relevant, to be weighed against possible ozone increases. The finding motivates further studies in real-world environments. We innovate in using econometrics to quantify a key source of urban ultrafine particles.The biofuel ethanol has been introduced into urban transportation in many countries. Here, by measuring aerosols in São Paulo, the authors find that high ethanol prices coincided with an increase in harmful nanoparticles by a third, as drivers switched from ethanol to cheaper gasoline, showing a benefit of ethanol.

Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice

PubMed Central

Schweitzer, Paul; Cates-Gatto, Chelsea; Varodayan, Florence P.; Nadav, Tali; Roberto, Marisa; Lasek, Amy W.; Roberts, Amanda J.

2016-01-01

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the brain and implicated in alcohol abuse in humans and behavioral responses to ethanol in mice. Previous studies have shown an association of human ALK with acute responses to alcohol and alcohol dependence. In addition, Alk knockout (Alk −/−) mice consume more ethanol in a binge-drinking test and show increased sensitivity to ethanol sedation. However, the function of ALK in excessive drinking following the establishment of ethanol dependence has not been examined. In this study, we tested Alk −/− mice for dependence-induced drinking using the chronic intermittent ethanol-two bottle choice drinking (CIE-2BC) protocol. We found that Alk −/− mice initially consume more ethanol prior to CIE exposure, but do not escalate ethanol consumption after exposure, suggesting that ALK may promote the escalation of drinking after ethanol dependence. To determine the mechanism(s) responsible for this behavioral phenotype we used an electrophysiological approach to examine GABA neurotransmission in the central nucleus of the amygdala (CeA), a brain region that regulates alcohol consumption and shows increased GABA signaling after chronic ethanol exposure. GABA transmission in ethanol-naïve Alk −/− mice was enhanced at baseline and potentiated in response to acute ethanol application when compared to wild-type (Alk +/+) mice. Moreover, basal GABA transmission was not elevated by CIE exposure in Alk −/− mice as it was in Alk +/+ mice. These data suggest that ALK plays a role in dependence-induced drinking and the regulation of presynaptic GABA release in the CeA. PMID:26946429

FOREBRAIN AND HINDBRAIN DEVELOPMENT IN ZEBRAFISH IS SENSITIVE TO ETHANOL EXPOSURE INVOLVING AGRIN, FGF AND SONIC HEDGEHOG FUNCTION

PubMed Central

Zhang, Chengjin; Ojiaku, Princess; Cole, Gregory J.

2014-01-01

BACKGROUND Ethanol is a teratogen that affects numerous developmental processes in the nervous system, which includes development and survival of GABAergic and glutamatergic neurons. Possible molecular mechanisms accounting for ethanol’s effects on nervous system development include perturbed fibroblast growth factor (Fgf) and Sonic hedgehog (Shh) signaling. In zebrafish, forebrain GABAergic neuron development is dependent on Fgf19 and Shh signaling. The present study was conducted to test the hypothesis that ethanol affects GABAergic and glutamatergic neuron development by disrupting Fgf, Shh, and agrin function. METHODS Zebrafish embryos were exposed to varying concentrations of ethanol during a range of developmental stages, in the absence or presence of morpholino oligonucleotides (MOs) that disrupt agrin or Shh function. In situ hybridization was employed to analyze glutamic acid decarboxylase (GAD1) gene expression, as well as markers of glutamatergic neurons. RESULTS Acute ethanol exposure results in marked reduction in GAD1 gene expression in forebrain and hindbrain, and reduction of glutamatergic neuronal markers in hindbrain. Subthreshold ethanol exposure, combined with agrin or Shh MO treatment, produces a similar diminution in expression of markers for GABAergic and glutamatergic neurons. Consistent with the ethanol effects on Fgf and Shh pathways, Fgf19, Fgf8 or Shh mRNA overexpression rescues ethanol-induced decreases in GAD1 and atonal1a gene expression. CONCLUSIONS These studies demonstrate that GABAergic and glutamatergic neuron development in zebrafish forebrain or cerebellum is sensitive to ethanol exposure, and provides additional evidence that a signaling pathway involving agrin, Fgfs and Shh may be a critical target of ethanol exposure during zebrafish embryogenesis. PMID:23184466

Effects of stress on serum triglycerides, nonsterified fatty acids, and total cholesterol levels in male rats after ethanol administration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hershock, D.; Vogel, W.H.

1989-02-09

Serum triglycerides, nonesterified fatty acids (NEFA), and total cholesterol were determined during one hour immobilization stress in adult male Sprague-Dawley rats after ethanol administration (2g/kg, i.p.). Stress and ethanol effects were evaluated in two experiments: (1) rats maintained on Purina Rodent Chow for six weeks and fasted for 24 hours; and (2) rats maintained on the same diet supplemented with 1% cholesterol and 10% peanut oil for six weeks and nonfasted prior to experimentation. Blood was obtained from indwelling jugular catheters. In each experiment, differences were seen in triglyceride and NEFA levels but not in total cholesterol. In the regularmore » diet-fed rats (1), serum triglyceride levels were not affected by either stress or ethanol. However, NEFA levels did show differences in the response to ethanol and stress. A 63% decrease from baseline after 5{prime} of stress was partially abolished by ethanol; instead, a 24% increase was observed. Also, a stress-induced increase in NEFA which occurred after 15{prime} was not observed in the ethanol treated rats; rather, a decrease in NEFA was noted. Total cholesterol did not change in response to stress or ethanol. In the high cholesterol diet-fed rats (2), ethanol did not suppress a stress-induced increase in triglyceride levels. NEFA levels in ethanol-treated rats were higher during the first 15{prime} of stress as compared to stress alone. A decrease in NEFA was however seen in the ethanol-treated rats after 30{prime} of stress and these levels remained lower than the stress alone group. A diet-induced increase in total cholesterol levels was observed; however, no changes were seen due to either or ethanol. Thus, ethanol administration prior to acute immobilization stress did affect serum triglyceride and NEFA levels but did not change total cholesterol.« less

Functional interaction and cross-tolerance between ethanol and Δ9-THC: possible modulation by mouse cerebellar adenosinergic A1/GABAergic-A receptors.

PubMed

Dar, M Saeed

2014-08-15

We have previously shown a functional motor interaction between ethanol and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) that involved cerebellar adenosinergic A1 and GABAergic A receptor modulation. We now report the development of cross-tolerance between intracerebellar Δ(9)-THC and intraperitoneal ethanol using ataxia as the test response in male CD-1 mice. The drugs [Δ(9)-THC (20 μg), N(6)-cyclohexyladenosine, CHA (12 ng), muscimol (20 ng)] used in the study were directly microinfused stereotaxically via guide cannulas into the cerebellum except ethanol. Δ(9)-THC, infused once daily for 5 days followed 16 h after the last infusion by acute ethanol (2g/kg) and Rotorod evaluation, virtually abolished ethanol ataxia indicating development of cross-tolerance. The cross-tolerance was also observed when the order of ethanol and Δ(9)-THC treatment was reversed, i.e., ethanol injected once daily for 5 days followed 16 h after the last ethanol injection by Δ(9)-THC infusion. The cross-tolerance appeared within 24-48 h, lasted over 72 h and was maximal in 5-day ethanol/Δ(9)-THC-treated animals. Finally, tolerance in chronic ethanol/Δ(9)-THC/-treated animals developed not only to ethanol/Δ(9)-THC-induced ataxia, respectively, but also to the ataxia potentiating effect of CHA and muscimol, indicating modulation by cerebellar adenosinergic A1 and GABAA receptors. A practical implication of these results could be that marijuana smokers may experience little or no negative effects such as ataxia following alcohol consumption. Clinically, such antagonism of ethanol-induced ataxia can be observed in marijuana users thereby encouraging more alcohol consumption and thus may represent a risk factor for the development of alcoholism in this segment of population. Copyright © 2014 Elsevier B.V. All rights reserved.

The sap of Acer okamotoanum decreases serum alcohol levels after acute ethanol ingestion in rats.

PubMed

Yoo, Yeong-Min; Jung, Eui-Man; Kang, Ha-Young; Choi, In-Gyu; Choi, Kyung-Chul; Jeung, Eui-Bae

2011-10-01

In the present study, we examined whether Acer okamotoanum (A. okamotoanum) sap decreased the serum alcohol and acetaldehyde levels after acute ethanol treatment in a rat model. Male rats were orally administered 25, 50 or 100% A. okamotoanum sap 30 min prior to oral challenge with 3 ml of ethanol (15 ml/kg of a 20% ethanol solution in water), and the blood concentrations of alcohol and acetaldehyde were analyzed up to 7 h after the treatment. Pre-treatment with the sap significantly decreased the blood ethanol and acetaldehyde concentrations after 5 h when compared with ethanol treatment alone (a negative control). The expression levels of liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) mRNA were increased significantly in animals pre-treated with A. okamotoanum sap when compared with negative and positive controls. The data suggest that sap pre-treatment enhanced the alcohol metabolism rate in the rat liver. To investigate the involvement of mitochondrial regulation in the ethanol-induced hepatocyte apoptosis, we carried out an immunohistochemical analysis of Bax and Bcl-2. Pre-treatment with sap significantly decreased Bax expression and increased Bcl-2 expression 7 h after ethanol administration when compared with the negative control. The data suggest that A. okamotoanum sap pre-treatment may reduce the alcohol-induced oxidative stress in the rat liver.

Chronic intermittent ethanol inhalation increases ethanol self-administration in both C57BL/6J and DBA/2J mice.

PubMed

McCool, Brian A; Chappell, Ann M

2015-03-01

Inbred mouse strains provide significant opportunities to understand the genetic mechanisms controlling ethanol-directed behaviors and neurobiology. They have been specifically employed to understand cellular mechanisms contributing to ethanol consumption, acute intoxication, and sensitivities to chronic effects. However, limited ethanol consumption by some strains has restricted our understanding of clinically relevant endpoints such as dependence-related ethanol intake. Previous work with a novel tastant-substitution procedure using monosodium glutamate (MSG or umami flavor) has shown that the procedure greatly enhances ethanol consumption by mouse strains that express limited drinking phenotypes using other methods. In the current study, we employ this MSG-substitution procedure to examine how ethanol dependence, induced with passive vapor inhalation, modifies ethanol drinking in C57BL/6J and DBA/2J mice. These strains represent 'high' and 'low' drinking phenotypes, respectively. We found that the MSG substitution greatly facilitates ethanol drinking in both strains, and likewise, ethanol dependence increased ethanol consumption regardless of strain. However, DBA/2J mice exhibited greater sensitivity dependence-enhanced drinking, as represented by consumption behaviors directed at lower ethanol concentrations and relative to baseline intake levels. DBA/2J mice also exhibited significant withdrawal-associated anxiety-like behavior while C57BL/6J mice did not. These findings suggest that the MSG-substitution procedure can be employed to examine dependence-enhanced ethanol consumption across a range of drinking phenotypes, and that C57BL/6J and DBA/2J mice may represent unique neurobehavioral pathways for developing dependence-enhanced ethanol consumption. Copyright © 2015 Elsevier Inc. All rights reserved.

Deficiency in AMPK attenuates ethanol-induced cardiac contractile dysfunction through inhibition of autophagosome formation

PubMed Central

Guo, Rui; Ren, Jun

2012-01-01

Aims Binge drinking often triggers compromised myocardial contractile function while activating AMP-activated protein kinase (AMPK). Given the role of AMPK in the initiation of autophagy through the mammalian target of rapamycin complex 1 (mTORC1) and Unc51-like kinase (ULK1), this study was designed to examine the impact of AMPK deficiency on cardiac function and the mechanism involved with a focus on autophagy following an acute ethanol challenge. Methods and results Wild-type (WT) and transgenic mice overexpressing a kinase-dead (KD) α2 isoform (K45R mutation) of AMPK were challenged with ethanol. Glucose tolerance, echocardiography, Langendorff heart and cardiomyocyte contractile function, autophagy, and autophagic signalling including AMPK, acetyl-CoA carboxylase (ACC), mTOR, the mTORC1-associated protein Raptor, and ULK1 were examined. Ethanol exposure triggered glucose intolerance and compromised cardiac contraction accompanied by increased phosphorylation of AMPK and ACC as well as autophagosome accumulation (increased LC3II and p62), the effects of which were attenuated or mitigated by AMPK deficiency or inhibition. Ethanol dampened and stimulated, respectively, the phosphorylation of mTOR and Raptor, the effects of which were abolished by AMPK deficiency. ULK1 phosphorylation at Ser757 and Ser777 was down-regulated and up-regulated, respectively, by ethanol, the effect of which was nullified by AMPK deficiency or inhibition. Moreover, the ethanol challenge enhanced LC3 puncta in H9c2 cells and promoted cardiac contractile dysfunction, and these effects were ablated by the inhibition of autophagy or AMPK. Lysosomal inhibition failed to accentuate ethanol-induced increases in LC3II and p62. Conclusion In summary, these data suggest that ethanol exposure may trigger myocardial dysfunction through a mechanism associated with AMPK-mTORC1-ULK1-mediated autophagy. PMID:22451512

Forced ethanol ingestion by Wistar rats from a juvenile age increased voluntary alcohol consumption in adulthood, with the involvement of orexin-A.

PubMed

Mendoza-Ruiz, Luis-Gabriel; Vázquez-León, Priscila; Martínez-Mota, Lucía; Juan, Eduardo Ramírez San; Miranda-Páez, Abraham

2018-08-01

Human adolescents who drink alcohol are more likely to become alcoholics in adulthood. Alcohol administration (intraperitoneally) or drinking (in a 2-bottle free choice paradigm) during the juvenile/adolescent age of rats promotes voluntary alcohol consumption in adulthood. On the other hand, there is growing evidence that the orexinergic system plays a role in several rewarded behaviors, including alcohol ingestion. Since it is unknown what effect is exerted in adulthood by forced oral ethanol intake and/or administration of orexin-A (OX-A) in juvenile rats, the present study aimed to evaluate this question. A group of male Wistar rats was forced to drink ethanol (10% v/v) as the only liquid in the diet from weaning (postnatal day 21) to postnatal day 67 (46 days), followed by a forced withdrawal period. An age-matched group was raised drinking tap water (control). OX-A or its vehicle was microinjected intracerebroventricularly (i.c.v.) (1 nmol/0.6 μL) to explore its effect as well. Locomotor activity and voluntary ethanol consumption were later assessed in all groups. The rats forced to consume ethanol early in life showed an elevated level of ambulation and alcohol ingestion in adulthood. A single injection of OX-A increased locomotor activity and acute ethanol intake in rats with or without prior exposure to alcohol at the juvenile stage. In conclusion, forced ethanol consumption in juvenile rats led to increased voluntary alcohol drinking behavior during adulthood, an effect likely facilitated by OX-A. Copyright © 2018 Elsevier Inc. All rights reserved.

Rhamnogalacturonan from Acmella oleracea (L.) R.K. Jansen: gastroprotective and ulcer healing properties in rats.

PubMed

Maria-Ferreira, Daniele; da Silva, Luisa Mota; Mendes, Daniel Augusto Gasparin Bueno; Cabrini, Daniela de Almeida; Nascimento, Adamara Machado; Iacomini, Marcello; Cipriani, Thales Ricardo; Santos, Adair Roberto Soares; Werner, Maria Fernanda de Paula; Baggio, Cristiane Hatsuko

2014-01-01

A rhamnogalacturonan (RGal) isolated from Acmella oleracea (L.) R.K. Jansen administered by oral route showed gastroprotective activity against acute lesions induced by ethanol. In this study, we investigated the gastric ulcer healing effect of RGal and its mechanisms of action. Intraperitoneal treatment of animals with RGal protected the gastric mucosa against acute lesions induced by ethanol, with participation of gastric mucus. Furthermore, in the chronic ulcer model, oral administration of RGal accelerates the gastric ulcer healing, accompanied by increasing of cellular proliferation and gastric mucus content, reducing inflammatory parameters and oxidative stress. In addition, the repeated 7 days-treatment of animals with RGal did not show alterations of clinical and behavioral symptoms, body and organs weights or plasmatic biochemical parameters. Collectively, these results showed that RGal has an interesting antiulcerogenic activity and could constitute an attractive molecule of interest for the development of new antiulcer agents.

Modulation of the lipid profile and insulin levels of streptozotocin induced diabetic rats by ethanol extract of Cnidoscolus aconitifolius leaves and some fractions: Effect on the oral glucose tolerance of normoglycemic rats.

PubMed

Achi, N K; Ohaeri, O C; Ijeh, I I; Eleazu, C

2017-02-01

No study to date has investigated the effect of different polar solvent extracts from Cnidoscolus aconitifolius leaves on glycemic control as used in folk medicine. Hence this study which investigated the effect of ethanol extract and fractions of C. aconitifolius leaves on body weights, relative organ weights, serum levels of glucose, lipid profiles and insulin in streptozotocin induced diabetic rats and on oral glucose tolerance of normoglycemic rats. The ethanol extract was partitioned using methanol, hexane and chloroform to obtain different fractions. The ethanol extract, fractions or glibenclamide demonstrated hypoglycemic/therapeutic actions as seen from the reduction of serum glucose but increase in serum insulin and body weights of the diabetic rats at the end of experimentation following their administration, unlike the diabetic control that had significant alteration of these parameters with respect to the normal control. Whereas the diabetic control had significant increase in pancreatic weights with no alteration in the heart weights, the ethanol extract, fractions or glibenclamide had no effect on these organs. The ethanol extract, methanol fractions or glibenclamide showed better hypoglycemic actions than the n-hexane or chloroform fractions at the doses used and results obtained were corroborated by histology. Furthermore, the ethanol extract, n-hexane (at 250mg/kg) and methanol fractions or glibenclamide improved glucose tolerance in glucose loaded normal rats. The methanol fraction (500mg/kg) demonstrated anti-hypercholesterolemic, anti-hypertriglyceridemic and insulin modulatory properties in a manner akin to glibenclamide. Acute toxicity study revealed the non toxicity of the plant CONCLUSION: The study justifies the use of polar solvent extracts of this plant in the management of diabetes mellitus. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use

PubMed Central

Skelly, Mary J; Weiner, Jeff L

2014-01-01

Background Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Methods Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Results Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). Conclusions These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior. PMID:25161814

Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.

PubMed

Skelly, Mary J; Weiner, Jeff L

2014-07-01

Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.

Alcohol-induced tolerance and physical dependence in mice with ethanol insensitive α1 GABAA receptors

PubMed Central

Werner, David F.; Swihart, Andrew R.; Ferguson, Carolyn; Lariviere, William R.; Harrison, Neil L.; Homanics, Gregg E.

2009-01-01

Background Although many people consume alcohol (ethanol), it remains unknown why some become addicted. Elucidating the molecular mechanisms of tolerance and physical dependence (withdrawal) may provide insight into alcohol addiction. While the exact molecular mechanisms of ethanol action are unclear, γ-aminobutyric acid type A receptors (GABAA-Rs) have been extensively implicated in ethanol action. The α1 GABAA-R subunit is associated with tolerance and physical dependence, but its exact role remains unknown. In this report, we tested the hypothesis that α1-GABAA-Rs mediate in part these effects of ethanol. Methods Ethanol-induced behavioral responses related to tolerance and physical dependence were investigated in knockin mice that have ethanol-insensitive α1 GABAA-Rs and wildtype controls. Acute functional tolerance (AFT) was assessed using the stationary dowel and loss of righting reflex assays. Chronic tolerance was assessed on the loss of righting reflex, fixed speed rotarod, hypothermia, and radiant tail flick assays following ten consecutive days of ethanol exposure. Withdrawal-related hyperexcitability was assessed by handling-induced convulsions following 3 cycles of ethanol vapor exposure/withdrawal. Immunoblots were used to assess α1 protein levels. Results Compared to controls, knockin mice displayed decreased AFT and chronic tolerance to ethanol-induced motor ataxia, and also displayed heightened ethanol-withdrawal hyperexcitability. No differences between wildtype and knockin mice were seen in other ethanol-induced behavioral measures. Following chronic exposure to ethanol, control mice displayed reductions in α1 protein levels, but knockins did not. Conclusions We conclude that α1-GABAA-Rs play a role in tolerance to ethanol-induced motor ataxia and withdrawal-related hyperexcitability. However, other aspects of behavioral tolerance and physical dependence do not rely on α1-containing GABAA-Rs. PMID:19032579

Does retigabine affect the development of alcohol dependence?--A pharmaco-EEG study.

PubMed

Zwierzyńska, Ewa; Andrzejczak, Dariusz; Pietrzak, Bogusława

2016-01-12

New antiepileptic drugs have been investigated for their potential role in the treatment of alcohol dependence. One of these drugs is retigabine and this study examines the effect of retigabine co-administered with ethanol on the development of alcohol dependence and the course of acute withdrawal syndrome. A pharmaco-EEG method was used to examine this impact in selected brain structures of rabbits (midbrain reticular formation, hippocampus and frontal cortex). Retigabine was administered p.o. at a dose of 5mg/kg/day with ethanol ad libitum for 6 weeks and then alone for 2 weeks during an abstinence period. Changes in bioelectric activity, which demonstrated the inhibitory effect of alcohol on the brain structures, were already visible after 2 weeks of ethanol administration. In the abstinence period, changes were of a different nature and significant neuronal hyperactivity was observed, particularly in the midbrain reticular formation and the hippocampus. This findings reveal that retigabine decreased ethanol-induced changes during both alcohol administration and abstinence periods. In particular, the modulatory effect of retigabine on the hippocampus may be a significant element of its mechanism of action in alcohol dependence therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Pulmonary hypertensive crisis following ethanol sclerotherapy for a complex vascular malformation.

PubMed

Cordero-Schmidt, G; Wallenstein, M B; Ozen, M; Shah, N A; Jackson, E; Hovsepian, D M; Palma, J P

2014-09-01

Anhydrous ethanol is a commonly used sclerotic agent for treating vascular malformations. We describe the case of a full-term 15-day-old female with a complex venolymphatic malformation involving the face and orbit. During treatment of the lesion with ethanol sclerotherapy, she suffered acute pulmonary hypertensive crisis. We discuss the pathophysiology of pulmonary hypertension related to ethanol sclerotherapy, and propose that hemolysis plays a significant role. Recommendations for evaluation, monitoring and management of this complication are also discussed.

Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction.

PubMed

Karkhanis, Anushree; Holleran, Katherine M; Jones, Sara R

2017-01-01

The dynorphin/kappa opioid receptor (KOR) system is implicated in the "dark side" of addiction, in which stress exacerbates maladaptive responses to drug and alcohol exposure. For example, acute stress and acute ethanol exposure result in an elevation in dynorphin, the KOR endogenous ligand. Activation of KORs results in modulation of several neurotransmitters; however, this chapter will focus on its regulatory effects on dopamine in mesolimbic areas. Specifically, KOR activation has an inhibitory effect on dopamine release, thereby influencing reward processing. Repeated stimulation of KORs, for example, via chronic drug and/or stress exposure, results in increased function of the dynorphin/KOR system. This augmentation in KOR function shifts the homeostatic balance in favor of an overall reduction in dopamine signaling via either by reducing dopamine release or by increasing dopamine transporter function. This chapter examines the effects of chronic ethanol exposure on KOR function and the downstream effects on dopamine transmission. Additionally, the impact of chronic cocaine exposure and its effects on KOR function will be explored. Further, KORs may also be involved in driving excessive consumption of food, contributing to the risk of developing obesity. While some studies have shown that KOR agonists reduce drug intake, other studies have shown that antagonists reduce addiction-like behaviors, demonstrating therapeutic potential. For example, KOR inhibition reduces ethanol intake in dependent animals, motivation to self-administer cocaine in chronic stress-exposed animals, and food consumption in obese animals. This chapter will delve into the mechanisms by which modulation of the dynorphin/KOR system may be therapeutic. © 2017 Elsevier Inc. All rights reserved.

Quantitative trait loci for response to ethanol in an intercontinental set of recombinant inbred lines of Drosophila melanogaster.

PubMed

Defays, Raquel; Bertoli, Carlos Ignacio

2012-12-01

Alcohol, a drug widely abused, impacts the central nervous system functioning of diverse organisms. The behavioral responses to acute alcohol exposure are remarkably similar among humans and fruit flies. In its natural environment, rich in fermentation products, the fruit fly Drosophila melanogaster encounters relatively high levels of ethanol. The effects of ethanol and its metabolites on Drosophila have been studied for decades, as a model for adaptive evolution. Although extensive work has been done for elucidating patterns of genetic variation, substantially less is known about the genomic regions or genes that underlie the genetic variation of this important trait. To identify regions containing genes involved in the responses to ethanol, we used a mapping population of recombinant inbred (RIL) lines to map quantitative trait loci (QTL) that affect variation in resistance and recovery from ethanol sedation in adults and ethanol resistance in larvae. We mapped fourteen QTL affecting the response to ethanol on the three chromosomes. Seven of the QTL influence the resistance to ethanol in adults, two QTL are related to ethanol-coma recovery in adults and five affect the survival to ethanol in larvae. Most of the QTL were trait specific, suggesting that overlapping but generally unique genetic architectures underlie each trait. Each QTL explained up to 16.8% of the genetic variance among lines. Potential candidate loci contained within our QTL regions were identified and analyzed. Copyright © 2012 Elsevier Inc. All rights reserved.

Assessing Ethanol's Actions in the Suprachiasmatic Circadian Clock Using In vivo and In vitro Approaches

PubMed Central

2014-01-01

Research over the past decade has demonstrated substantial interactions between the circadian system and the processes through which alcohol affects behavior and physiology. Here we summarize the results of our collaborative efforts focused on this intersection. Using a combination of in vivo and in vitro approaches, we have shown that ethanol affects many aspects of the mammalian circadian system, both acutely as well as after chronic administration. Conversely, we have shown circadian influences on ethanol consumption. Importantly, we are beginning to delve into the cellular mechanisms associated with these effects. We are also starting to form a picture of the neuroanatomical bases for many of these actions. Finally, we put our current findings into perspective by suggesting new avenues of inquiry for our future efforts. PMID:25457753

Emergency department length of stay for ethanol intoxication encounters.

PubMed

Klein, Lauren R; Driver, Brian E; Miner, James R; Martel, Marc L; Cole, Jon B

2017-12-08

Emergency Department (ED) encounters for ethanol intoxication are becoming increasingly common. The purpose of this study was to explore factors associated with ED length of stay (LOS) for ethanol intoxication encounters. This was a multi-center, retrospective, observational study of patients presenting to the ED for ethanol intoxication. Data were abstracted from the electronic medical record. To explore factors associated with ED LOS, we created a mixed-effects generalized linear model. We identified 18,664 eligible patients from 6 different EDs during the study period (2012-2016). The median age was 37years, 69% were male, and the median ethanol concentration was 213mg/dL. Median LOS was 348min (range 43-1658). Using a mixed-effects generalized linear model, independent variables associated with a significant increase in ED LOS included use of parenteral sedation (beta=0.30, increase in LOS=34%), laboratory testing (beta=0.21, increase in LOS=23%), as well as the hour of arrival to the ED, such that patients arriving to the ED during evening hours (between 18:00 and midnight) had up to an 86% increase in LOS. Variables not significantly associated with an increase in LOS included age, gender, ethanol concentration, psychiatric disposition, using the ED frequently for ethanol intoxication, CT use, and daily ED volume. Variables such as diagnostic testing, treatments, and hour of arrival may influence ED LOS in patients with acute ethanol intoxication. Identification and further exploration of these factors may assist in developing hospital and community based improvements to modify LOS in this population. Copyright © 2017 Elsevier Inc. All rights reserved.

Antidiarrheal effect of Alpinia oxyphylla Miq. (Zingiberaceae) in experimental mice and its possible mechanism of action.

PubMed

Wang, Sheng; Zhao, Yang; Zhang, Junqing; Huang, Xiaoxing; Wang, Yifei; Xu, Xiaotao; Zheng, Bin; Zhou, Xue; Tian, Huajie; Liu, Li; Mei, Qibing

2015-06-20

The fructus Alpinia oxyphylla Miq. (AOM) has been used for treating diarrhea with spleen deficiency and gastralgia for thousands of years. A number of traditional Chinese medicine formulae provide AOM as an alternative herbal treatment for diarrhea, but the scientific basis for this usage has not been well defined. In this study, we tried to investigate the antidiarrheal activity and possible mechanisms of Fructus AOM, aiming to enrich our understanding to the scientific meanings and theoretical significance of Fructus AOM in clinical practice. The fructus of AOM collected from Hainan province in China were macerated in the 95% ethanol to obtain the crude 95% ethanol extract, followed by subjected to chromatographic separation over a Diaion HP20 column to obtain 90% and 50% ethanol eluted fractions. The activities of the crude extract and fractions on castor oil induced acute diarrhea, rhubarb induced chronic diarrhea, gastrointestinal transit (GIT) in mice, and contractions of isolated guinea-pig ileum were evaluated. Additionally, nitric oxide (NO), gastrointestinal peptides gastrin (GAS), motilin (MTL) and somatostatin (SS) levels that related to gastrointestinal motilities were detected to demonstrate the potential mechanisms. Ultimately, LC-MS/MS method was utilized to ensure the chemical consistency. The 95% ethanol extract and 90% ethanol eluted fraction significantly delayed the onset time and decreased the wet faeces proportion compared with control group in the castor oil induced acute diarrhea mice. In terms of further evaluation of antidiarrheal activity, the 95% ethanol extract and 90% ethanol elution displayed significant inhibition of the intestinal propulsion at the two highest oral doses of 20 g crude drug/kg and 1g/kg. Moreover the 95% ethanol extract (10 and 20 g crude drug/kg) and 90% ethanol elution (0.5 and 1g/kg) could significantly inhibit the GIT, which was partially attributed to the increase in NO and SS levels, and the decreased MTL. In vitro spontaneous contractions of the isolated guinea pig ileum induced by carbachol, neostigmine and histamine were attenuated by both the extract and elution. Phytochemical analysis of 95% ethanol extract and its fractions identified the presence of diphenylheptanes, sesquiterpenes, and flavones as the major components. Our in vivo and in vitro data could partly support and justify the traditional usage of Fructus AOM on the treatment of diarrhea in traditional medicine. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Ethanol Administration Impairs Pancreatic Repair Following Injury

PubMed Central

Mahan Schneider, Katrina J.; Scheer, Marc; Suhr, Mallory; Clemens, Dahn L.

2012-01-01

Objectives Alcohol abuse is one of the most common factors associated with acute and chronic pancreatitis. Although it is evident that alcohol abuse can have an important role in the development of pancreatitis, it does not appear that alcohol abuse alone is responsible for this disease. We investigated the involvement of ethanol in impairment of pancreatic repair after induction of pancreatitis. Methods A biologically relevant mouse model of alcoholic pancreatitis, combining chronic ethanol consumption and coxsackievirus infection, was used to investigate the effects of ethanol on pancreatic regeneration. Tissues were harvested and analyzed by RT-PCR and immunoblot. Results These studies demonstrate that chronic ethanol consumption impairs the structural repair of the exocrine pancreas. This is accompanied by a delay in the restitution of lipase expression. Additionally, impaired expression of the critical pancreatic transcription factors, PDX1 and PTF1, and the mediator of Notch signaling, HES1, were observed. Conclusions Chronic ethanol consumption impairs the structural repair and functional restitution of the pancreas after severe injury. These impairments may, in part, be explained by impaired expression of factors important in the development and maintenance of the exocrine pancreas. Impaired pancreatic regeneration may have a role in the pathogenesis of alcoholic pancreatitis. PMID:22617711

The role of connexin-36 gap junctions in alcohol intoxication and consumption.

PubMed

Steffensen, Scott C; Bradley, Katie D; Hansen, David M; Wilcox, Jeffrey D; Wilcox, Rebecca S; Allison, David W; Merrill, Collin B; Edwards, Jeffrey G

2011-08-01

Ventral tegmental area (VTA) GABA neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in alcohol reward. The aim of this study was to examine the role of midbrain connexin-36 (Cx36) gap junctions (GJs) in ethanol intoxication and consumption. Using behavioral, molecular, and electrophysiological methods, we compared the effects of ethanol in mature Cx36 knockout (KO) mice and age-matched wild-type (WT) controls. Compared to WT mice, Cx36 KO mice exhibited significantly more ethanol-induced motor impairment in the open field test, but less disruption in motor coordination in the rotarod paradigm. Cx36 KO mice, and WT mice treated with the Cx36 antagonist mefloquine (MFQ), consumed significantly less ethanol than their WT controls in the drink-in-the-dark procedure. The firing rate of VTA GABA neurons in WT mice was inhibited by ethanol with an IC₅₀ of 0.25 g/kg, while VTA GABA neurons in KO mice were significantly less sensitive to ethanol. Dopamine neuron GABA-mediated sIPSC frequency was reduced by ethanol (30 mM) in WT mice, but not affected in KO mice. Cx36 KO mice evinced a significant up-regulation in DAT and D2 receptors in the VTA, as assessed by quantitative RT-PCR. These findings demonstrate the behavioral relevance of Cx36 GJ-mediated electrical coupling between GABA neurons in mature animals, and suggest that loss of coupling between VTA GABA neurons results in disinhibition of DA neurons, a hyper-DAergic state and lowered hedonic valence for ethanol consumption. Copyright © 2010 Wiley-Liss, Inc.

Inhibitors of biofilm formation by fuel ethanol contaminants

USDA-ARS?s Scientific Manuscript database

Industrial fuel ethanol production suffers from chronic and acute infections that reduce yields and cause “stuck fermentations” that result in costly shutdowns. Lactic acid bacteria, particularly Lactobacillus sp., are recognized as major contaminants. In previous studies, we observed that certain...

A study of the anti-inflammatory effect of the leaves of Psidium guajava Linn. on experimental animal models

PubMed Central

Dutta, Sarmistha; Das, Swarnamoni

2010-01-01

Introduction: The aim is to study the anti-inflammatory effect of the ethanolic extract of the leaves of Psidium guajava(PGE) on experimental animal models. Materials and Methods: Fresh leaves were collected, air-dried, powdered, and percolated in 95% ethanol. Acute toxicity test was done according to OECD guidelines. Four groups of animals of either sex, weighing 150–200g of the species Rattus norvegicus were taken for the study (n = 6). Group A was taken as control (3% gum acacia in 10 mL/kg body weight), Group B as test group (PGE 250 mg/kg body weight), Group C as test group (PGE 500 mg/kg body weight), and Group D as standard (Aspirin 100 mg/kg body weight). The animals were studied for acute inflammation by Carrageenan-induced rat paw edema, subacute inflammation by Granuloma pouch method, and chronic inflammation by Freund’s adjuvant-induced arthritis method. Statistical analysis was done by one-way analysis of variance followed by multiple comparison tests. Results: In acute inflammation, there was significant inhibition of paw edema in Groups B, C, and D in comparison with Group A (P < 0.05). In subacute inflammation, there was significant inhibition of exudate formation in Groups B, C, and D in comparison to Group A (P < 0.05). In chronic inflammation, there was significant inhibition of paw edema and inhibition of weight reduction in Groups B, C, and D compared with Group A. Downregulation of arthritis index was also significant in Groups B, C, and D in comparison with Group A (P < 0.05). Conclusion: The ethanolic extract of PGE has significant anti-inflammatory activity. PMID:21589759

Cholera toxin-induced ADP-ribosylation of a 46 kDa protein is decreased in brains of ethanol-fed mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nhamburo, P.T.; Hoffman, P.L.; Tabakoff, B.

1988-01-01

The acute in vitro effects of ethanol on cerebral cortical adenylate cyclase activity and beta-adrenergic receptor characteristics suggested a site of action of ethanol at Gs, the stimulatory guanine nucleotide binding protein. After chronic ethanol ingestion, the beta-adrenergic receptor appeared to be uncoupled (i.e., the form of the receptor with high affinity for agonist was undetectable), and stimulation of adenylate cyclase activity by isoproterenol or guanine nucleotides was reduced, suggesting an alteration in the properties of Gs. To further characterize this change, cholera and pertussis toxin-mediated /sup 32/P-ADP-ribosylation of mouse cortical membranes was assessed in mice that had chronically ingestedmore » ethanol in a liquid diet. /sup 32/P-labeled proteins were separated by SDS-PAGE and quantitated by autoradiography. There was a selective 30-50% decrease in cholera toxin-induced labeling of 46 kDa protein band in membranes of ethanol-fed mice, with no apparent change in pertussis toxin-induced labeling. The 46 kDa protein has a molecular weight similar to that of the alpha subunit of Gs, suggesting a reduced amount of this protein or a change in its characteristics as a substrate for cholera toxin-induced ADP-ribosylation in cortical membranes of ethanol-fed mice.« less

Acute ethanol and taurine intake affect absolute alpha power in frontal cortex before and after exercise.

PubMed

Paulucio, Dailson; da Costa, Bruno M; Santos, Caleb G; Velasques, Bruna; Ribeiro, Pedro; Gongora, Mariana; Cagy, Mauricio; Alvarenga, Renato L; Pompeu, Fernando A M S

2017-09-14

Taurine and alcohol has been popularly ingested through energy drinks. Reports from both compounds shows they are active on nervous system but little is known about the acute effect of these substances on the frontal cortex in an exercise approach. The aim of this study was to determine the effects of 0,6mldL -1 of ethanol (ET), 6g of taurine (TA), and taurine with ethanol (TA+ET) intake on absolute alpha power (AAP) in the frontal region, before and after exercise. Nine participants were recruited, five women (22±3years) and four men (26±5years), for a counterbalanced experimental design. For each treatment, the tests were performed considering three moments: "baseline", "peak" and "post-exercise". In the placebo treatment (PL), the frontal areas showed AAP decrease at the post-exercise. However, in the TA, AAP decreased at peak and increased at post-exercise. In the ET treatment, AAP increased at the peak moment for the left frontal electrodes. In the TA+ET treatment, an AAP increase was observed at peak, and it continued after exercise ended. These substances were able to produce electrocortical activity changes in the frontal regions after a short duration and low intensity exercise. Left and right regions showed different AAP dynamics during peak and post-exercise moments when treatments were compared. Copyright © 2017 Elsevier B.V. All rights reserved.

Alcohol and acute pancreatitis. An experimental study in the rat.

PubMed

Jalovaara, P; Apaja, M

1978-01-01

The effect of chronic alcohol pretreatment and various pancreatobiliary secretions on the severity of experimental pancreatitis was studied in the rat. 95 rats were pretreated with ethanol (20% w/v, 1.1 ml/100 g body weight) five times weekly for 10 to 12 weeks by gastric intubation. 88 rats served as controls. Pancreatic lesions were produced by retograde injection of different pancreatobiliary secretions into the pancreatic ducts. The secretions were collected from both normal and chronically alcohol-fed rats, and each was used for induction of experimental pancreatitis in the control and alcohol pretreated rats. Bile obtained from normal rats was no more toxic to the pancreas than 0.9% saline solution, while bile obtained from the chronically alcohol-fed rats caused significantly more serious lesions to the pancreas than did normal rat bile. Bile-pancreatic juice (mixture of secretions at papilla of Vater) of normal and chronically alcohol-fed rats was as toxic as the bile of the alcohol-fed rats. Alcohol pretreatment had no significant effect on the severity of pancreatitis when control and alcohol-fed groups separately or the whole material according to pretreatment was examined. These results suggest that the metabolic effects of ethanol on the pancreas as such do not sensitize the pancreas to acute pancreatitis. An exogenous mechanism is required. The reflux of toxic alcoholic bile into the pancreas might act as an induction factor in acute alcohol pancreatitis.

Acute alcohol-induced protection against infarction in rabbit hearts: differences from and similarities to ischemic preconditioning.

PubMed

Krenz, M; Baines, C P; Heusch, G; Downey, J M; Cohen, M V

2001-11-01

Recent studies reveal that brief ethanol exposure induces cardioprotection against simulated ischemia in cardiomyocytes by the activation of protein kinase C- epsilon. The present study tests the ability of ethanol to induce protection in rabbit hearts in which infarct size was the end-point and explores the signal transduction pathways involved. In isolated rabbit hearts, 50 m m ethanol infused for 5 min with 10 min of washout prior to 30 min of regional ischemia reduced infarct size (triphenyltetrazolium chloride staining) by 49%. Neither adenosine receptor blockade with 8-(p -sulfophenyl) theophylline nor the free radical scavenger N-2-mercaptopropionyl glycine inhibited the protection triggered by ethanol. In contrast, protein kinase C inhibition with chelerythrine, protein tyrosine kinase inhibition with genistein, and blockade of ATP-sensitive potassium channels (K(ATP)) with either 5-hydroxydecanoate or glibenclamide did abolish protection. Thus, transient ethanol exposure followed by washout prior to ischemia elicits a preconditioning-like effect involving protein kinase C, at least one protein tyrosine kinase, and K(ATP)channels, but neither adenosine nor free radicals. Copyright 2001 Academic Press.

Environmental novelty and illumination modify ethanol-induced open-field behavioral effects in mice.

PubMed

Fukushiro, Daniela F; Benetti, Liliane F; Josino, Fabiana S; Oliveira, Gabriela P; Fernandes, Maiara deM; Saito, Luis P; Uehara, Regina A; Wuo-Silva, Raphael; Oliveira, Camila S; Frussa-Filho, Roberto

2010-03-01

Both spontaneous and drug-induced animal behaviors can be modified by exposure to novel stimuli or different levels of environmental illumination. However, research into how these factors specifically impact ethanol (ETH)-induced behavioral effects is currently lacking. We aimed to investigate the effects of these two factors, considered separately or in conjunction, on ETH-induced acute hyperlocomotor effect and its sensitization in adult male Swiss mice. Mice were placed in a novel or familiar open-field under normal light (200 lx) or low light (9 lx) immediately after receiving an ip injection of either 1.8 g/kg ETH or saline (SAL). After 7 days, all animals received an ip challenge injection of 1.8 g/kg ETH, and were placed in the open-field under the same light conditions described above. Novelty increased central locomotion and decreased grooming, while low light increased grooming. Acute ETH administration increased both total and peripheral locomotion and these effects were potentiated by low light. Both low light and novelty were able to facilitate ETH-induced locomotor sensitization, which was detected by the central locomotion parameter. However, there was no synergism between the effects of these two modulating factors on ETH-induced behavioral sensitization. We conclude that both the acute behavioral effects of ETH and behavioral sensitization induced by previous administration of this drug can be critically modified by environmental factors. In addition, our study stresses the importance of using different behavioral parameters to evaluate the interaction between environmental factors and ETH effects. (c) 2009 Elsevier Inc. All rights reserved.

Male adolescent rats display blunted cytokine responses in the CNS after acute ethanol or lipopolysaccharide exposure

PubMed Central

Doremus-Fitzwater, Tamara L.; Gano, Anny; Paniccia, Jacqueline E.; Deak, Terrence

2015-01-01

Alcohol induces widespread changes in cytokine expression, with recent data from our laboratory having demonstrated that, during acute ethanol intoxication, adult rats exhibit consistent increases in interleukin (IL)-6 mRNA expression in several brain regions, while showing reductions in IL-1 and TNFα expression. Given evidence indicating that adolescence may be an ontogenetic period in which some neuroimmune processes and cells may not yet have fully matured, the purpose of the current experiments was to examine potential age differences in the central cytokine response of adolescent (P31–33 days of age) and adult (69–71 days of age) rats to either an acute immune (lipopolysaccharide; LPS) or non-immune challenge (ethanol). In Experiment 1, male Sprague-Dawley rats were given an intraperitoneal (i.p.) injection of either sterile saline, LPS (250 µg/kg), or ethanol (4-g/kg), and then trunk blood and brain tissue were collected 3 hr later for measurement of blood EtOH concentrations (BECs), plasma endotoxin, and central mRNA expression of several immune-related gene targets. In Experiment 2, the response to intragastrically (i.g.) administered ethanol was examined and compared to animals given tap water (i.g.). Results showed that LPS stimulated robust increases in expression of IL-1, IL-6, TNFα, and IκBα in the hippocampus, PVN, and amygdala, and that these increases were generally less pronounced in adolescents relative to adults. Following an i.p. EtOH challenge, IL-6 and IκBα expression were significantly increased in both ages in the PVN and amygdala, and adults exhibited even greater increases in IκBα than adolescents. I.g. administration of ethanol also increased IL-6 and IκBα expression in all three brain regions, with hippocampal IL-6 expression elevated even more so in adults compared to adolescents. Furthermore, assessment of plasma endotoxin concentrations revealed (i) whereas robust increases in plasma endotoxin were observed in adults injected with LPS, no corresponding elevations were seen in adolescents after LPS; and (ii) neither adolescents nor adults demonstrated increases in plasma endotoxin concentrations following i.p. or i.g. ethanol administration. Analysis of BECs indicated that, for both routes of exposure, adolescents exhibited lower BECs than adults. Taken together, these data suggest that categorically different mechanisms are involved in the central cytokine response to antigen exposure versus ethanol administration. Furthermore, these findings confirm once again that acute ethanol intoxication is a potent activator of brain cytokines, and calls for future studies to identify the mechanisms underlying age-related differences in the cytokine response observed during ethanol intoxication. PMID:25708278

Conditioned effects of ethanol on the immune system

PubMed Central

Gano, Anny; Doremus-Fitzwater, Tamara L; Deak, Terrence

2017-01-01

Several studies indicate that the immune system can be subjected to classical conditioning. Acute ethanol intoxication significantly modulates several pro-inflammatory cytokines (e.g. interleukins-1 and 6 [IL-1β and IL-6, respectively] and tumor necrosis factor alpha [TNFα])) in several brain areas, including amygdala (AMG), paraventricular nucleus (PVN), and hippocampus (HPC). It is unknown, however, whether cues associated with ethanol can elicit conditioned alterations in cytokine expression. The present study analyzed, in male Sprague-Dawley rats, whether ethanol-induced changes in the central cytokine response may be amenable to conditioning. In Experiments 1 and 2, the rats were given one or two pairings between a distinctive odor (conditional stimulus, CS) and the post-absorptive effects of a high (3.0 or 4.0 g/kg, Experiments 1 and 2, respectively) ethanol dose. Neither of these experiments revealed conditioning of IL-6, IL-1β, or TNFα, as measured via mRNA levels. Yet, re-exposure to the lemon-odor CS in Experiment 1 significantly increased C-Fos levels in the PVN. In Experiment 3, the rats were given four pairings between an odor CS and a moderate ethanol dose (2.0 g/kg), delivered intraperitoneally (i.p.) or intragastrically (i.g.). Re-exposure to the odor CS significantly increased IL-6 levels in HPC and AMG, an effect only evident in paired rats administered ethanol i.p. Overall, this study suggests that ethanol exposure can regulate the levels of IL-6 at HPC and AMG via classical conditioning mechanisms. These ethanol-induced, conditioned alterations in cytokine levels may ultimately affect the intake and motivational effects of ethanol. Impact statement This study examines, across three experiments, whether odor cues associated with ethanol exposure can condition changes in cytokine expression. The analysis of ethanol-induced conditioning of immune responses is a novel niche that can help understand the transition from social drinking to alcohol abuse and dependence. Ethanol-induced conditioning of the immune system could likely exacerbate neuroinflammation and drug-related toxicity, which in turn may facilitate further engagement in ethanol intake. The main new finding of the present study was that, after four pairings of ethanol’s unconditioned effects and a distinctive odor, the latter CS increased IL-6 levels in HPC and AMG. This suggests that ethanol’s effects upon IL-6 in HPC and AMG may come under conditioned control, particularly after repeated pairings between distinctive odor cues and ethanol’s effects. This article advances our knowledge of conditioned increases in cytokine responses, which should help understand the mechanisms underlying alcohol use, abuse, and relapse. PMID:28201924

Role of neutrophilic elastase in ethanol induced injury to the gastric mucosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kvietys, P.R.; Carter, P.R.

1990-02-26

Intragastric administration of ethanol (at concentrations likely to be encountered by the mucosa during acute intoxication) produces gastritis. Recent studies have implicated neutrophils in the gastric mucosal injury induced by luminal ethanol. The objective of the present study was to assess whether neutrophilic elastase contributes to the ethanol-induced gastric mucosal injury. Sprague-Dawley rats were instrumented for perfusion of the gastric lumen with saline or ethanol. Mucosal injury was quantitated by continuously measuring the blood-to-lumen clearance of {sup 51}Cr-EDTA. The experimental protocol consisted of a 40 minute control period (saline perfusion) followed by three successive 40 minute experimental periods (ethanol perfusion).more » During the three experimental periods the concentration of ethanol was progressively increased to 10, 20, and 30%. The experiments were performed in untreated animals and in animals pretreated with either Eglin c (an inhibitor of elastase and cathepsin G activity) or L 658 (a specific inhibitor of elastase activity). The effects of ethanol on EDTA clearance (x control) in untreated (n = 9) and L658 treated (n = 5) animals are shown in the Table below. Pretreatment with L 658 significantly attenuated the ethanol-induced increases in EDTA clearance. Pretreatment with Eglin c (n = 6) also provided some protection against ethanol-induced injury, but not to the extent as that provided by L658. The results of the authors studies suggest that neutrophilic elastase contributes to a gastric mucosal injury induced by luminal perfusion of the stomach with physiologically relevant concentrations of ethanol.« less

Acute toxicity evaluation, antibacterial, antioxidant and immunomodulatory effects of Melastoma malabathricum.

PubMed

Alnajar, Zahra A Amin; Abdulla, Mahmood A; Ali, Hapipah M; Alshawsh, Mohammed A; Hadi, A Hamid A

2012-03-20

Melastoma malabathricum (MM) is a well-known plant in Malaysian traditional medicine, locally known as senduduk. Its ethanol and aqueous extracts have been used in the present investigation to study the immunomodulatory role on human peripheral blood mononuclear cell (PBMC), and the DPPH, ABTS and FRAP free radical scavenging activities were also measured. Total flavonoids and total phenolic contents were assayed and the antibacterial effect was tested against four species of bacteria; two Gram-positive (Staphylococcus aureus and Streptococcus agalactiae) and two Gram-negative (Escherichia coli and Klebsilla pneumonia). The tests were carried out using the disc diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods. Moreover, the acute toxicity was evaluated in vivo on the ethanol extract of MM to establish its safety when administered orally. In our results, both extracts of MM showed abilities to scavenge DPPH and ABTS free radicals, IC(50) values: (11.599 ± 0.84, 10.573 ± 0.58 µmol/L) and (62.657 ± 0.78, 63.939 ± 0.48 µmol/L) for ethanol and aqueous extracts respectively. Indeed the ethanol extract evidenced high phenolic content (384.33 ± 0.005 mg/g), flavonoids contents (85.8 ± 0.009 mg/g) and ferric reducing antioxidant power (33,590 ± 0.038 mmol/g), with high activity against S. aureus and S. agalactiae (11 ± 0.3 and 12 ± 0.6 mm inhibition zones). Likewise, the percentage of peripheral blood mononuclear cells (PBMC) viability was increased in response to MM, IC(50) values (1.781 ± 1.2 and 6.545 ± 0.93 µg/mL) for ethanol and aqueous extracts, respectively. In addition, our results showed that the MM extract is safe even at a high dose of 5,000 mg/kg and has no oral toxicity. These findings suggest the excellent medicinal bioactivity of MM and explain the popularity of this plant in the folk medicine as a remedy for different illnesses.

Choline Ameliorates Deficits in Balance Caused by Acute Neonatal Ethanol Exposure.

PubMed

Bearer, Cynthia F; Wellmann, Kristen A; Tang, Ningfeng; He, Min; Mooney, Sandra M

2015-08-01

Fetal alcohol spectrum disorder (FASD) is estimated to occur in 1 % of all live births. The developing cerebellum is vulnerable to the toxic effects of alcohol. People with FASD have cerebellar hypoplasia and developmental deficits associated with cerebellar injury. Choline is an essential nutrient, but many diets in the USA are choline deficient. In rats, choline given with or following alcohol exposure reduces many alcohol-induced neurobehavioral deficits but not those associated with cerebellar function. Our objective was to determine if choline supplementation prior to alcohol exposure would ameliorate the impact of ethanol on a cerebellar-associated behavioral test in mice. Pregnant C57Bl6/J mice were maintained on a choline-deficient diet from embryonic day 4.5. On postnatal day 1 (P1), pups were assigned to one of eight treatment groups: choline (C) or saline (S) pre-treatment from P1 to P5, ethanol (6 g/kg) or Intralipid(®) on P5, C and or S post-treatment from P6 to P20. On P30, balance and coordination were tested using the dowel crossing test. Overall, there was a significant effect of treatment and females crossed longer distances than males. Ethanol exposure significantly reduced the total distance crossed. Choline pre-treatment increased the distance crossed by males, and both pre- and post-treatment with choline significantly increased total distance crossed for females and males. There was no effect of choline on Intralipid®-exposed animals. This is the first study to show that choline ameliorates ethanol-induced effects on balance and coordination when given before ethanol exposure. Choline fortification of common foodstuffs may reduce the effects of alcohol.

CHOLINE AMELIORATES DEFICITS IN BALANCE CAUSED BY ACUTE NEONATAL ETHANOL EXPOSURE

PubMed Central

Bearer, Cynthia F.; Wellmann, Kristen A.; Tang, Ningfeng; He, Min; Mooney, Sandra M.

2015-01-01

Fetal alcohol spectrum disorder (FASD) is estimated to occur in 1% of all live births. The developing cerebellum is vulnerable to the toxic effects of alcohol. People with FASD have cerebellar hypoplasia and developmental deficits associated with cerebellar injury. Choline is an essential nutrient but many diets in the USA are choline deficient. In rats, choline given with or following alcohol exposure reduces many alcohol-induced neurobehavioral deficits, but not those associated with cerebellar function. Our objective was to determine if choline supplementation prior to alcohol exposure would ameliorate the impact of ethanol on a cerebellar-associated behavioral test in mice. Pregnant C57Bl6/J mice were maintained on a choline deficient diet from embryonic day 4.5. On postnatal day 1 (P1), pups were assigned to one of 8 treatment groups: choline (C) or saline (S) pre-treatment from P1-5, ethanol (6 g/kg) or Intralipid® on P5, C or S post-treatment from P6-20. On P30, balance and coordination were tested using the dowel crossing test. Overall, there was a significant effect of treatment and females crossed longer distances than males. Ethanol exposure significantly reduced the total distance crossed. Choline pre-treatment increased the distance crossed by males, and both pre- and post-treatment with choline significantly increased total distance crossed for females and males. There was no effect of choline on Intralipid®-exposed animals. This is the first study to show that choline ameliorates ethanol-induced effects on balance and coordination when given before ethanol exposure. Choline fortification of common foodstuffs may reduce the effects of alcohol. PMID:26085462

Evidence for a causative role of N-methyl-D-aspartate receptors in an in vitro model of alcohol withdrawal hyperexcitability.

PubMed

Thomas, M P; Monaghan, D T; Morrisett, R A

1998-10-01

Synaptic mechanisms underlying hyperexcitability due to withdrawal from chronic ethanol exposure were investigated in a hippocampal explant model system using electrophysiological techniques. Whole-cell voltage clamp recordings from CA1 pyramidal cells demonstrated that acute ethanol exposure inhibited N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents by over 40%. Chronic ethanol exposure for 6 to 11 days at 35 or 75 mM induced no differences from control explants in the fast component of the population synaptic response (non-NMDAR-mediated). Prolonged field potential recordings (to 10 hr) were used to monitor the withdrawal process in vitro. Ethanol-exposed explants from both 35 and 75 mM groups displayed an increase (60% and 89%, respectively) in the NMDAR-mediated component of synaptic transmission on withdrawal from chronic exposure. Prolonged tonic-clonic electrographic seizure activity was consistently observed after ethanol withdrawal only after the increase in NMDAR function. This hyperexcitability was inhibited by the NMDAR antagonist D-2-amino-5-phosphonovaleric acid and returned once the NMDAR component was reestablished after antagonist washout. In situ hybridization studies suggest that expression of NR2B subunit mRNA may be enhanced in explants after chronic ethanol exposure. No lasting differences were observed in the NMDAR component after acute in vitro ethanol exposure and withdrawal. These data suggest that the occurance of ethanol withdrawal hyperexcitability in this system may be directly dependent on alterations in NMDAR function after chronic exposure. Since this region and others that contain ethanol sensitive NMDARs may serve as epileptic foci, long term alterations in NMDAR function may be expected to generate paroxysmal depolarizing shifts underlying ictal events after withdrawal from ethanol exposure.

α6β2 nicotinic acetylcholine receptors influence locomotor activity and ethanol consumption.

PubMed

Kamens, Helen M; Peck, Colette; Garrity, Caitlin; Gechlik, Alex; Jenkins, Brenita C; Rajan, Akshat

2017-06-01

Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system have been implicated in ethanol behaviors. In particular, work in genetically engineered mice has demonstrated that α6-containing nAChRs are involved in ethanol consumption and sedation. A limitation of these studies is that the alteration in the receptor was present throughout development. The recently described α6β2 antagonist, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), now makes it possible to test for the involvement of these receptors using a pharmacological approach. The aim of this study was to examine the role of α6β2 nAChRs in ethanol behaviors using a pharmacological approach. Adolescent C57BL/6J mice were treated with bPiDI 30 min prior to testing the mice for binge-like ethanol consumption in the drinking-in-the-dark (DID) test, ethanol-induced motor incoordination using the balance beam, and ethanol-induced sedation using the Loss of Righting Reflex (LORR) paradigm. Adolescent animals were chosen because they express a high amount of α6 mRNA relative to adult animals. Control studies were also performed to determine the effect of bPiDI on locomotor activity and ethanol metabolism. Female mice treated with 20 mg/kg bPiDI had reduced locomotor activity compared to saline-treated animals during the first 30 min following an acute injection. Pretreatment with the α6β2 antagonist reduced adolescent ethanol consumption but also reduced saccharin consumption. No significant effects were observed on ethanol-induced ataxia, sedation, or metabolism. This study provides evidence that α6β2 nAChRs are involved in locomotor activity as well as ethanol and saccharin consumption in adolescent animals. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.

PubMed

Lin, Chih-Wen; Zhang, Hao; Li, Min; Xiong, Xiwen; Chen, Xi; Chen, Xiaoyun; Dong, Xiaocheng C; Yin, Xiao-Ming

2013-05-01

Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulation of macroautophagy could be an effective approach to alleviate fatty liver condition and liver injury. C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4-week oral feeding regime (chronic), or high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured. In both acute and chronic ethanol condition, macroautophagy was activated. Carbamazepine, as well as rapamycin, enhanced ethanol-induced macroautophagy in hepatocytes in vitro and in vivo. Hepatic steatosis and liver injury were exacerbated by chloroquine, but alleviated by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity were also demonstrated in high fat diet-induced non-alcoholic fatty liver condition. These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Consequences of adolescent ethanol exposure in male Sprague-Dawley rats on fear conditioning and extinction in adulthood

NASA Astrophysics Data System (ADS)

Broadwater, Margaret A.

Some evidence suggests that adolescents are more vulnerable than adults to alcohol-induced cognitive deficits and that these deficits may persist into adulthood. Five experiments were conducted to assess long-term consequences of ethanol exposure on tone and context Pavlovian fear conditioning in male Sprague-Dawley rats. Experiment 1 examined age-related differences in sensitivity to ethanol-induced disruptions of fear conditioning to a pre-conditioning ethanol challenge. Experiments 2 examined fear conditioning 22 days after early-mid adolescent (P28-48) or adult (P70-90) exposure to 4 g/kg i.g. ethanol or water given every other day (total of 11 exposures). In Experiment 3, mid-late adolescents (P35-55) were exposed in the same manner to assess whether timing of ethanol exposure within the adolescent period would differentially affect later fear conditioning. Experiment 4 assessed the influence of prior adolescent or adult ethanol exposure on the disrupting effects of a pre-conditioning ethanol challenge. In Experiment 5, neurogenesis (doublecortin---DCX) and cholinergic (choline acetyltransferase---ChAT) markers were measured to assess potential long-term ethanol-induced changes in neural mechanisms important for learning and memory. Results indicated that the long-lasting behavioral effects of ethanol exposure varied depending on exposure age, with early-mid adolescent exposed animals showing attenuated context fear retention (a relatively hippocampal-dependent task), whereas mid-late adolescent and adult exposed animals showed slower context extinction (thought to be reliant on the mPFC). Early-mid adolescent ethanol-exposed animals also had significantly less DCX and ChAT expression than their water-exposed counterparts, possibly contributing to deficits in context fear. Tone fear was not influenced by prior ethanol exposure at any age. In terms of age differences in ethanol sensitivity, adolescents were less sensitive than adults to ethanol-induced disruption of context fear retention; however, acute ethanol-induced disruptions of context fear did not differ as a function of prior ethanol exposure at either exposure age in adulthood. Together these results reflect differential influence of ethanol on the brain as it changes throughout ontogeny, with the hippocampus seemingly vulnerable to early adolescent exposure, whereas the mPFC may be more affected by ethanol exposure in mid-adolescence through adulthood. These data have implications for alcohol use not only throughout adolescence, but also in adulthood.

Zingiber officinale Roscoe ameliorates anticancer antibiotic doxorubicin-induced acute cardiotoxicity in rat.

PubMed

Ajith, Thekkuttuparambil Ananthanarayanan; Hema, Unnikrishnan; Aswathi, Sreedharan

2016-07-01

Oxidative stress (OS) has been suggested in the cardiotoxicity induced by anticancer antibiotic doxorubicin (DXN). The cardioprotective effects of aqueous ethanol extract of Zingiber officinale was evaluated against DXN-induced acute cardiac damage in rat. The results of the study demonstrated that Z. officinale significantly and dose dependently protected the cardiotoxicity induced by DXN. The activities of serum glutamate oxaloacetate transaminase and serum lactate dehydrogenase activity in the DXN alone treated group of animals were significantly (p<0.01) elevated when compared to normal animals. The activities were reduced in the Z. officinale (200 and 400 mg/kg, p.o) plus DXN treated groups. The cardiac malondialdehyde was elevated in the DXN alone treated group and declined significantly in the Z. officinale (400 mg/kg) plus DXN treated group. The results concluded that aqueous ethanol extract of Z. officinale ameliorated DXN-induced cardiotoxicity. The protection can be ascribed to the free radical scavenging activity of Z. officinale. This protective effect may suggest the adjuvant role of Z. officinale against OS induced by cancer chemotherapeutants, which warrant further research. © 2016 Old City Publishing, Inc.

Ulcer Prevention Effect Of 3,4,5-Tihydroxy-N0-[(2-Methyl-1H-Indol-3yl)Methylidene]Benzohydrazide In HCl/Ethanol-Induced Gastric Mucosal Damage In Rats.

PubMed

Tayeby, Faezeh; Salman, Abbas Abdul Ameer; Kamran, Sareh; Khaing, Si Lay; Salehen, Nur'ain Binti; Mohan, Gokula Mohan A/L Duchiyanda

2017-01-01

The newly synthesized, 3,4,5-Trihydroxy-N 0-[(2-methyl-1H-indol-3-yl)-methylidene] benzohydrazide (TIBH), is an indole and gallic acid derivative. The aim of this research investigation was to evaluate the acute toxicity and the ulcer prevention potential of TIBH in HCl/Ethanol-induced gastric ulcer rat model. Six groups of rats were orally received 5ml/kg of vehicle (1 % Carboxy methyl cellulose) for the normal and ulcer control groups each, Omeprazole (20mg/kg) for positive control, 50 mg/kg, 100 mg/kg and 200 mg/kg of TIBH for experimental groups, respectively. After one hour, instead of rats in the normal group which received 5ml/kg of 1% CMC, other groups received 5ml/kg of HCl/Ethanol. All rats were sacrificed after one additional hour. Gastric juice, gastric mucosa, morphologies of gastric ulcers and protein expressions of both control and treatment groups were evaluated. TIBH showed a ulcer prevention potential by increase of the mucus secretion, decrease of the gastric acidity, up-regulation of HSP70 protein, down-regulation of Bax protein, decrease of the lipid peroxidation and the increase of the Superoxide dismutase (SOD) activity in gastric tissue homogenate. Acute toxicity assay exposed valuable information on the safety of this compound. TIBH had a dose dependent ulcer prevention potential against HCl/Ethanol-triggered gastric ulcer.

Ulcer Prevention Effect Of 3,4,5-Tihydroxy-N0-[(2-Methyl-1H-Indol-3yl)Methylidene]Benzohydrazide In HCl/Ethanol-Induced Gastric Mucosal Damage In Rats

PubMed Central

Tayeby, Faezeh; Salman, Abbas Abdul Ameer; Kamran, Sareh; Khaing, Si Lay; Salehen, Nur'ain Binti; Mohan, Gokula Mohan A/L Duchiyanda

2017-01-01

The newly synthesized, 3,4,5-Trihydroxy-N 0-[(2-methyl-1H-indol-3-yl)-methylidene] benzohydrazide (TIBH), is an indole and gallic acid derivative. The aim of this research investigation was to evaluate the acute toxicity and the ulcer prevention potential of TIBH in HCl/Ethanol-induced gastric ulcer rat model. Six groups of rats were orally received 5ml/kg of vehicle (1 % Carboxy methyl cellulose) for the normal and ulcer control groups each, Omeprazole (20mg/kg) for positive control, 50 mg/kg, 100 mg/kg and 200 mg/kg of TIBH for experimental groups, respectively. After one hour, instead of rats in the normal group which received 5ml/kg of 1% CMC, other groups received 5ml/kg of HCl/Ethanol. All rats were sacrificed after one additional hour. Gastric juice, gastric mucosa, morphologies of gastric ulcers and protein expressions of both control and treatment groups were evaluated. TIBH showed a ulcer prevention potential by increase of the mucus secretion, decrease of the gastric acidity, up-regulation of HSP70 protein, down-regulation of Bax protein, decrease of the lipid peroxidation and the increase of the Superoxide dismutase (SOD) activity in gastric tissue homogenate. Acute toxicity assay exposed valuable information on the safety of this compound. TIBH had a dose dependent ulcer prevention potential against HCl/Ethanol-triggered gastric ulcer. PMID:29200945

An integrative analysis of ethanol tolerance and withdrawal in zebrafish (Danio rerio)

PubMed Central

Tran, Steven; Chatterjee, Diptendu; Gerlai, Robert

2014-01-01

The zebrafish is emerging as a popular animal model for alcohol (ethanol or EtOH) addiction due to its simplicity and practical advantages. Two phenomena associated with ethanol addiction are the development of tolerance and withdrawal. Using a multi-level approach in the current study, we characterize ethanol tolerance and withdrawal in zebrafish. We first investigate the temporal trajectory of ethanol concentration in the zebrafish brain in response to an acute exposure and during withdrawal. We report that ethanol concentrations approach a steady state within 60 minutes of exposure to 0.50% and 1.00% v/v ethanol and rapidly decline and return to zero within 60 minutes following withdrawal from chronic ethanol exposure (0.50% v/v). We characterize the changes associated with ethanol tolerance and withdrawal in zebrafish by focusing on 3 domains relevant to ethanol addiction: motor patterns, physiological responses (i.e. cortisol levels), and neurochemical alterations. The use of multiple domains of investigation allowed an in-depth analysis of ethanol induced changes in zebrafish. PMID:24598276

Genetic differences in ethanol-induced hyperglycemia and conditioned taste aversion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Risinger, F.O.; Cunningham, C.L.

1992-01-01

Genetic differences in the hyperglycemic response to acute ethanol exposure and ethanol-induced conditioned taste aversion were examined using inbred mice. Adult male C57BL/6J and DBA/2J mice were injected with ethanol and blood glucose levels determined over 4 h. C57 mice demonstrated greater dose-dependent elevations in blood glucose compared to DBA mice. In a conditioned taste aversion procedure, water deprived mice received ethanol injections immediately after access to a NaCl flavored solution. DBA mice developed aversion to the ethanol-paired flavor at a lower dose than C57 mice. These results provide further support for a possible inverse genetic relationship between sensitivity tomore » ethanol-induced hyperglycemia and sensitivity to conditioned taste aversion.« less

Ethanol Induction of CYP2A5: Role of CYP2E1-ROS-Nrf2 Pathway

PubMed Central

Lu, Yongke; Zhang, Xu Hannah

2012-01-01

Chronic ethanol consumption was previously shown to induce CYP2A5 in mice, and this induction of CYP2A5 by ethanol was CYP2E1 dependent. In this study, the mechanisms of CYP2E1-dependent ethanol induction of CYP2A5 were investigated. CYP2E1 was induced by chronic ethanol consumption to the same degree in wild-type (WT) mice and CYP2A5 knockout (Cyp2a5 –/–) mice, suggesting that unlike the CYP2E1-dependent ethanol induction of CYP2A5, ethanol induction of CYP2E1 is not CYP2A5 dependent. Microsomal ethanol oxidation was about 25% lower in Cyp2a5 –/– mice compared with that in WT mice, suggesting that CYP2A5 can oxidize ethanol although to a lesser extent than CYP2E1 does. CYP2A5 was induced by short-term ethanol consumption in human CYP2E1 transgenic knockin (Cyp2e1 –/– KI) mice but not in CYP2E1 knockout (Cyp2e1 –/–) mice. The redox-sensitive transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) was also induced by acute ethanol in Cyp2e1 –/– KI mice but not in Cyp2e1 –/– mice. Ethanol induction of CYP2A5 in Nrf2 knockout (Nrf2 –/–) mice was lower compared with that in WT mice, whereas CYP2E1 induction by ethanol was comparable in WT and Nrf2 –/– mice. Antioxidants (N-acetyl-cysteine and vitamin C), which blocked oxidative stress induced by chronic ethanol in WT mice and acute ethanol in Cyp2e1 –/– KI mice, also blunted the induction of CYP2A5 and Nrf2 by ethanol but not the induction of CYP2E1 by ethanol. These results suggest that oxidative stress induced by ethanol via induction of CYP2E1 upregulates Nrf2 activity, which in turn regulates ethanol induction of CYP2A5. Results obtained from primary hepatocytes, mice gavaged with binge ethanol or fed chronic ethanol, show that Nrf2-regulated ethanol induction of CYP2A5 protects against ethanol-induced steatosis. PMID:22552773

Age differences in fear retention and extinction in male Sprague-Dawley rats: Effects of ethanol challenge during conditioning

PubMed Central

Broadwater, Margaret; Spear, Linda P.

2013-01-01

Pavlovian fear conditioning is an ideal model to investigate how learning and memory are influenced by alcohol use during adolescence because the neural mechanisms involved have been studied extensively. In Exp 1, adolescent and adult male Sprague-Dawley rats were non-injected or injected with saline, 1 or 1.5 g/kg ethanol intraperitoneally 10 minutes prior to tone or context conditioning. Twenty-four hours later, animals were tested for tone or context retention and extinction, with examination of extinction retention conducted 24 hours thereafter. In Exp 2, a context extinction session was inserted between the tone conditioning and the tone fear retention/extinction days to reduce pre-CS baseline freezing levels at test. Basal levels of acquisition, fear retention, extinction, and extinction retention after tone conditioning were similar between adolescent and adult rats. In contrast adolescents showed faster context extinction than adults, while again not differing from adults during context acquisition, retention or extinction retention. In terms of ethanol effects, adolescents were less sensitive to ethanol-induced context retention deficits than adults. No age differences emerged in terms of tone fear retention, with ethanol disrupting tone fear retention at both ages in Exp1, but at neither age in Exp 2, a difference seemingly due to group differences in pre-CS freezing during tone testing in Exp 1, but not Exp 2. These results suggest that age differences in the acute effects of ethanol on cognitive function are task-specific, and provide further evidence for age differences cognitive functioning in a task thought to be hippocampally-related. PMID:23810415

Alcohol and the pancreas.

PubMed

Schenker, S; Montalvo, R

1998-01-01

Alcoholic pancreatitis may be one of the most serious adverse consequences of alcohol abuse. Its diagnosis, as it has for many years, depends primarily on clinical acumen in interpreting properly the symptoms and signs of abdominal distress, buttressed by elevated pancreatic enzymes (amylase and lipase). More recently, the use of computerized tomography (CT) in selected situations has been both of confirmatory and prognostic value. Severity of abnormality by CT correlates reasonably well with a variety of clinical-laboratory clusters (APACHE system, Ranson's criteria, etc.) and aids in therapy. The pathogenesis of alcoholic pancreatitis is not fully defined. The ultimate picture is one of tissue autolysis by activated proteolytic enzymes. The triggers for such activation, however, are still not known. They are represented by three main theories: (1) large duct obstruction and/or increased permeability relative to pancreatic secretion, (2) small duct obstruction due to proteinaceous precipitates, and (3) a direct toxic-metabolic effect of ethanol on pancreatic acinar cells. While not mutually exclusive, we favor the last hypothesis as being most consistent with the effects of ethanol on other organ systems. The direct effects of ethanol and/or its metabolites may be mediated, at least in part, via oxidative stress or the generation of fatty acid ethyl esters. Autolysis (regardless of proximate mechanism(s)) leads to inflammation likely mediated via release of various cytokines. It also should be appreciated that "acute" pancreatitis (the topic of this chapter) likely represents an acute process within a chronic pancreatic exposure and injury from alcoholic abuse. The key question of why pancreatitis develops in only a small number of alcohol abusers is not resolved. Therapy depends on the severity of alcoholic pancreatitis, which is defined by clinical-laboratory and often CT criteria. Mild pancreatitis usually resolves acutely with alcohol abstention and supportive therapy. Severe pancreatitis has a significant morbidity and mortality, mainly related to the degree of pancreatic necrosis and infection. It requires meticulous combined medical-surgical care.

Neuroprotective effect of acute ethanol intoxication in TBI is associated to the hierarchical modulation of early transcriptional responses.

PubMed

Chandrasekar, Akila; Aksan, Bahar; Heuvel, Florian Olde; Förstner, Philip; Sinske, Daniela; Rehman, Rida; Palmer, Annette; Ludolph, Albert; Huber-Lang, Markus; Böckers, Tobias; Mauceri, Daniela; Knöll, Bernd; Roselli, Francesco

2018-04-01

Ethanol intoxication is a risk factor for traumatic brain injury (TBI) but clinical evidence suggests that it may actually improve the prognosis of intoxicated TBI patients. We have employed a closed, weight-drop TBI model of different severity (2cm or 3cm falling height), preceded (-30min) or followed (+20min) by ethanol administration (5g/Kg). This protocol allows us to study the interaction of binge ethanol intoxication in TBI, monitoring behavioral changes, histological responses and the transcriptional regulation of a series of activity-regulated genes (immediate early genes, IEGs). We demonstrate that ethanol pretreatment before moderate TBI (2cm) significantly reduces neurological impairment and accelerates recovery. In addition, better preservation of neuronal numbers and cFos+cells was observed 7days after TBI. At transcriptional level, ethanol reduced the upregulation of a subset of IEGs encoding for transcription factors such as Atf3, c-Fos, FosB, Egr1, Egr3 and Npas4 but did not affect the upregulation of others (e.g. Gadd45b and Gadd45c). While a subset of IEGs encoding for effector proteins (such as Bdnf, InhbA and Dusp5) were downregulated by ethanol, others (such as Il-6) were unaffected. Notably, the majority of genes were sensitive to ethanol only when administered before TBI and not afterwards (the exceptions being c-Fos, Egr1 and Dusp5). Furthermore, while severe TBI (3cm) induced a qualitatively similar (but quantitatively larger) transcriptional response to moderate TBI, it was no longer sensitive to ethanol pretreatment. Thus, we have shown that a subset of the TBI-induced transcriptional responses were sensitive to ethanol intoxication at the instance of trauma (ultimately resulting in beneficial outcomes) and that the effect of ethanol was restricted to a certain time window (pre TBI treatment) and to TBI severity (moderate). This information could be critical for the translational value of ethanol in TBI and for the design of clinical studies aimed at disentangling the role of ethanol intoxication in TBI. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of hecogenin and its possible mechanism of action on experimental models of gastric ulcer in mice.

PubMed

Santos Cerqueira, Gilberto; dos Santos e Silva, Gabriela; Rios Vasconcelos, Emiliano; Fragoso de Freitas, Ana Paula; Arcanjo Moura, Brinell; Silveira Macedo, Danielle; Lopes Souto, Augusto; Barbosa Filho, José Maria; de Almeida Leal, Luzia Kalyne; de Castro Brito, Gerly Anne; Souccar, Caden; de Barros Viana, Glauce Socorro

2012-05-15

This study investigates the gastroprotective effects of hecogenin, a steroid saponin isolated from Agave sisalana, on experimental models of gastric ulcer. Male Swiss mice were used in the models of ethanol- and indometacin-induced gastric ulcer. To clarify the hecogenin mechanism of action, the roles of nitric oxide (NO), sulfhydryls (GSH), K⁺(ATP) channels and prostaglandins were also investigated, and measurements of lipid peroxidation (TBARS assay) and nitrite levels in the stomach of hecogenin-treated and untreated animals were performed. Furthermore, the effects of hecogenin on myeloperoxidase (MPO) release from human neutrophils were assessed in vitro. Our results showed that hecogenin (3.1, 7.5, 15, 30, 60 and 90 mg/kg, p.o.) acutely administered, before ethanol or indomethacin, exhibited a potent gastroprotective effect. Although the pretreatments with L-NAME, an iNOS inhibitor, and capsazepine, a TRPV1 receptor agonist, were not able to reverse the hecogenin effect, this was reversed by glibenclamide, a K⁺(ATP) blocker, and indomethacin in the model of ethanol-induced gastric lesions. The hecogenin pretreatment normalized GSH levels and significantly reduced lipid peroxidation and nitrite levels in the stomach, as evaluated by the ethanol-induced gastric lesion model. The drug alone increased COX-2 expression and this effect was further enhanced in the presence of ethanol. It also decreased MPO release and significantly protected the gastric mucosa. In conclusion, we showed that hecogenin presents a significant gastroprotective effect that seems to be mediated by K⁺(ATP) channels opening and the COX-2/PG pathway. In addition, its antioxidant and anti-inflammatory properties may play a role in the gastroprotective drug effect. Copyright © 2012 Elsevier B.V. All rights reserved.

Gastroprotective activity of ferruginol in mice and rats: effects on gastric secretion, endogenous prostaglandins and non-protein sulfhydryls.

PubMed

Areche, Carlos; Theoduloz, Cristina; Yáñez, Tania; Souza-Brito, Alba R M; Barbastefano, Víctor; de Paula, Débora; Ferreira, Anderson L; Schmeda-Hirschmann, Guillermo; Rodríguez, Jaime A

2008-02-01

The gastroprotective mechanism of the natural diterpene ferruginol was assessed in mice and rats. The involvement of gastric prostaglandins (PGE(2)), reduced glutathione, nitric oxide or capsaicin receptors was evaluated in mice either treated or untreated with indometacin, N-ethylmaleimide (NEM), N-nitro-L-arginine methyl ester (L-NAME) or ruthenium red, respectively, and then orally treated with ferruginol or vehicle. Gastric lesions were induced by oral administration of ethanol. The effects of ferruginol on the parameters of gastric secretion were assessed in pylorus-ligated rats. Gastric PGE(2) content was determined in rats treated with ferruginol and/or indometacin. The reduction of gastric glutathione (GSH) content was determined in rats treated with ethanol after oral administration of ferruginol, lansoprazole or vehicle. Finally, the acute oral toxicity was assessed in mice. Indometacin reversed the gastroprotective effect of ferruginol (25 mg kg(-1)) but not NEM, ruthenium red or L-NAME. The diterpene (25 mg kg(-1)) increased the gastric juice volume and its pH value, and reduced the titrable acidity but was devoid of effect on the gastric mucus content. Ferruginol (25, 50 mg kg(-1)) increased gastric PGE(2) content in a dose-dependent manner and prevented the reduction in GSH observed due to ethanol-induced gastric lesions in rats. Single oral doses up to 3 g kg(-1) ferruginol did not elicit mortality or acute toxic effects in mice. Our results showed that ferruginol acted as a gastroprotective agent stimulating the gastric PGE(2) synthesis, reducing the gastric acid output and improving the antioxidant capacity of the gastric mucosa by maintaining the GSH levels.

Ethanol produces corticotropin releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala

PubMed Central

Silberman, Yuval; Fetterly, Tracy L.; Awad, Elias K.; Milano, Elana J.; Usdin, Ted B.; Winder, Danny G.

2015-01-01

Background Ethanol modulation of Central Amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin releasing factor (CRF) receptor system. Previous work has predominantly focused on ethanol/CRF interactions on the CeA GABA circuitry; however our lab recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine if ethanol modulates CeA glutamate transmission via activation of CRF signaling. Methods The effects of ethanol on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRFCeAhDTR) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post-hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRFDTA mice) ablated CRF neurons throughout the CNS, as assessed by qRT-PCR quantification of CRF mRNA. Results Acute bath application of ethanol significantly increased sEPSC frequency in a concentration dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRF receptor 1 and CRF receptor 2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, ethanol did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of ethanol to enhance CeA sEPSC frequency was not altered in CRFCeAhDTR mice despite a ~78% reduction in CeA CRF cell counts. The ability of ethanol to enhance CeA sEPSC frequency was also not altered in the CRFDTA mice despite a three-fold reduction in CRF mRNA levels. Conclusion These findings demonstrate that ethanol enhances spontaneous glutamatergic transmission in the CeA via a CRF receptor dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF. PMID:26503065

Potential Effect of Bacopa monnieri on Nitrobenzene Induced Liver Damage in Rats.

PubMed

Menon, B Rajalakshmy; Rathi, M A; Thirumoorthi, L; Gopalakrishnan, V K

2010-10-01

The study was designed to evaluate the hepatoprotective activity of ethanolic extract of Bacopa monnieri in acute experimental liver injury induced by Nitrobenzene in rats. The extract at the dose of 200 mg/kg body weight was administered orally once every day for 10 days. The increased serum marker enzymes, Aspartate transaminase, Alanine transaminase and alkaline phosphatase were restored towards normalization significantly by the extract. Significant increase in SOD, CAT and GPx was observed in extract treated liver injured experimental rats. Histopathological examination of the liver tissues supported the hepatoprotection. It is concluded that the ethanolic extract of Bacopa monieri plant possess good hepatoprotective activity.

ARGININOSUCCINATE SYNTHASE CONDITIONS THE RESPONSE TO ACUTE AND CHRONIC ETHANOL-INDUCED LIVER INJURY IN MICE

PubMed Central

Yan, Wei; Morón-Concepción, Jose A.; Ward, Stephen C.; Ge, Xiaodong; de la Rosa, Laura Conde; Nieto, Natalia

2012-01-01

Background and Aim Argininosuccinate synthase (ASS) is the rate-limiting enzyme in both the urea and the l-citrulline/nitric oxide (NO·) cycles regulating protein catabolism, ammonia levels and NO· generation (1-2). Since a proteomics analysis identified ASS and nitric oxide synthase-2 (NOS2) as co-induced in rat hepatocytes by chronic ethanol consumption, which also occurred in alcoholic liver disease (ALD) and in cirrhotic patients, we hypothesized that ASS could play a role in ethanol binge and chronic ethanol-induced liver damage. Methods To investigate the contribution of ASS to the pathophysiology of ALD, wild-type (WT) and Ass+/− mice (Ass−/− are lethal due to hyperammonemia) were exposed to an ethanol binge or to chronic ethanol drinking. Results Compared with WT, Ass+/− mice given an ethanol binge exhibited decreased steatosis, lower NOS2 induction and less 3-nitrotyrosine (3-NT) protein residues, indicating that reducing nitrosative stress via the l-citrulline/NO· pathway plays a significant role in preventing liver damage. However, chronic ethanol treated Ass+/− mice displayed enhanced liver injury compared with WT mice. This was due to hyperammonemia, lower phosphorylated AMP-activated protein kinase (pAMPKα) to total AMPKα ratio, decreased sirtuin (Sirt-1) and peroxisomal proliferator-activated receptor coactivator-1α (Pgc1α) mRNAs, lower fatty acid β-oxidation due to down-regulation of carnitine palmitoyl transferase-II (CPT-II), decreased antioxidant defense and elevated lipid peroxidation end-products in spite of comparable nitrosative stress but likely reduced NOS3. Conclusion Partial Ass ablation protects only in acute ethanol-induced liver injury by decreasing nitrosative stress but not in a more chronic scenario where oxidative stress and impaired fatty acid β-oxidation are key events. PMID:22213272

Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.

PubMed

Leung, Tung Ming; Lu, Yongke; Yan, Wei; Morón-Concepción, Jose A; Ward, Stephen C; Ge, Xiaodong; Conde de la Rosa, Laura; Nieto, Natalia

2012-05-01

Argininosuccinate synthase (ASS) is the rate-limiting enzyme in both the urea and the L-citrulline/nitric oxide (NO·) cycles regulating protein catabolism, ammonia levels, and NO· generation. Because a proteomics analysis identified ASS and nitric oxide synthase-2 (NOS2) as coinduced in rat hepatocytes by chronic ethanol consumption, which also occurred in alcoholic liver disease (ALD) and in cirrhosis patients, we hypothesized that ASS could play a role in ethanol binge and chronic ethanol-induced liver damage. To investigate the contribution of ASS to the pathophysiology of ALD, wildtype (WT) and Ass(+/-) mice (Ass(-/-) are lethal due to hyperammonemia) were exposed to an ethanol binge or to chronic ethanol drinking. Compared with WT, Ass(+/-) mice given an ethanol binge exhibited decreased steatosis, lower NOS2 induction, and less 3-nitrotyrosine (3-NT) protein residues, indicating that reducing nitrosative stress by way of the L-citrulline/NO· pathway plays a significant role in preventing liver damage. However, chronic ethanol-treated Ass(+/-) mice displayed enhanced liver injury compared with WT mice. This was due to hyperammonemia, lower phosphorylated AMP-activated protein kinase alpha (pAMPKα) to total AMPKα ratio, decreased sirtuin-1 (Sirt-1) and peroxisomal proliferator-activated receptor coactivator-1α (Pgc1α) messenger RNAs (mRNAs), lower fatty acid β-oxidation due to down-regulation of carnitine palmitoyl transferase-II (CPT-II), decreased antioxidant defense, and elevated lipid peroxidation end-products in spite of comparable nitrosative stress but likely reduced NOS3. Partial Ass ablation protects only in acute ethanol-induced liver injury by decreasing nitrosative stress but not in a more chronic scenario where oxidative stress and impaired fatty acid β-oxidation are key events. Copyright © 2011 American Association for the Study of Liver Diseases.

Synergetic analgesic effect of the combination of arnica and hydroxyethyl salicylate in ethanolic solution following cutaneous application by transcutaneous electrostimulation.

PubMed

Kucera, Miroslav; Horácek, Ondrej; Kálal, Jan; Kolár, Pavel; Korbelar, Peter; Polesná, Zora

2003-01-01

A combination of the active agents arnica and hydroxyethyl salicylate (HES) in ethanolic solution (Sportino Acute Spray) is cutaneously applied for the treatment of sports injuries and diseases of the locomotor apparatus. The aim was to examine the efficacy and synergism of the single substances and the combination with regard to the analgesic effect after cutaneous application as well as to validate the method of transcutaneous electronic stimulation as a method of measuring the analgesic effect. In the present article, the method of transcutaneous electrostimulation was used in a randomized, controlled, single-blind trial on healthy volunteers to provide objective evidence that the combination of active agents displays a significantly greater analgesic effect than the individual active agents. Thus there is synergy between the active agents arnica and hydroxyethyl salicylate in the combination preparation. In addition, the effect of the vehicle ethanol and the reference substance water could be determined within the framework of these comparative experiments and the difference between the combination preparation and the individual substances arnica and HES could be shown. The method of transcutaneous electrostimulation used for the objective measurement of the analgesic effect was validated.

A hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn ameliorates hyperalgesia and allodynia in vincristine-induced neuropathic pain in rats.

PubMed

Amoateng, Patrick; Adjei, Samuel; Osei-Safo, Dorcas; Ameyaw, Elvis Ofori; Ahedor, Believe; N'guessan, Benoit Banga; Nyarko, Alexander Kwadwo

2015-07-01

The hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn whole plant has demonstrated analgesic effects in acute pain models. The extract has also demonstrated anticonvulsant effects in murine models of experimental epilepsy. The present study illustrates an evaluation of the hydro-ethanolic extract of the plant for possible analgesic properties in hyperalgesia and allodynia associated with vincristine-induced neuropathy in rats. Neuropathic pain was induced in Sprague-Dawley rats by injecting 100 μg/kg of vincristine sulphate on alternative days for 6 days (days 0, 2, 4, 8, 10 and 12). Vincristine-induced cold allodynia, mechanical hyperalgesia and thermal hyperalgesia were measured pre-vincristine administration and on days 15, 17 and 19 post-vincristine administration. The rats were then treated with S. nodiflora extract (SNE) (100, 300 and 1000 mg/kg), pregabalin (10, 30 and 100 mg/kg) and distilled water as vehicle daily for 5 days and pain thresholds were measured on alternate days for 3 days. SNE and pregabalin produced analgesic properties observed as increased paw withdrawal latencies to mechanical, tactile, cold water stimuli and thermal hyperalgesic tests during the 5 days of treatment. The findings suggest that hydro-ethanolic extract of S. nodiflora possesses anti-hyperalgesic and anti-allodynic effects in vincristine-induced neuropathic pain in rats.

The Ethanolic Stem-Bark Extract of Antrocaryon micraster Inhibits Carrageenan-Induced Pleurisy and Pedal Oedema in Murine Models of Inflammation

PubMed Central

Essel, Leslie B.; Duduyemi, Babatunde M.

2017-01-01

We investigated the antioxidant and anti-inflammatory effects of a 70% v/v ethanol extract of the stem bark of Antrocaryon micraster on murine models of carrageenan-induced pleurisy and paw oedema. Rat pleural fluid was analysed for volume, protein content, and leucocytes, while lung histology was assessed for damage. Lung tissue homogenates were assayed for glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and myeloperoxidase (MPO). Phytochemical analysis was carried out on the stem bark. Acute toxicity studies were conducted in rats. In the pleurisy model the extract (30–300 mg/kg) significantly reduced the volume and amount of proteins and leucocytes in the exudate and also protected against lung injury. Tissue level of GSH and SOD and CAT expression were increased while MDA level and MPO activity were reduced. The peak and total oedema responses were significantly suppressed when given both preemptively and curatively in the mice paw oedema test. Saponins, alkaloids, triterpenoids, and tannins were present in the stem bark. A. micraster extract exhibited no apparent acute toxicity. We conclude that the ethanolic stem-bark extract of A. micraster has antioxidant action and exhibits significant anti-inflammatory activity through suppression of pleurisy and paw oedema induced with carrageenan. PMID:28798953

Hyptis suaveolens (L.) Poit (Lamiaceae), a medicinal plant protects the stomach against several gastric ulcer models.

PubMed

Jesus, N Z T; Falcão, H S; Lima, G R M; Caldas Filho, M R D; Sales, I R P; Gomes, I F; Santos, S G; Tavares, J F; Barbosa-Filho, J M; Batista, L M

2013-12-12

Hyptis suaveolens is used by the traditional population in several parts of the world to treat inflammation, gastric ulcer and infection and is used as a crude drug to relieve symptoms related with gastric ulcer or gastritis in northeaster and central region of Brazil. the standardized ethanolic extract (Hs-EtOHE) and hexanic fraction (Hs-HexF) of Hyptis suaveolens (62,5, 125, 250 and 500 mg/kg) was evaluated in several models of acute gastric ulcers. The participation of NO was evaluated by pretreatment with L-NAME and non-protein sulfyhydryls by NEM in the gastroprotective effect. Hs-EtOHE and Hs-HexF markedly reduced the gastric lesions induced by all ulcerogenic agents (HCl/ethanol, ethanol, NSAIDs and hypothermic restraint-stress). Gastric ulcerations were exacerbated by administration of NEM suggesting that the gastroprotective mechanism of action of Hs-EtOHE and Hs-HexF involves sulfhydryl groups. Ours results show that an extract of Hyptis suaveolens, administered orally to rodents, present gastro protective activity in different models of acute of gastric ulcer and give some support to the reported claims on the use of this plant as a gastro protective agent. © 2013 Published by Elsevier Ireland Ltd.

Acute Ethanol Causes Hepatic Mitochondrial Depolarization in Mice: Role of Ethanol Metabolism

PubMed Central

Zhong, Zhi; Ramshesh, Venkat K.; Rehman, Hasibur; Liu, Qinlong; Theruvath, Tom P.; Krishnasamy, Yasodha; Lemasters, John J.

2014-01-01

Background/Aims An increase of ethanol metabolism and hepatic mitochondrial respiration occurs in vivo after a single binge of alcohol. Here, our aim was to determine how ethanol intake affects hepatic mitochondrial polarization status in vivo in relation to ethanol metabolism and steatosis. Methods Hepatic mitochondrial polarization, permeability transition (MPT), and reduce pyridine nucleotides, and steatosis in mice were monitored by intravital confocal/multiphoton microscopy of the fluorescence of rhodamine 123 (Rh123), calcein, NAD(P)H, and BODIPY493/503, respectively, after gavage with ethanol (1–6 g/kg). Results Mitochondria depolarized in an all-or-nothing fashion in individual hepatocytes as early as 1 h after alcohol. Depolarization was dose- and time-dependent, peaked after 6 to 12 h and maximally affected 94% of hepatocytes. This mitochondrial depolarization was not due to onset of the MPT. After 24 h, mitochondria of most hepatocytes recovered normal polarization and were indistinguishable from untreated after 7 days. Cell death monitored by propidium iodide staining, histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was low throughout. After alcohol, mitochondrial NAD(P)H autofluorescence increased and decreased, respectively, in hepatocytes with polarized and depolarized mitochondria. Ethanol also caused steatosis mainly in hepatocytes with depolarized mitochondria. Depolarization was linked to ethanol metabolism, since deficiency of alcohol dehydrogenase and cytochrome-P450 2E1 (CYP2E1), the major ethanol-metabolizing enzymes, decreased mitochondrial depolarization by ∼70% and ∼20%, respectively. Activation of aldehyde dehydrogenase decreased depolarization, whereas inhibition of aldehyde dehydrogenase enhanced depolarization. Activation of aldehyde dehydrogenase also markedly decreased steatosis. Conclusions Acute ethanol causes reversible hepatic mitochondrial depolarization in vivo that may contribute to steatosis and increased mitochondrial respiration. Onset of this mitochondrial depolarization is linked, at least in part, to metabolism of ethanol to acetaldehyde. PMID:24618581

Estimates of Ethanol Exposure in Children from Food not Labeled as Alcohol-Containing

PubMed Central

Gorgus, Eva; Hittinger, Maike; Schrenk, Dieter

2016-01-01

Abstract Ethanol is widely used in herbal medicines, e.g., for children. Furthermore, alcohol is a constituent of fermented food such as bread or yogurt and “non-fermented” food such as fruit juices. At the same time, exposure to very low levels of ethanol in children is discussed as possibly having adverse effects on psychomotoric functions. Here, we have analyzed alcohol levels in different food products from the German market. It was found that orange, apple and grape juice contain substantial amounts of ethanol (up to 0.77 g/L). Furthermore, certain packed bakery products such as burger rolls or sweet milk rolls contained more than 1.2 g ethanol/100 g. We designed a scenario for average ethanol exposure by a 6-year-old child. Consumption data for the “categories” bananas, bread and bakery products and apple juice were derived from US and German surveys. An average daily exposure of 10.3 mg ethanol/kg body weight (b.w.) was estimated. If a high (acute) consumption level was assumed for one of the “categories,” exposure rose to 12.5–23.3 mg/kg b.w. This amount is almost 2-fold (average) or up to 4-fold (high) higher than the lowest exposure from herbal medicines (6 mg/kg b.w.) suggested to require warning hints for the use in children. PMID:27405361

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

PubMed Central

Karkhanis, Anushree N; Rose, Jamie H; Weiner, Jeffrey L; Jones, Sara R

2016-01-01

Chronic early-life stress increases vulnerability to alcoholism and anxiety disorders during adulthood. Similarly, rats reared in social isolation (SI) during adolescence exhibit augmented ethanol intake and anxiety-like behaviors compared with group housed (GH) rats. Prior studies suggest that disruption of dopamine (DA) signaling contributes to SI-associated behaviors, although the mechanisms underlying these alterations are not fully understood. Kappa opioid receptors (KORs) have an important role in regulating mesolimbic DA signaling, and other kinds of stressors have been shown to augment KOR function. Therefore, we tested the hypothesis that SI-induced increases in KOR function contribute to the dysregulation of NAc DA and the escalation in ethanol intake associated with SI. Our ex vivo voltammetry experiments showed that the inhibitory effects of the kappa agonist U50,488 on DA release were significantly enhanced in the NAc core and shell of SI rats. Dynorphin levels in NAc tissue were observed to be lower in SI rats. Microdialysis in freely moving rats revealed that SI was also associated with reduced baseline DA levels, and pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI) increased DA levels selectively in SI subjects. Acute ethanol elevated DA in SI and GH rats and nor-BNI pretreatment augmented this effect in SI subjects, while having no effect on ethanol-stimulated DA release in GH rats. Together, these data suggest that KORs may have increased responsiveness following SI, which could lead to hypodopaminergia and contribute to an increased drive to consume ethanol. Indeed, SI rats exhibited greater ethanol intake and preference and KOR blockade selectively attenuated ethanol intake in SI rats. Collectively, the findings that nor-BNI reversed SI-mediated hypodopaminergic state and escalated ethanol intake suggest that KOR antagonists may represent a promising therapeutic strategy for the treatment of alcohol use disorders, particularly in cases linked to chronic early-life stress. PMID:26860203

Evaluation of the Toxicokinetic Study of 1,2-Propanediol Dinitrate (PGDN) in the Dog.

DTIC Science & Technology

1982-05-01

Values as high as 50% contributed to a delayed drug effect of increased heart rate. Urine production, presumably changed due to blood pressure...Andersen and Mehl (1973) compared the effects of acute doses of PGDN and triethylene glycol dinitrate in rats, mice and guinea pigs. Although both...death when exposure ceases. Additional metabolic effects of PGDN and similar compounds were noted by Komura (1974). Here, ethanol preference and

Mice expressing a “hyper-sensitive” form of the CB1 cannabinoid receptor (CB1) show modestly enhanced alcohol preference and consumption

PubMed Central

Gonek, Maciej; Zee, Michael L.; Farnsworth, Jill C.; Amin, Randa A.; Andrews, Mary-Jeanette; Davis, Brian J.; Mackie, Ken; Morgan, Daniel J.

2017-01-01

We recently characterized S426A/S430A mutant mice expressing a desensitization-resistant form of the CB1 receptor. These mice display an enhanced response to endocannabinoids and ∆9-THC. In this study, S426A/S430A mutants were used as a novel model to test whether ethanol consumption, morphine dependence, and reward for these drugs are potentiated in mice with a “hyper-sensitive” form of CB1. Using an unlimited-access, two-bottle choice, voluntary drinking paradigm, S426A/S430A mutants exhibit modestly increased intake and preference for low (6%) but not higher concentrations of ethanol. S426A/S430A mutants and wild-type mice show similar taste preference for sucrose and quinine, exhibit normal sensitivity to the hypothermic and ataxic effects of ethanol, and have normal blood ethanol concentrations following administration of ethanol. S426A/S430A mutants develop robust conditioned place preference for ethanol (2 g/kg), morphine (10 mg/kg), and cocaine (10 mg/kg), demonstrating that drug reward is not changed in S426A/S430A mutants. Precipitated morphine withdrawal is also unchanged in opioid-dependent S426A/S430A mutant mice. Although ethanol consumption is modestly changed by enhanced CB1 signaling, reward, tolerance, and acute sensitivity to ethanol and morphine are normal in this model. PMID:28426670

Protective effects of alginate–chitosan microspheres loaded with alkaloids from Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. (Zuojin Pill) against ethanol-induced acute gastric mucosal injury in rats

PubMed Central

Wang, Qiang-Song; Zhu, Xiao-Ning; Jiang, Heng-Li; Wang, Gui-Fang; Cui, Yuan-Lu

2015-01-01

Zuojin Pill (ZJP), a traditional Chinese medicine formula, consists of Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in a ratio of 6:1 (w/w) and was first recorded in “Danxi’s experiential therapy” for treating gastrointestinal disorders in the 15th century. However, the poor solubility of alkaloids from ZJP restricted the protective effect in treating gastritis and gastric ulcer. The aim of the study was to investigate the protective mechanism of mucoadhesive microspheres loaded with alkaloids from C. chinensis Franch. and E. rutaecarpa (Juss.) Benth. on ethanol-induced acute gastric mucosal injury in rats. Surface morphology, particle size, drug loading, encapsulation efficiency, in vitro drug release, mucoadhesiveness, and fluorescent imaging of the microspheres in gastrointestinal tract were studied. The results showed that the mucoadhesive microspheres loaded with alkaloids could sustain the release of drugs beyond 12 hours and had gastric mucoadhesive property with 82.63% retention rate in vitro. The fluorescence tracer indicated high retention of mucoadhesive microspheres within 12 hours in vivo. The mucoadhesive microspheres loaded with alkaloids could reduce the gastric injury by decreasing the mucosal lesion index, increasing the percentage of inhibition and increasing the amount of mucus in the gastric mucosa in an ethanol-induced gastric mucosal injury rat model. Moreover, the mucoadhesive microspheres loaded with alkaloids reduce the inflammatory response by decreasing the levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), downregulating the mRNA expression of inducible nitric oxide synthase, TNF-α, and IL-1β in gastric mucosa. All the results indicate that mucoadhesive microspheres loaded with alkaloids could not only increase the residence time of alkaloids in rat stomach, but also exert gastroprotective effects through reducing the inflammatory response on ethanol-induced gastric mucosal damage. Thus, these microspheres could be developed as a potential controlled release drug for treatment of gastric ulcer. PMID:26640368

Sex Differences in the Effect of Finasteride on Acute Ethanol Withdrawal Severity in C57BL/6J and DBA/2J Mice

PubMed Central

Gorin-Meyer, Rebecca E.; Wiren, Kristine M.; Tanchuck, Michelle A.; Long, Season L.; Yoneyama, Naomi; Finn, Deborah A.

2007-01-01

The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA (GABAA) receptors that can modulate ethanol (EtOH) withdrawal. The 5α-reductase inhibitor finasteride can block the formation of ALLO and other GABAergic neurosteroids and also reduce certain effects of EtOH. Treatment with finasteride during chronic EtOH exposure decreased EtOH withdrawal severity and blood EtOH concentrations (BECs), suggesting an additional effect of finasteride on EtOH pharmacokinetics. Thus, the purpose of the present study was to determine the effect of finasteride on acute EtOH withdrawal severity, to minimize the effect of finasteride on EtOH metabolism. Male and female C57BL/6J and DBA/2J mice received a pretreatment of finasteride (50 mg/kg i.p.) or vehicle 24 hours prior to an injection of EtOH (4 g/kg i.p.) or saline. Handling-induced convulsions (HICs) were scored at baseline, and then over a 24 hr period after EtOH or saline injection. In another experiment, plasma estradiol and corticosterone levels were assessed at selected time points (0, 2, 8, and 24 hrs). In a final study, retro-orbital blood samples were collected at 30, 60, 120, and 240 minutes post-EtOH administration to access finasteride’s effects on EtOH clearance parameters. Pretreatment with finasteride increased acute EtOH withdrawal severity in female C57BL/6J and DBA/2J mice but decreased withdrawal severity in male mice of both strains. Finasteride did not alter BECs, EtOH clearance, estradiol, or corticosterone concentrations in a manner that appeared to contribute to the sex difference in finasteride’s effect on acute EtOH withdrawal severity. These findings suggest that male and female C57BL/6J and DBA/2J mice differ in their sensitivity to changes in ALLO or other GABAergic neurosteroid levels during acute EtOH withdrawal. Sex differences in the modulation of GABAergic 5α-reduced steroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics. PMID:17428611

Patients presenting with acute poisoning to an outpatient emergency clinic: a one-year observational study in Oslo, Norway.

PubMed

Vallersnes, Odd Martin; Jacobsen, Dag; Ekeberg, Øivind; Brekke, Mette

2015-08-13

In Oslo, the majority of patients with acute poisoning are treated in primary care, at an emergency outpatient clinic with limited diagnostic and treatment resources. We describe the poisonings currently seen in this setting. We compare our findings with previous studies, with special concern for the appearance of new toxic agents, and changes in overall numbers and patterns of poisoning. Observational study. Patients above the age of 12 years presenting at Oslo Accident and Emergency Outpatient Clinic (Oslo Legevakt) with acute poisoning were included consecutively from October 2011 through September 2012. Physicians and nurses registered data on preset forms. Main outcome measures were toxic agents, age, sex, intention, referral and time of presentation. There were 2923 episodes of acute poisoning in 2261 patients. Median age of the patients was 32 years, and 1430 (63%) were males. The most frequent toxic agents were ethanol in 1684 (58%) episodes, heroin in 542 (19 %), benzodiazepines in 521 (18%), amphetamine in 275 (9%), fire smoke in 192 (7%), gamma-hydroxybutyrate (GHB) in 144 (5%), and cannabis in 143 (5%). In 904 (31%) poisonings there were more than one toxic agent. In 493 episodes (17%), the patient was hospitalised, and in 60 episodes (2%) admitted to a psychiatric ward. Most poisonings, 2328 (80%), were accidental overdoses with substances of abuse, 276 (9%) were suicide attempts, and 312 (11%) were accidents. Among ethanol poisonings in patients above the age of 26 years, 685/934 (73%) were in males, and 339/934 (36%) presented during weekends. However, among ethanol poisonings in patients under the age of 26 years, 221/451 (49 ) were in females, and 297/451 (66%) presented during weekends. The poisonings treated in this primary care setting were mostly due to accidental overdoses with ethanol or other substances of abuse. There is a disconcerting weekend drinking pattern among adolescents and young adults, with young females presenting as often as young males with ethanol poisoning.

Transurethral ethanol injection therapy of benign prostatic hyperplasia: four-year follow-up.

PubMed

Sakr, Mostafa; Eid, Ahmed; Shoukry, Mohammed; Fayed, Abdelaziz

2009-02-01

Evaluating long-term (50 months) efficacy of transurethral intraprostatic injection of absolute ethanol to treat benign prostatic hyperplasia (BPH). A prospective study was conducted to evaluate 35 patients with BPH treated by transurethral injection of dehydrated ethanol. Mean age was 66.3 years. Endoscopic injection of 6-12 mL ethanol was carried out at 5-10 sites in the prostate. International Prostate Symptom Score (IPSS), maximum flow rate, prostate volume, postvoid residual and side effects or complications incidence were logged. Mean IPSS +/- standard deviation improved significantly from 22.0 +/- 3.89 preoperatively to 9.85 +/- 2.23 at 50 months follow-up. Mean peak urinary flow rate increased from 5.87 +/- 3.69 mL/s to 16.89 +/- 4.12 after 4 years. Mean residual urine volume had decreased from 68.6 +/- 49.98 mL to 36.02 +/- 20.87 after 4 years (P < 0.05). The prostate volume decreased from 52.67 +/- 20.43 g preoperatively to 49.94 +/- 21.28 g after 4 years (statistically significant). There were no intra-operative complications but post-operative urine retention occurred in all patients requiring catheterization for a mean 6.7 days. Acute epididymitis and chronic prostatitis occurred in two patients. Urethral stricture occurred in one patient. This technique appears to be safe and cost effective. No occurrence of retrograde ejaculation was detected. The long-term effects of ethanol injection of the prostate were satisfactory and acceptable as a minimally invasive therapeutic modality of selected patients.

Importance of NO/cGMP signalling via cGMP-dependent protein kinase II for controlling emotionality and neurobehavioural effects of alcohol.

PubMed

Werner, Claudia; Raivich, Gennadij; Cowen, Michael; Strekalova, Tatyana; Sillaber, Inge; Buters, Jeroen T; Spanagel, Rainer; Hofmann, Franz

2004-12-01

Cyclic GMP is a second messenger for nitric oxide (NO) that acts as a mediator for many different physiological functions. The cGMP-dependent protein kinases (cGKs) mediate cellular signalling induced by NO and cGMP. Here, we explored the localization of cGMP-dependent protein kinase type II (cGKII) in the mouse brain. In situ hybridization revealed high levels of cGKII mRNA in cerebral cortex, thalamic nuclei, hypothalamic nuclei, and in several basal forebrain regions including medial septum, striatum and amygdala. The close link to NO and the distribution pattern of cGKII suggested that this enzyme might be involved in emotional reactions and responses to drugs of abuse. Therefore, cGKII knockout animals (cGKII-/-) were compared with littermate controls in behavioural tests (i) for emotion-linked and (ii) for acute and chronic ethanol responses. Deletion of cGKII did not influence aggressive behaviour but led to enhanced anxiety-like behaviour. In terms of acute responses to ethanol, cGKII-/- mice were hyposensitive to hypnotic doses of ethanol as measured by the loss of righting reflex, without an alteration in their blood alcohol elimination. In a two-bottle free choice test, cGKII-/- mice showed elevated alcohol consumption. No taste differences to sweet solutions were observed compared to control animals. In summary, our data show that cGKII activity modulates anxiety-like behaviour and neurobehavioural effects of alcohol.

Gastroprotection studies of Schiff base zinc (II) derivative complex against acute superficial hemorrhagic mucosal lesions in rats.

PubMed

Golbabapour, Shahram; Gwaram, Nura Suleiman; Hassandarvish, Pouya; Hajrezaie, Maryam; Kamalidehghan, Behnam; Abdulla, Mahmood Ameen; Ali, Hapipah Mohd; Hadi, A Hamid A; Majid, Nazia Abdul

2013-01-01

The study was carried out to assess the gastroprotective effect of the zinc (II) complex against ethanol-induced acute hemorrhagic lesions in rats. The animals received their respective pre-treatments dissolved in tween 20 (5% v/v), orally. Ethanol (95% v/v) was orally administrated to induce superficial hemorrhagic mucosal lesions. Omeprazole (5.790×10(-5) M/kg) was used as a reference medicine. The pre-treatment with the zinc (II) complex (2.181×10(-5) and 4.362×10(-5) M/kg) protected the gastric mucosa similar to the reference control. They significantly increased the activity levels of nitric oxide, catalase, superoxide dismutase, glutathione and prostaglandin E2, and decreased the level of malondialdehyde. The histology assessments confirmed the protection through remarkable reduction of mucosal lesions and increased the production of gastric mucosa. Immunohistochemistry and western blot analysis indicated that the complex might induced Hsp70 up-regulation and Bax down-regulation. The complex moderately increased the gastroprotectiveness in fine fettle. The acute toxicity approved the non-toxic characteristic of the complex (<87.241×10(-5) M/kg). The gastroprotective effect of the zinc (II) complex was mainly through its antioxidant activity, enzymatic stimulation of prostaglandins E2, and up-regulation of Hsp70. The gastric wall mucus was also a remarkable protective mechanism.

Diminished neutrophil extracellular trap (NET) formation is a novel innate immune deficiency induced by acute ethanol exposure in polymicrobial sepsis, which can be rescued by CXCL1

PubMed Central

Jin, Liliang; Batra, Sanjay

2017-01-01

Polymicrobial sepsis is the result of an exaggerated host immune response to bacterial pathogens. Animal models and human studies demonstrate that alcohol intoxication is a key risk factor for sepsis-induced mortality. Multiple chemokines, such as CXCL1, CXCL2 and CXCL5 are critical for neutrophil recruitment and proper function of neutrophils. However, it is not quite clear the mechanisms by which acute alcohol suppresses immune responses and whether alcohol-induced immunosuppression can be rescued by chemokines. Thus, we assessed whether acute ethanol challenge via gavage diminishes antibacterial host defense in a sepsis model using cecal ligation and puncture (CLP) and whether this immunosuppression can be rescued by exogenous CXCL1. We found acute alcohol intoxication augments mortality and enhances bacterial growth in mice following CLP. Ethanol exposure impairs critical antibacterial functions of mouse and human neutrophils including reactive oxygen species production, neutrophil extracellular trap (NET) formation, and NET-mediated killing in response to both Gram-negative (E. coli) and Gram-positive (Staphylococcus aureus) pathogens. As compared with WT (C57Bl/6) mice, CXCL1 knockout mice display early mortality following acute alcohol exposure followed by CLP. Recombinant CXCL1 (rCXCL1) in acute alcohol challenged CLP mice increases survival, enhances bacterial clearance, improves neutrophil recruitment, and enhances NET formation (NETosis). Recombinant CXCL1 (rCXCL1) administration also augments bacterial killing by alcohol-treated and E. coli- and S. aureus-infected neutrophils. Taken together, our data unveils novel mechanisms underlying acute alcohol-induced dysregulation of the immune responses in polymicrobial sepsis, and CXCL1 is a critical mediator to rescue alcohol-induced immune dysregulation in polymicrobial sepsis. PMID:28922428

A Drosophila model for developmental nicotine exposure

PubMed Central

2017-01-01

Despite the known health risks of tobacco smoking, many people including pregnant women continue smoking. The effects of developmental nicotine exposure are known, but the underlying mechanisms are not well understood. Drosophila melanogaster is a model organism that can be used for uncovering genetic and molecular mechanisms for drugs of abuse. Here I show that Drosophila can be a model to elucidate the mechanisms for nicotine’s effects on a developing organism. Drosophila reared on nicotine food display developmental and behavioral effects similar to those in mammals including decreased survival and weight, increased developmental time, and decreased sensitivity to acute nicotine and ethanol. The Drosophila nicotinic acetylcholine receptor subunit alpha 7 (Dα7) mediates some of these effects. A novel role for Dα7 on ethanol sedation in Drosophila is also shown. Future research taking advantage of the genetic and molecular tools for Drosophila will allow additional discovery of the mechanisms behind the effects of nicotine during development. PMID:28498868

Acute Ethanol Intake Induces NAD(P)H Oxidase Activation and Rhoa Translocation in Resistance Arteries.

PubMed

Simplicio, Janaina A; Hipólito, Ulisses Vilela; Vale, Gabriel Tavares do; Callera, Glaucia Elena; Pereira, Camila André; Touyz, Rhian M; Tostes, Rita de Cássia; Tirapelli, Carlos R

2016-11-01

The mechanism underlying the vascular dysfunction induced by ethanol is not totally understood. Identification of biochemical/molecular mechanisms that could explain such effects is warranted. To investigate whether acute ethanol intake activates the vascular RhoA/Rho kinase pathway in resistance arteries and the role of NAD(P)H oxidase-derived reactive oxygen species (ROS) on such response. We also evaluated the requirement of p47phox translocation for ethanol-induced NAD(P)H oxidase activation. Male Wistar rats were orally treated with ethanol (1g/kg, p.o. gavage) or water (control). Some rats were treated with vitamin C (250 mg/kg, p.o. gavage, 5 days) before administration of water or ethanol. The mesenteric arterial bed (MAB) was collected 30 min after ethanol administration. Vitamin C prevented ethanol-induced increase in superoxide anion (O2-) generation and lipoperoxidation in the MAB. Catalase and superoxide dismutase activities and the reduced glutathione, nitrate and hydrogen peroxide (H2O2) levels were not affected by ethanol. Vitamin C and 4-methylpyrazole prevented the increase on O2- generation induced by ethanol in cultured MAB vascular smooth muscle cells. Ethanol had no effect on phosphorylation levels of protein kinase B (Akt) and eNOS (Ser1177 or Thr495 residues) or MAB vascular reactivity. Vitamin C prevented ethanol-induced increase in the membrane: cytosol fraction ratio of p47phox and RhoA expression in the rat MAB. Acute ethanol intake induces activation of the RhoA/Rho kinase pathway by a mechanism that involves ROS generation. In resistance arteries, ethanol activates NAD(P)H oxidase by inducing p47phox translocation by a redox-sensitive mechanism. O mecanismo da disfunção vascular induzido pelo consumo de etanol não é totalmente compreendido. Justifica-se, assim a identificação de mecanismos bioquímicos e moleculares que poderiam explicar tais efeitos. Investigar se a ingestão aguda de etanol ativa a via vascular RhoA/Rho quinase em artérias de resistência e o papel das espécies reativas de oxigênio (ERO) derivadas da NAD(P)H oxidase nessa resposta. Nós também avaliamos se ocorreu translocação da p47phox e ativação da NAD(P)H oxidase após o consumo agudo de etanol. Ratos Wistar machos foram tratados com etanol via oral (1g/kg, p.o. gavagem) ou água (controle). Alguns ratos foram tratados com vitamina C (250 mg/kg, p.o. gavagem, 5 dias) antes de água ou etanol. O leito arterial mesentérico (LAM) foi coleado 30 min após a administração de etanol. A vitamina C preveniu o aumento da geração de ânion superóxido (O2 -) e lipoperoxidação no LAM induzidos pelo etanol. A atividade da catalase (CAT), da superóxido dismutase (SOD) e os níveis de glutationa reduzida(GSH), nitrato e peróxido de hidrogênio (H2O2) não foram afetados após a ingestão aguda de etanol. A vitamina C e o 4-metilpirazol preveniram o aumento na geração de O2 - induzido pelo etanol em cultura de células do músculo liso vascular (CMLV). O etanol não afetou a fosforilação da proteína quinase B (Akt) e nem da óxido nítrico sintase endotelial (eNOS) (nos resíduos de Ser1177 ou Thr495) ou a reatividade vascular do LAM. A vitamina C preveniu o aumento da razão membrana:citosol da p47phox e a expressão da RhoA no LAM de rato induzido pelo etanol. A ingestão aguda de etanol induz a ativação da via RhoA/Rho quinase por um mecanismo que envolve a geração de ERO. Nas artérias de resistência, o etanol ativa NAD(P)H oxidase induzindo a translocação da p47phox por um mecanismo redox-sensível.

Further characterization of the GlyT-1 inhibitor Org25935: anti-alcohol, neurobehavioral, and gene expression effects.

PubMed

Lidö, Helga Höifödt; Jonsson, Susanne; Hyytiä, Petri; Ericson, Mia; Söderpalm, Bo

2017-05-01

The glycine transporter-1 inhibitor Org25935 is a promising candidate in a treatment concept for alcohol use disorder targeting the glycine system. Org25935 inhibits ethanol-induced dopamine elevation in brain reward regions and reduces ethanol intake in Wistar rats. This study aimed to further characterise the compound and used ethanol consumption, behavioral measures, and gene expression as parameters to investigate the effects in Wistar rats and, as pharmacogenetic comparison, Alko-Alcohol (AA) rats. Animals were provided limited access to ethanol in a two-bottle free-choice paradigm with daily drug administration. Acute effects of Org25935 were estimated using locomotor activity and neurobehavioral status. Effects on gene expression in Wistar rats were measured with qPCR. The higher but not the lower dose of Org25935 reduced alcohol intake in Wistar rats. Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies). Neurobehavioral effects by Org25935 differed between the strains (AA-rats towards sedation). Org25935 did not affect gene expression at the mRNA level in the glycine system of Wistar rats. The data indicate a small therapeutic range for the anti-alcohol properties of Org25935, a finding that may guide further evaluations of the clinical utility of GlyT-1 inhibitors. The results point to the importance of pharmacogenetic considerations when developing drugs for alcohol-related medical concerns. Despite the lack of successful clinical outcomes, to date, the heterogeneity of drug action of Org25935 and similar agents and the unmet medical need justify further studies of glycinergic compounds in alcohol use disorder.

Anti-ulcerogenic effect of cavidine against ethanol-induced acute gastric ulcer in mice and possible underlying mechanism.

PubMed

Li, Weifeng; Wang, Xiumei; Zhang, Hailin; He, Zehong; Zhi, Wenbing; Liu, Fang; Wang, Yu; Niu, Xiaofeng

2016-09-01

Cavidine, a major alkaloid compound isolated from Corydalis impatiens, has various pharmacological effects but its effect on gastric ulcer has not been previously explored. The current study aimed to investigate the possible anti-ulcerogenic potential of cavidine in the model of ethanol-induced gastric ulcer. Mice received cavidine (1, 5 or 10mg/kg, ig), cimetidine (CMD, 100mg/kg, ig) or vehicle at 12h and 1h before absolute ethanol administration (0.5mL/100g), and animals were euthanized 3h after ethanol ingestion. Gross and histological gastric lesions, biochemical, immunological and Western blot parameters were taken into consideration. The results showed that ethanol administration produced apparent mucosal injuries with morphological and histological damage, whereas cavidine pre-treatment reduced the gastric injuries. Cavidine pre-treatment also ameliorated the contents of malonaldehyde (MDA) and myeloperoxidase (MPO) activity, and increased the mucosa levels of glutathione (GSH), superoxide dismutase (SOD) and prostaglandin E2 (PGE2), relative to the model group. Also cavidine was able to decrease the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), inhibit the up-regulation of cyclo-oxygenase-2 (COX-2) expression and activation of Nuclear factor-kappa B (NF-κB) pathway. Taken together, these results indicated that cavidine exerts a gastroprotective effect against gastric ulceration, and the underlying mechanism might be associated with the stimulation of PGE2, reduction of oxidative stress, suppression of NF-κB expression and subsequent reduced COX-2 and pro-inflammatory cytokines. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of active constituents, acute toxicity, anti-nociceptive and anti-inflammatory activities of Porana sinensis Hemsl., Erycibe obtusifolia Benth. and Erycibe schmidtii Craib.

PubMed

Chen, Zhiyong; Liao, Liping; Zhang, Zijia; Wu, Lihong; Wang, Zhengtao

2013-11-25

Erycibe obtusifolia and Erycibe schmidtii, which belong to the same genus as Erycibe, are widely used in traditional medicine for the treatment of joint pain and rheumatoid arthritis (RA). Porana sinensis has become a widely used substitute for Erycibe obtusifolia and Erycibe schmidtii as they have declined in the wild. In the present work, the content of the main active components, the acute toxicity, the anti-nociceptive and anti-inflammatory activities of Porana sinensis, Erycibe obtusifolia and Erycibe schmidtii were compared, and the mechanisms of anti-nociceptive and anti-inflammatory activities were discussed. A quantitative HPLC (high performance liquid chromatography) method was first developed to compare the content of the main active components (scopoletin, scopolin and chlorogenic acid). The anti-inflammatory and anti-nociceptive activities of 40% ethanolic extracts of the three plants were compared using the models of xylene-induced ear edema, formalin-induced inflammation, carrageenan-induced air pouch inflammation, acetic acid-induced writhing and formalin-induced nociception. The acute toxicity of the 40% ethanolic extracts of the three plants was studied. The assay suggested a large content of scopoletin, scopolin and chlorogenic acid in the three plants. The 40% ethanolic extracts of the three plants were almost non-toxic at the dose of 5g/kg and all of them showed significant anti-inflammatory effects in the tests of xylene-induced ear edema and formalin-induced inflammation. In the carrageenan-induced air pouch inflammation test, the synthesis of PGE2 was significantly inhibited by all the extracts. They significantly inhibited the number of contortions induced by acetic acid and the second phase of the formalin-induced licking response. Naloxone was not able to reverse the analgesic effect of these extracts. The study identifies the similarity of the three plants in their main active components as well as acute toxicity, anti-nociceptive and anti-inflammatory activities. It supports the use of Porana sinensis as a suitable substitute, but further studies are needed to confirm this. © 2013 Elsevier Ireland Ltd. All rights reserved.

Caffeinated Alcoholic Beverages – An Emerging Trend in Alcohol Abuse

PubMed Central

Franklin, Kelle M; Hauser, Sheketha R; Bell, Richard L.; Engleman, Eric A

2014-01-01

Alcohol use disorders are pervasive in society and their impact affects quality of life, morbidity and mortality, as well as individual productivity. Alcohol has detrimental effects on an individual’s physiology and nervous system, and is associated with disorders of many organ and endocrine systems impacting an individual’s health, behavior, and ability to interact with others. Youth are particularly affected. Unfortunately, adolescent usage also increases the probability for a progression to dependence. Several areas of research indicate that the deleterious effects of alcohol abuse may be exacerbated by mixing caffeine with alcohol. Some behavioral evidence suggests that caffeine increases alcohol drinking and binge drinking episodes, which in turn can foster the development of alcohol dependence. As a relatively new public health concern, the epidemiological focus has been to establish a need for investigating the effects of caffeinated alcohol. While the trend of co-consuming these substances is growing, knowledge of the central mechanisms associated with caffeinated ethanol has been lacking. Research suggests that caffeine and ethanol can have additive or synergistic pharmacological actions and neuroadaptations, with the adenosine and dopamine systems in particular implicated. However, the limited literature on the central effects of caffeinated ethanol provides an impetus to increase our knowledge of the neuroadaptive effects of this combination and their impact on cognition and behavior. Research from our laboratories indicates that an established rodent animal model of alcoholism can be extended to investigate the acute and chronic effects of caffeinated ethanol. PMID:25419478

Acute Ethanol Exposure Prevents PMA-mediated Augmentation of N-methyl-d-aspartate Receptor Function in Primary Cultured Cerebellar Granule Cells

PubMed Central

Reneau, Jason; Reyland, Mary E.; Popp, R. Lisa

2011-01-01

Many intracellular proteins and signaling cascades contribute to the ethanol sensitivity of native N-methyl-d-aspartate receptors (NMDARs). One putative protein is the serine / threonine kinase, Protein kinase C (PKC). The purpose of this study was to assess if PKC modulates the ethanol sensitivity of native NMDARs expressed in primary cultured cerebellar granule cells (CGCs). With the whole-cell patch-clamp technique, we assessed if ethanol inhibition of NMDA-induced currents (INMDA) (100 μM NMDA plus 10 μM glycine) were altered in CGCs in which the novel and classical PKC isoforms were activated by phorbol-12-myristate-13-acetate (PMA). Percent inhibition by 10, 50 or 100 mM ethanol of NMDA-induced steady-state (ISS) or peak current amplitudes (IPk) of NMDARs expressed in CGCs in which PKC was activated by a 12.5 min, 100 nM PMA exposure at 37° C did not differ from currents obtained from receptors contained in control cells. However, PMA-mediated augmentation of IPk in the absence of ethanol was abolished after brief applications of 10 or 1 mM ethanol co-applied with agonists, and this suppression of enhanced receptor function was observed for up to eight minutes post-ethanol exposure. Because we had previously shown that PMA-mediated augmentation of INMDA of NMDARs expressed in these cells is by activation of PKCα, we assessed the effect of ethanol (1, 10, 50 and 100 mM) on PKCα activity. Ethanol decreased PKCα activity by 18% for 1 mM ethanol and activity decreased with increasing ethanol concentrations with a 50% inhibition observed with 100 mM ethanol. The data suggest that ethanol disruption of PMA-mediated augmentation of INMDA may be due to a decrease in PKCα activity by ethanol. However, given the incomplete blockade of PKCα activity and the low concentration of ethanol at which this phenomenon is observed, other ethanol-sensitive signaling cascades must also be involved. PMID:21624785

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

PubMed Central

Griffin III, William C; Haun, Harold L; Hazelbaker, Callan L; Ramachandra, Vorani S; Becker, Howard C

2014-01-01

Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free-choice, limited access (2 h/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions, whereas the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to ∼3.5 g/kg), whereas drinking remained relatively stable at baseline levels (2–2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLUEX) levels in the NAc were increased approximately twofold in EtOH mice compared with CTL mice, and this difference was observed 7 days after final CIE exposure, indicating that this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLUEX in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, threo-β-benzyloxyaspartate (TBOA), was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the metabotropic glutamate receptor-2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels, whereas having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence. PMID:24067300

Farnesoid X receptor regulates forkhead Box O3a activation in ethanol-induced autophagy and hepatotoxicity

PubMed Central

Manley, Sharon; Ni, Hong-Min; Williams, Jessica A.; Kong, Bo; DiTacchio, Luciano; Guo, Grace; Ding, Wen-Xing

2014-01-01

Alcoholic liver disease encompasses a wide spectrum of pathogenesis including steatosis, fibrosis, cirrhosis, and alcoholic steatohepatitis. Autophagy is a lysosomal degradation process that degrades cellular proteins and damaged/excess organelles, and serves as a protective mechanism in response to various stresses. Acute alcohol treatment induces autophagy via FoxO3a-mediated autophagy gene expression and protects against alcohol-induced steatosis and liver injury in mice. Farnesoid X Receptor (FXR) is a nuclear receptor that regulates cellular bile acid homeostasis. In the present study, wild type and FXR knockout (KO) mice were treated with acute ethanol for 16 h. We found that ethanol treated-FXR KO mice had exacerbated hepatotoxicity and steatosis compared to wild type mice. Furthermore, we found that ethanol treatment had decreased expression of various essential autophagy genes and several other FoxO3 target genes in FXR KO mice compared with wild type mice. Mechanistically, we did not find a direct interaction between FXR and FoxO3. Ethanol-treated FXR KO mice had increased Akt activation, increased phosphorylation of FoxO3 resulting in decreased FoxO3a nuclear retention and DNA binding. Furthermore, ethanol treatment induced hepatic mitochondrial spheroid formation in FXR KO mice but not in wild type mice, which may serve as a compensatory alternative pathway to remove ethanol-induced damaged mitochondria in FXR KO mice. These results suggest that lack of FXR impaired FoxO3a-mediated autophagy and in turn exacerbated alcohol-induced liver injury. PMID:25460735

Potential Effect of Bacopa monnieri on Nitrobenzene Induced Liver Damage in Rats

PubMed Central

Menon, B. Rajalakshmy; Rathi, M. A.; Thirumoorthi, L.

2010-01-01

The study was designed to evaluate the hepatoprotective activity of ethanolic extract of Bacopa monnieri in acute experimental liver injury induced by Nitrobenzene in rats. The extract at the dose of 200 mg/kg body weight was administered orally once every day for 10 days. The increased serum marker enzymes, Aspartate transaminase, Alanine transaminase and alkaline phosphatase were restored towards normalization significantly by the extract. Significant increase in SOD, CAT and GPx was observed in extract treated liver injured experimental rats. Histopathological examination of the liver tissues supported the hepatoprotection. It is concluded that the ethanolic extract of Bacopa monieri plant possess good hepatoprotective activity. PMID:21966114

Effects of selenium-enriched Agaricus blazei Murill on liver metabolic dysfunction in mice, a comparison with selenium-deficient Agaricus blazei Murill and sodium selenite.

PubMed

Yu, Lei; Yang, Shaolong; Sun, Lei; Jiang, Yan-Fang; Zhu, Li-Ying

2014-07-01

In the present study, we investigated the effects of Se-enriched Agaricus blazei Murill (Se-AbM) on liver injury in mice induced by acute alcohol administration. Mice received ethanol (5 g/kg body weight (BW)) by gavage every 12 h for a total of 3 doses. Se-AbM was administrated before ethanol administration. Subsequent serum alanine aminotransferase (ALT) level, aspartate aminotransaminase (AST) level, maleic dialdehyde (MDA) level, hepatic total antioxidant status (TAOS), nuclear factor kappa B (NF-κB) level, polymorphonuclear cells (PMN) level, interleukin-1β (IL-1β) level, inducible nitric oxide synthase (iNOS) level, tumor necrosis factor-α (TNF-α) level, intercellular adhesion molecule 1 (ICAM-1), and cyclooxygenase-2 (COX-2) were determined by ELISA and immunohistochemistry, respectively. Se-AbM administration markedly (p < 005) decreased serum ALT, AST, and MDA levels, hepatic IL-1β and TNF-α levels, as well as PMN infiltration and the expression of ICAM-1, COX-2, iNOS, and NF-κB compared with alcohol administration. In conclusion, we observed that Se-AbM supplementation could restrain the hepatic damage caused by acute alcohol exposure.

S-adenosylmethionine decreases the peak blood alcohol levels 3 h after an acute bolus of ethanol by inducing alcohol metabolizing enzymes in the liver.

PubMed

Bardag-Gorce, Fawzia; Oliva, Joan; Wong, Wesley; Fong, Stephanie; Li, Jun; French, Barbara A; French, Samuel W

2010-12-01

An alcohol bolus causes the blood alcohol level (BAL) to peak at 1-2 h post ingestion. The ethanol elimination rate is regulated by alcohol metabolizing enzymes, primarily alcohol dehydrogenase (ADH1), acetaldehyde dehydrogenase (ALDH), and cytochrome P450 (CYP2E1). Recently, S-adenosylmethionine (SAMe) was found to reduce acute BALs 3 h after an alcohol bolus. The question, then, was: what is the mechanism involved in this reduction of BAL by feeding SAMe? To answer this question, we investigated the changes in ethanol metabolizing enzymes and the epigenetic changes that regulate the expression of these enzymes during acute binge drinking and chronic drinking. Rats were fed a bolus of ethanol with or without SAMe, and were sacrificed at 3 h or 12 h after the bolus. RT-PCR and Western blot analyses showed that SAMe significantly induced ADH1 levels in the 3 h liver samples. However, SAMe did not affect the changes in ADH1 protein levels 12 h post bolus. Since SAMe is a methyl donor, it was postulated that the ADH1 gene expression up regulation at 3 h was due to a histone modification induced by methylation from methyl transferases. Dimethylated histone 3 lysine 4 (H3K4me2), a modification responsible for gene expression activation, was found to be significantly increased by SAMe at 3 h post bolus. These results correlated with the low BAL found at 3 h post bolus, and support the concept that SAMe increased the gene expression to increase the elimination rate of ethanol in binge drinking by increasing H3K4me2. Copyright © 2010 Elsevier Inc. All rights reserved.

Protective effects of Lactococcus chungangensis CAU 28 on alcohol-metabolizing enzyme activity in rats.

PubMed

Konkit, Maytiya; Kim, Kiyoung; Kim, Jong-Hwa; Kim, Wonyong

2018-04-19

In this study, we investigated the beneficial effects of Lactococcus chungangensis CAU 28, a bacterial strain of nondairy origin, on alcohol metabolism in rats treated with ethanol, focusing on alcohol elimination and prevention of damage and comparing the effects with those observed for Lactococcus lactis ssp. lactis ATCC 19435. Male Sprague-Dawley rats were orally administered 20% ethanol and 3 substrates (freeze-dried cells, cream cheese, and yogurt) containing Lc. chungangensis CAU 28 or Lc. lactis ssp. lactis ATCC 19435, which were provided 1 h before or 1 h after ethanol ingestion. Blood samples were collected from the tail veins of the rats at 1, 3, 6, 12, and 24 h after ingestion of ethanol, Lc. chungangensis CAU 28 substrate, or Lc. lactis ssp. lactis ATCC 19435 substrate. Alcohol and acetaldehyde concentrations in the Lc. chungangensis CAU 28 substrate-treated rats were significantly reduced in a time-dependent manner compared with those in the Lc. lactis ssp. lactis ATCC 19435 substrate-treated rats. Among the experimental groups, treatment with cream cheese before ingestion of 20% ethanol was found to be the most effective method for reducing both alcohol and acetaldehyde levels in the blood. Alanine aminotransferase and aspartate aminotransferase activities in the Lc. chungangensis CAU 28 substrate-treated rats were significantly lower than those in the positive controls. Moreover, in the Lc. chungangensis CAU 28 cream cheese-treated group, rats showed a reduction of liver enzymes by up to 60%, with good effectiveness observed for both pre- and post-ethanol ingestion. These results suggested that intake of lactic acid bacteria, particularly in Lc. chungangensis CAU 28-supplemented dairy products, may reduce blood alcohol and acetaldehyde concentrations, thereby mitigating acute alcohol-induced hepatotoxicity by altering alcohol-metabolizing enzyme activities. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Ethanol-induced disruption of Golgi apparatus morphology, primary neurite number and cellular orientation in developing cortical neurons

PubMed Central

Powrozek, Teresa A.; Olson, Eric C.

2012-01-01

Prenatal ethanol exposure disrupts cortical neurite initiation and outgrowth, but prior studies have reported both ethanol-dependent growth promotion and inhibition. To resolve this ambiguity and better approximate in vivo conditions, we quantitatively analyzed neuronal morphology using a new, whole hemisphere explant model. In this model, Layer 6 (L6) cortical neurons migrate, laminate and extend neurites in an organotypic fashion. To selectively label L6 neurons we performed ex utero electroporation of a GFP expression construct at embryonic day 13 and allowed the explants to develop for 2 days in vitro. Explants were exposed to (400mg/dL) ethanol for either 4 or 24 hrs prior to fixation. Complete 3-D reconstructions were made of >80 GFP-positive neurons in each experimental condition. Acute responses to ethanol exposure included compaction of the Golgi apparatus accompanied by elaboration of supernumerary primary apical neurites, as well as a modest (~15%) increase in higher order apical neurite length. With longer exposure time, ethanol exposure leads to a consistent, significant disorientation of the cell (cell body, primary apical neurite, and Golgi) with respect to the pial surface. The effects on cellular orientation were accompanied by decreased expression of cytoskeletal elements, microtubule associated protein 2 and F-actin. These findings indicate that upon exposure to ethanol, developing L6 neurons manifest disruptions in Golgi apparatus and cytoskeletal elements which may in turn trigger selective and significant perturbations to primary neurite formation and neuronal polarity. PMID:22840816

Estimates of Ethanol Exposure in Children from Food not Labeled as Alcohol-Containing.

PubMed

Gorgus, Eva; Hittinger, Maike; Schrenk, Dieter

2016-09-01

Ethanol is widely used in herbal medicines, e.g., for children. Furthermore, alcohol is a constituent of fermented food such as bread or yogurt and "non-fermented" food such as fruit juices. At the same time, exposure to very low levels of ethanol in children is discussed as possibly having adverse effects on psychomotoric functions. Here, we have analyzed alcohol levels in different food products from the German market. It was found that orange, apple and grape juice contain substantial amounts of ethanol (up to 0.77 g/L). Furthermore, certain packed bakery products such as burger rolls or sweet milk rolls contained more than 1.2 g ethanol/100 g. We designed a scenario for average ethanol exposure by a 6-year-old child. Consumption data for the "categories" bananas, bread and bakery products and apple juice were derived from US and German surveys. An average daily exposure of 10.3 mg ethanol/kg body weight (b.w.) was estimated. If a high (acute) consumption level was assumed for one of the "categories," exposure rose to 12.5-23.3 mg/kg b.w. This amount is almost 2-fold (average) or up to 4-fold (high) higher than the lowest exposure from herbal medicines (6 mg/kg b.w.) suggested to require warning hints for the use in children. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The utility of zebrafish to study the mechanisms by which ethanol affects social behavior and anxiety during early brain development.

PubMed

Parker, Matthew O; Annan, Leonette V; Kanellopoulos, Alexandros H; Brock, Alistair J; Combe, Fraser J; Baiamonte, Matteo; Teh, Muy-Teck; Brennan, Caroline H

2014-12-03

Exposure to moderate levels of ethanol during brain development has a number of effects on social behavior but the molecular mechanisms that mediate this are not well understood. Gaining a better understanding of these factors may help to develop therapeutic interventions in the future. Zebrafish offer a potentially useful model in this regard. Here, we introduce a zebrafish model of moderate prenatal ethanol exposure. Embryos were exposed to 20mM ethanol for seven days (48hpf-9dpf) and tested as adults for individual social behavior and shoaling. We also tested their basal anxiety with the novel tank diving test. We found that the ethanol-exposed fish displayed reductions in social approach and shoaling, and an increase in anxiety in the novel tank test. These behavioral differences corresponded to differences in hrt1aa, slc6a4 and oxtr expression. Namely, acute ethanol caused a spike in oxtr and ht1aa mRNA expression, which was followed by down-regulation at 7dpf, and an up-regulation in slc6a4 at 72hpf. This study confirms the utility of zebrafish as a model system for studying the molecular basis of developmental ethanol exposure. Furthermore, it proposes a putative developmental mechanism characterized by ethanol-induced OT inhibition leading to suppression of 5-HT and up-regulation of 5-HT1A, which leads, in turn, to possible homeostatic up-regulation of 5-HTT at 72hpf and subsequent imbalance of the 5-HT system. Copyright © 2014 Elsevier Inc. All rights reserved.

Dephosphorylation of GluN2B C-Terminal Tyrosine Residues Does Not Contribute to Acute Ethanol Inhibition of Recombinant NMDA Receptors

PubMed Central

Hughes, Benjamin A.; Smothers, Corigan T.; Woodward, John J.

2013-01-01

N-methyl-D-aspartate (NMDA) receptors are ion channels activated by the neurotransmitter glutamate and are highly expressed by neurons. These receptors are critical for excitatory synaptic signaling and inhibition of NMDA receptors leads to impaired cognition and learning. Ethanol inhibits NMDA currents at concentrations associated with intoxication and this action may underlie some of the behavioral effects of ethanol. Although numerous sites and mechanisms of action have been tested, the manner in which ethanol inhibits NMDA receptors remains unclear. Recent findings in the literature suggest that ethanol, via facilitation of tyrosine phosphatase activity, may dephosphorylate key tyrosine residues in the C-terminus of GluN2B subunits resulting in diminished channel function. To directly test this hypothesis, we engineered GluN2B mutants that contained phenylalanine in place of tyrosine at three different sites and transiently expressed them with the GluN1 subunit in human embryonic kidney (HEK) cells. Whole-cell patch clamp electrophysiology was used to record glutamate-activated currents in the absence and presence of ethanol (10–600 mM). All mutants were functional and did not differ from one another with respect to current amplitude, steady-state to peak ratio, or magnesium block. Analysis of ethanol dose-response curves showed no significant difference in IC50 values between wild-type receptors and Y1252F, Y1336F, Y1472F or triple Y-F mutants. These findings suggest that dephosphorylation of C-terminal tyrosine residues does not account for ethanol inhibition of GluN2B receptors. PMID:23357553

Binge drinking disturbs hepatic microcirculation after transplantation: prevention with free radical scavengers.

PubMed

Zhong, Z; Arteel, G E; Connor, H D; Schemmer, P; Chou, S C; Raleigh, J A; Mason, R P; Lemasters, J J; Thurman, R G

1999-08-01

Disturbances in hepatic microcirculation increase graft injury and failure; therefore, this study evaluates the effects of ethanol on microcirculation after liver transplantation. Donor rats were given one dose of ethanol (5 g/kg) by gavage 20 h before explantation, and grafts were stored in University of Wisconsin solution for 24 h before implantation. Acute ethanol treatment decreased 7-day survival of grafts from about 90 to 30%, increased transaminase release nearly 4-fold, and decreased bile production by 60%. Moreover, portal pressure increased significantly and liver surface oxygen tension decreased about 50%, indicating that ethanol disturbs hepatic microcirculation. Pimonidazole, a 2-nitroimidazole hypoxia marker, was given i.v. to recipients 30 min after implantation, and grafts were harvested 1 h later. Ethanol increased hepatic pimonidazole binding about 3-fold, indicating that ethanol led to hypoxia in fatty grafts. Ethanol also significantly increased free radicals in bile. Catechin (30 mg/kg i.v. upon reperfusion), a free radical scavenger, and Carolina Rinse solution, which contains several agents that inhibit free radical formation, minimized disturbances in microcirculation and prevented pimonidazole adduct formation significantly. These treatments also blunted increases in transaminase release and improved survival of fatty grafts. Destruction of Kupffer cells with GdCl(3) (20 mg/kg i.v. 24 h before explantation) or inhibition of formation of leukotrienes with MK-886 (50 microM in University of Wisconsin or rinse solution) also minimized hypoxia and improved survival after transplantation. Taken together, these results demonstrate that ethanol disturbs hepatic microcirculation, leading to graft hypoxia after transplantation, most likely by activating Kupffer cells and increasing free radical production.

Hepatoprotective effect of ethanol extract from Berchemia lineate against CCl4-induced acute hepatotoxicity in mice.

PubMed

Li, Cong; Yi, Li-Tao; Geng, Di; Han, Yuan-Yuan; Weng, Lian-Jin

2015-05-01

The roots of Berchemia lineate (L.) DC. (Rhamnaceae) have been long used as a remedy for the treatment of some diseases in Guangxi Province, China. The present study investigates the hepatoprotective effect of Berchemia lineate ethanol extract (BELE) on CCl4-induced acute liver damage in mice. Effect of BELE administrated for 7 consecutive days was evaluated in mice by the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), albulin (ALB), globulin (GLB), and total protein (TP) levels, as well as liver superoxide dismutase (SOD) activity and malondialdehyde (MDA) level. Moreover, histopathological examinations were also taken. Compared with the model group, administration of 400 mg/kg BELE for 7 d in mice significantly decreased the serum ALT (56.25 U/L), AST (297.67 U/L), ALP (188.20 U/L), and TBIL (17.90 mol/L), along with the elevation of TP (64.67 g/L). In addition, BELE (100, 200, and 400 mg/kg, i.g.) treated mice recorded a dose-dependent increment of SOD (291.17, 310.32, and 325.67 U/mg prot) and reduction of MDA (7.27, 6.77, and 5.33 nmol/mg prot) levels. Histopathological examinations also confirmed that BELE can ameliorate CCl4-induced liver injuries, characterized by extensive hepatocellular degeneration/necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation. The results indicated that BELE possessed remarkable protective effect against acute hepatotoxicity and oxidative injuries induced by CCl4, and that the hepatoprotective effects of BELE may be due to both the inhibition of lipid peroxidation and the increase of antioxidant activity.

Effect of acute and chronic moderate red or white wine consumption on fasted and postprandial lipemia in the rat.

PubMed

Daher, Costantine F; Slaiby, Rita; Haddad, Najib; Boustany, Karim; Baroody, George M

2006-06-01

The effects of acute and chronic (10 wk) red or white wine consumption on fasted and postprandial lipemia in the rat model are reported. Fasted rats, in the acute study, were loaded intragastrically with 5 ml of an olive oil emulsion (30% w/v) in the presence or absence of wine (8% v/v ethanol), and either mesenteric lymph or blood was collected 3 h postprandially. Animals in the chronic study received either red or white wine in drinking water for a period of 10 wk (3% v/v ethanol). Blood samples were collected from animals in either the fasted state or after fat-wine loading. Postprandially, wine delayed gastric emptying, reduced lymph triacylglycerol (TAG) secretion concomitantly with increased number and decreased chylomicron (CM) size, and increased plasma TAG and CM concentrations. Phospholipid and cholesterol contents of CM, but not very-low-density lipoprotein (VLDL), were increased, indicating enhanced liver bile secretion; however, a significant increase in plasma VLDL concentration was observed. In the chronic study, a wine-fat load resulted in increased high-density lipoprotein (HDL) cholesterol concentration and less pronounced postprandial hypertriglyceridemia and hyperchylomicronemia. In the fasted state, plasma TAG and total apolipoprotein B concentrations were not modified in these animals, and an increase in HDL and a decrease in low-density lipoprotein (LDL)/HDL cholesterol ratios were observed. No liver function or intestinal lipid absorption impairment was observed. In conclusion, unlike binge drinking, chronic moderate wine consumption appears to have a cardioprotective effect in the fasted state, an effect attenuated by the observed temporary postprandial hyperchylomicronemia and hypertriglyceridemia resulting from a direct effect of alcohol on CM size and number.

Acute Toxicity and Gastroprotective Role of M. pruriens in Ethanol-Induced Gastric Mucosal Injuries in Rats

PubMed Central

Hassandarvish, Pouya; Abdul Majid, Nazia; Hadi, A. Hamid A.; Nordin, Noraziah; Abdulla, Mahmood A.

2013-01-01

The investigation was to evaluate gastroprotective effects of ethanolic extract of M. pruriens leaves on ethanol-induced gastric mucosal injuries in rats. Forty-eight rats were divided into 8 groups: negative control, extract control, ulcer control, reference control, and four experimental groups. As a pretreatment, the negative control and the ulcer control groups were orally administered carboxymethylcellulose (CMC). The reference control was administered omeprazole orally (20 mg/kg). The ethanolic extract of M. pruriens leaves was given orally to the extract control group (500 mg/kg) and the experimental groups (62.5, 125, 250, and 500 mg/kg). After 1 h, CMC was given orally to the negative and the extract control groups. The other groups received absolute ethanol. The rats were sacrificed after 1 h. The ulcer control group exhibited significant mucosal injuries with decreased gastric wall mucus and severe damage to the gastric mucosa. The extract caused upregulation of Hsp70 protein, downregulation of Bax protein, and intense periodic acid schiff uptake of glandular portion of stomach. Gastric mucosal homogenate showed significant antioxidant properties with increase in synthesis of PGE2, while MDA was significantly decreased. The ethanolic extract of M. pruriens leaves was nontoxic (<5 g/kg) and could enhance defensive mechanisms against hemorrhagic mucosal lesions. PMID:23781513

Acute ethanol administration affects zebrafish preference for a biologically inspired robot.

PubMed

Spinello, Chiara; Macrì, Simone; Porfiri, Maurizio

2013-08-01

Preclinical animal models constitute a cornerstone against which the reward processes involved in drug addiction are often studied and dissected. While rodents have traditionally represented the species of choice, a growing body of literature indicates that zebrafish are emerging as a valuable model organism. Specifically, several studies demonstrate that the effects of ethanol at the level of emotional- and cognitive-related domains can be reliably investigated using zebrafish. The rapidly evolving nature of these efforts allows substantial room for the development of novel experimental paradigms suited to this freshwater species. The field of ethorobotics may prove particularly beneficial, due to its ability to convey fully controllable and easily reproducible experimental tools. In this study, we addressed the possibility of using a biologically inspired robot to investigate the emotionally related properties of ethanol in a preference task in zebrafish. To this aim, we evaluated wild-type zebrafish preference toward a robotic stimulus and addressed whether ethanol administration (0.25% and 1.00% ethanol/water concentration) may alter such preferences. In accordance with our previous studies, we observed that zebrafish exhibit a natural attraction toward the robot. Additionally, in agreement with our predictions, we showed that ethanol administration abolishes such preferences. This work is the first to demonstrate that robotic stimuli can be used in zebrafish to investigate the reward-related properties of alcohol. Copyright © 2013 Elsevier Inc. All rights reserved.

Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF-kB danger signaling in rat frontal cortex and depressive-like behavior induced by ethanol binge administration.

PubMed

Antón, María; Alén, Francisco; Gómez de Heras, Raquel; Serrano, Antonia; Pavón, Francisco Javier; Leza, Juan Carlos; García-Bueno, Borja; Rodríguez de Fonseca, Fernando; Orio, Laura

2017-05-01

Alcohol abuse is frequently characterized by a specific pattern of intake in binge drinking episodes, inducing neuroinflammation and brain damage. Here, we characterized the temporal profile of neuroinflammation in rats exposed to intragastric binge ethanol administrations (3 times/day × 4 days) and tested the anti-inflammatory/neuroprotective properties of the satiety factor oleoylethanolamide (OEA). Pre-treatment with OEA (5 mg/kg, i.p.) previous each alcohol gavage blocked the expression of high mobility group box 1 (HMGB1) danger signal and the innate immunity Toll-like receptors 4 (TLR4) in frontal cortex, and inhibited the nuclear factor-kappa B (NF-kB) proinflammatory cascade induced by alcohol binge administration. OEA reduced the levels of interleukin-1beta (IL-1β), the monocyte chemoattractant protein-1 (MCP-1), and the enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in ethanol binged animals. Elevations in plasma tumor necrosis factor alpha (TNF-α) and IL-1β after ethanol were also inhibited by OEA. OEA also prevented ethanol-induced lipid peroxidation, caspase-8 and pro-apoptotic caspase-3 activation in frontal cortex. Additionally, OEA blocked the rise in blood corticosterone levels after ethanol with no alteration in blood ethanol levels and may affect ethanol-induced gut permeability for endotoxin. Finally, OEA, administered as a pre-treatment during the ethanol binge, exerted antidepressant-like effects during acute withdrawal. Altogether, results highlight a beneficial profile of OEA as a potent anti-inflammatory, antioxidant, neuroprotective and antidepressant-like compound to treat alcohol abuse. © 2016 Society for the Study of Addiction.

Alterations of motor performance and brain cortex mitochondrial function during ethanol hangover.

PubMed

Bustamante, Juanita; Karadayian, Analia G; Lores-Arnaiz, Silvia; Cutrera, Rodolfo A

2012-08-01

Ethanol has been known to affect various behavioral parameters in experimental animals, even several hours after ethanol (EtOH) is absent from blood circulation, in the period known as hangover. The aim of this study was to assess the effects of acute ethanol hangover on motor performance in association with the brain cortex energetic metabolism. Evaluation of motor performance and brain cortex mitochondrial function during alcohol hangover was performed in mice 6 hours after a high ethanol dose (hangover onset). Animals were injected i.p. either with saline (control group) or with ethanol (3.8 g/kg BW) (hangover group). Ethanol hangover group showed a bad motor performance compared with control animals (p < .05). Oxygen uptake in brain cortex mitochondria from hangover animals showed a 34% decrease in the respiratory control rate as compared with the control group. Mitochondrial complex activities were decreased being the complex I-III the less affected by the hangover condition; complex II-III was markedly decreased by ethanol hangover showing 50% less activity than controls. Complex IV was 42% decreased as compared with control animals. Hydrogen peroxide production was 51% increased in brain cortex mitochondria from the hangover group, as compared with the control animals. Quantification of the mitochondrial transmembrane potential indicated that ethanol injected animals presented 17% less ability to maintain the polarized condition as compared with controls. These results indicate that a clear decrease in proton motive force occurs in brain cortex mitochondria during hangover conditions. We can conclude that a decreased motor performance observed in the hangover group of animals could be associated with brain cortex mitochondrial dysfunction and the resulting impairment of its energetic metabolism. Copyright © 2012 Elsevier Inc. All rights reserved.

Ethanol enhances carbachol-induced protease activation and accelerates Ca2+ waves in isolated rat pancreatic acini.

PubMed

Orabi, Abrahim I; Shah, Ahsan U; Muili, Kamaldeen; Luo, Yuhuan; Mahmood, Syeda Maham; Ahmad, Asim; Reed, Anamika; Husain, Sohail Z

2011-04-22

Alcohol abuse is a leading cause of pancreatitis, accounting for 30% of acute cases and 70-90% of chronic cases, yet the mechanisms leading to alcohol-associated pancreatic injury are unclear. An early and critical feature of pancreatitis is the aberrant signaling of Ca(2+) within the pancreatic acinar cell. An important conductor of this Ca(2+) is the basolaterally localized, intracellular Ca(2+) channel ryanodine receptor (RYR). In this study, we examined the effect of ethanol on mediating both pathologic intra-acinar protease activation, a precursor to pancreatitis, as well as RYR Ca(2+) signals. We hypothesized that ethanol sensitizes the acinar cell to protease activation by modulating RYR Ca(2+). Acinar cells were freshly isolated from rat, pretreated with ethanol, and stimulated with the muscarinic agonist carbachol (1 μM). Ethanol caused a doubling in the carbachol-induced activation of the proteases trypsin and chymotrypsin (p < 0.02). The RYR inhibitor dantrolene abrogated the enhancement of trypsin and chymotrypsin activity by ethanol (p < 0.005 for both proteases). Further, ethanol accelerated the speed of the apical to basolateral Ca(2+) wave from 9 to 18 μm/s (p < 0.0005; n = 18-22 cells/group); an increase in Ca(2+) wave speed was also observed with a change from physiologic concentrations of carbachol (1 μM) to a supraphysiologic concentration (1 mM) that leads to protease activation. Dantrolene abrogated the ethanol-induced acceleration of wave speed (p < 0.05; n = 10-16 cells/group). Our results suggest that the enhancement of pathologic protease activation by ethanol is dependent on the RYR and that a novel mechanism for this enhancement may involve RYR-mediated acceleration of Ca(2+) waves.

Ethanol Enhances Carbachol-induced Protease Activation and Accelerates Ca2+ Waves in Isolated Rat Pancreatic Acini*

PubMed Central

Orabi, Abrahim I.; Shah, Ahsan U.; Muili, Kamaldeen; Luo, Yuhuan; Mahmood, Syeda Maham; Ahmad, Asim; Reed, Anamika; Husain, Sohail Z.

2011-01-01

Alcohol abuse is a leading cause of pancreatitis, accounting for 30% of acute cases and 70–90% of chronic cases, yet the mechanisms leading to alcohol-associated pancreatic injury are unclear. An early and critical feature of pancreatitis is the aberrant signaling of Ca2+ within the pancreatic acinar cell. An important conductor of this Ca2+ is the basolaterally localized, intracellular Ca2+ channel ryanodine receptor (RYR). In this study, we examined the effect of ethanol on mediating both pathologic intra-acinar protease activation, a precursor to pancreatitis, as well as RYR Ca2+ signals. We hypothesized that ethanol sensitizes the acinar cell to protease activation by modulating RYR Ca2+. Acinar cells were freshly isolated from rat, pretreated with ethanol, and stimulated with the muscarinic agonist carbachol (1 μm). Ethanol caused a doubling in the carbachol-induced activation of the proteases trypsin and chymotrypsin (p < 0.02). The RYR inhibitor dantrolene abrogated the enhancement of trypsin and chymotrypsin activity by ethanol (p < 0.005 for both proteases). Further, ethanol accelerated the speed of the apical to basolateral Ca2+ wave from 9 to 18 μm/s (p < 0.0005; n = 18–22 cells/group); an increase in Ca2+ wave speed was also observed with a change from physiologic concentrations of carbachol (1 μm) to a supraphysiologic concentration (1 mm) that leads to protease activation. Dantrolene abrogated the ethanol-induced acceleration of wave speed (p < 0.05; n = 10–16 cells/group). Our results suggest that the enhancement of pathologic protease activation by ethanol is dependent on the RYR and that a novel mechanism for this enhancement may involve RYR-mediated acceleration of Ca2+ waves. PMID:21372126

[Evaluation of selected socioeconomic factors in patients with acute ethanol intoxication and alcohol withdrawal syndrome].

PubMed

Lukasik-Głębocka, Magdalena; Sommerfeld, Karina

2014-01-01

Ethanol is commonly overused psychoactive substance in Poland and all around the world. It causes addiction, which occurs as a result of its chronic administration. One of the main symptoms of addiction is hunger due to psychoactive substance that prevents interruption of its adoption and contributes to relapse drinking. Acute poisoning with ethyl alcohol and alcohol withdrawal syndrome are diseases causing a potential danger to life. The prevalence of use and abuse of alcoholic beverages is a potential risk, causing health problems, including permanent damage of the central and peripheral nervous system and socio-economic problems. The aim of this study is to analyze certain aspects of the socio-economic situation of the patients hospitalized in the Department of Toxicology in Raszeja City Hospital in Poznan due to acute ethanol intoxication or alcohol withdrawal syndrome in 2010. 299 patients history was evaluated, among which 161 were treated for acute intoxication with ethanol and 138 due to alcohol withdrawal syndrome. Objects of interest were elements of subjective tests including: marital status of patients, their education and professional activity and the problem of homelessness. The study group consisted of 299 patients in age from 16 to 77 years, hospitalized in the Department of Toxicology in Raszeja City Hospital in Poznan due to acute ethanol intoxication or alcohol withdrawal syndrome. It was found that the largest group consisted of patients remaining married (42.81%) and unmarried (30.43%). Alcohol abuse affects people of all levels of education. In the present study, most patients had a vocational education (37.79%) and medium (23.08%). Patients were analyzed in terms of economic activity, among which about 40% were unemployed. In the whole group more than 10% of those were homeless. Ethyl alcohol intoxication and alcohol withdrawal represents a significant hazard. As a result of reliance, patients lose control of alcohol consumption and they cannot reduce the amount and the time of its adoption. Reducing the dose of alcohol can lead to unpleasant withdrawal symptoms that the patient eliminate by adopting another dose. Typical is to continue the alcohol consumption despite knowledge of its harmful health and difficulties such as professional (problems at work or loss), financial (lack of livelihood, poverty) and interpersonal (loss of friends, marriage breakdown, loss of relationships with relatives).

THERAPEUTIC POTENTIALS OF ETHANOLIC EXTRACT OF LEAVES OF HOLARRHENA FLORIBUNDA (G. DON) DUR. AND SCHINZ (APOCYNACEAE).

PubMed

Hoekou, Yao Patrick; Tchacondo, Tchadjobo; Karou, Simplice Damintoti; Yerbanga, Rakiswende Serge; Achoribo, Elom; Da, Ollo; Atakpama, Wouyo; Batawila, Komlan

2017-01-01

Holarrhena floribunda is a plant of wide usage in the Togolese folk medicine. A previous ethnobotanical survey on the latex plants of the Maritime region of the country revealed that this plant was included in several recipes curing malaria and microbial infections. Therefore, this study aimed to seek for the effectiveness of the ethanolic extract of the plant in the treatment of these diseases. The antimicrobial test was performed using the agar well-diffusion and the NCCLS broth microdilution methods, while the in vivo antimalarial activity was evaluated following the four-day suppressive test of Peters. The acute toxic effects of the extract were monitored after a single oral dose (5,000 mg/kg body weight) administration in NMRI mice. The results indicated that the ethanolic extract of leaves of H. floribunda was active on Staphylococcus aureus ATCC 29213 and clinical strains of Staphylococcus aureus, Salmonella typhi and Klebsiella pneumoniae with MICs ranging from 0.62 to 1.25 mg/mL. The extract also showed significant parasitaemia suppression in a dose-dependent manner. In the acute toxicity assay, the oral administration of the extract to the mice did not affect the relative weight of vital organs, and there were no signs of toxicity or death during the study period. The LD50 of the tested extract was found to be greater than 5,000 mg/kg, indicating its safety. This study demonstrates the antibacterial and antimalarial activities of leaves of H. floribunda and then, supports its medicinal use in the treatment of microbial infections.

THERAPEUTIC POTENTIALS OF ETHANOLIC EXTRACT OF LEAVES OF HOLARRHENA FLORIBUNDA (G. DON) DUR. AND SCHINZ (APOCYNACEAE)

PubMed Central

Hoekou, Yao Patrick; Tchacondo, Tchadjobo; Karou, Simplice Damintoti; Yerbanga, Rakiswende Serge; Achoribo, Elom; Da, Ollo; Atakpama, Wouyo; Batawila, Komlan

2017-01-01

Background: Holarrhena floribunda is a plant of wide usage in the Togolese folk medicine. A previous ethnobotanical survey on the latex plants of the Maritime region of the country revealed that this plant was included in several recipes curing malaria and microbial infections. Therefore, this study aimed to seek for the effectiveness of the ethanolic extract of the plant in the treatment of these diseases. Methods: The antimicrobial test was performed using the agar well-diffusion and the NCCLS broth microdilution methods, while the in vivo antimalarial activity was evaluated following the four-day suppressive test of Peters. The acute toxic effects of the extract were monitored after a single oral dose (5,000 mg/kg body weight) administration in NMRI mice. Results: The results indicated that the ethanolic extract of leaves of H. floribunda was active on Staphylococcus aureus ATCC 29213 and clinical strains of Staphylococcus aureus, Salmonella typhi and Klebsiella pneumoniae with MICs ranging from 0.62 to 1.25 mg/mL. The extract also showed significant parasitaemia suppression in a dose-dependent manner. In the acute toxicity assay, the oral administration of the extract to the mice did not affect the relative weight of vital organs, and there were no signs of toxicity or death during the study period. The LD50 of the tested extract was found to be greater than 5,000 mg/kg, indicating its safety. Conclusion: This study demonstrates the antibacterial and antimalarial activities of leaves of H. floribunda and then, supports its medicinal use in the treatment of microbial infections. PMID:28573239

Campomanesia lineatifolia Ruiz & Pav. as a gastroprotective agent.

PubMed

Madalosso, R C; Oliveira, G C; Martins, M T; Vieira, A E D; Barbosa, J; Caliari, M V; Castilho, R O; Tagliati, C A

2012-02-15

Campomanesia lineatifolia Ruiz and Pav. (Myrtaceae) is a native edible species found in the Amazon Rainforest, commonly known as gabiroba. In Brazil, Campomanesia species are frequently used in traditional medicine for gastrointestinal disorders. The present study performed phytochemical analyses and determined both the in vitro antioxidant activity of the ethanolic extract of Campomanesia lineatifolia leaves (EEC) as well as its ethyl acetate fraction (EAFC). In this analysis, quercetin was used as a positive control. Gastroprotective activity was also investigated at different oral doses in two experimental models in rats - gastric lesion induced by ethanol and gastric lesion induced by indomethacin. In this analysis, cimetidine and sucralfate were used as positive controls. The area of gastric lesion underwent macroscopic and histomorphometric evaluations, while the mucus content was estimated by applying the periodic acid-Schiff stain. Oral acute toxicity was also assessed. Phytochemical studies revealed the presence of flavonoids and tannins. Catechin and quercitrin were isolated by bioguided chromatographic fractionation of EAFC. EEC and EAFC presented in vitro antioxidant activity. The oral administration of EEC and EAFC at doses 100-400 mg/kg (ethanol model) and at doses of 400-1200 mg/kg (indomethacin model) proved to be effective in preventing gastric ulcerations in rats. Pretreatment with EAFC (400mg/kg) significantly increased the gastric mucus content in the ethanol model. No animals died during the acute oral toxicology test. Results confirm the Brazilian ethnopharmacological use of Campomanesia lineatifolia as a gastroprotective agent and indicate that the anti-ulcer effect is most likely mediated by scavenging free radicals due to the polyphenol content and, at least in part, by increasing the mucus secretion and the mucosal defense. In addition, EEC and EAFC were found to be safe when applied to a 2000 mg/kg single oral dose. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Gastroprotection Studies of Schiff Base Zinc (II) Derivative Complex against Acute Superficial Hemorrhagic Mucosal Lesions in Rats

PubMed Central

Golbabapour, Shahram; Gwaram, Nura Suleiman; Hassandarvish, Pouya; Hajrezaie, Maryam; Kamalidehghan, Behnam; Abdulla, Mahmood Ameen; Ali, Hapipah Mohd; Hadi, A. Hamid A; Majid, Nazia Abdul

2013-01-01

Background The study was carried out to assess the gastroprotective effect of the zinc (II) complex against ethanol-induced acute hemorrhagic lesions in rats. Methodology/Principal Finding The animals received their respective pre-treatments dissolved in tween 20 (5% v/v), orally. Ethanol (95% v/v) was orally administrated to induce superficial hemorrhagic mucosal lesions. Omeprazole (5.790×10−5 M/kg) was used as a reference medicine. The pre-treatment with the zinc (II) complex (2.181×10−5 and 4.362×10−5 M/kg) protected the gastric mucosa similar to the reference control. They significantly increased the activity levels of nitric oxide, catalase, superoxide dismutase, glutathione and prostaglandin E2, and decreased the level of malondialdehyde. The histology assessments confirmed the protection through remarkable reduction of mucosal lesions and increased the production of gastric mucosa. Immunohistochemistry and western blot analysis indicated that the complex might induced Hsp70 up-regulation and Bax down-regulation. The complex moderately increased the gastroprotectiveness in fine fettle. The acute toxicity approved the non-toxic characteristic of the complex (<87.241×10−5 M/kg). Conclusion/Significance The gastroprotective effect of the zinc (II) complex was mainly through its antioxidant activity, enzymatic stimulation of prostaglandins E2, and up-regulation of Hsp70. The gastric wall mucus was also a remarkable protective mechanism. PMID:24058648

Respiratory depression in the intoxicated trauma patient: are opioids to blame?

PubMed

Shenk, Eleni; Barton, Cassie A; Mah, Nathan D; Ran, Ran; Hendrickson, Robert G; Watters, Jennifer

2016-02-01

Providing effective pain management to acutely intoxicated trauma patients represents a challenge of balancing appropriate pain management with the risk of potential respiratory depression from opioid administration. The objective of this study was to quantify the incidence of respiratory depression in trauma patients acutely intoxicated with ethanol who received opioids as compared with those who did not and identify potential risk factors for respiratory depression in this population. Retrospective medical record review was conducted for subjects identified via the trauma registry who were admitted as a trauma activation and had a detectable serum ethanol level upon admission. Risk factors and characteristics compared included demographics, Injury Severity Score, Glasgow Coma Score, serum ethanol level upon arrival, urine drug screen results, incidence of respiratory depression, and opioid and other sedative medication use. A total of 233 patients were included (78.5% male). Patients who received opioids were more likely to have a higher Injury Severity Score and initial pain score on admission as compared with those who did not receive opioids. Blood ethanol content was higher in patients who did not receive opioids (0.205 vs 0.237 mg/dL, P = .015). Patients who did not receive opioids were more likely to be intubated within 4 hours of admission (1.7% vs 12.1%, P = .02). Opioid administration was not associated with increased risk of respiratory depression (19.7% vs 22.4%, P = .606). Increased cumulative fentanyl dose was associated with increased risk of respiratory depression. Increased cumulative fentanyl dose, but not opioid administration alone, was found to be a risk factor for respiratory depression. Copyright © 2015 Elsevier Inc. All rights reserved.

Objective Testing of Marijuana-Induced Vision Changes

DTIC Science & Technology

1973-04-30

related substances smokted by Americans abroad art much higher, The ar-v effects of acute and chronic I1 IIC use on moat human functions ame not...and P.E. MERRIAM. Auditory and Visua Threshold Effects of Marihuana on Man. Percep. Motor Shi~s. 29:755-759 (1969). CRANCER, A., J.M. DILLE, J.C...invest. Opbtbal. 6:145-154 (1967). HOLLISTER, L.E. and H.K. GILLESPIE. Marihuana , Ethanol and Dextroamphetamine: Mood and Mental Function Alterations

The effects of MDMA pretreatment on the behavioural effects of other drugs of abuse in the rat elevated plus-maze test.

PubMed

Sumnall, H R; O'Shea, E; Marsden, C A; Cole, J C

2004-04-01

Few preclinical studies have found long-term behavioural consequences of the serotonergic neurotoxicity produced by 3,4-methylenedioxymethamphetamine (MDMA). This study investigated whether pretreatment with MDMA altered the behavioural effects of other drugs of abuse. Adult male Lister hooded rats (n=10/group) were pretreated with 10 mg/kg MDMA or 1 ml/kg saline vehicle intraperitoneally every 2 h for 6 h. Fourteen days later, the behavioural effects of d-amphetamine (2 mg/kg), cocaine (10 mg/kg), ethanol (2.0 g/kg), heroin (0.5 mg/kg), or MDMA (10 mg/kg) were assessed in the elevated plus-maze test. MDMA pretreatment produced approximately 20-25% decrease in hippocampal 5-HT and 5-HIAA concentrations, and [(3)H]paroxetine binding when analysed 2 weeks later. Despite inducing neurotoxicity, this regimen had no effect upon the plus-maze behaviour induced by ethanol, heroin, and MDMA. Acutely, and independent of neurotoxic pretreatment, MDMA produced a clear anxiogenic-like behavioural profile with a reduction of open arm entries and suppression of explorative behaviours. Despite being acutely anxiogenic, pretreatment with a neurotoxic regimen of MDMA has little effect on the anxiety-related effects of other drugs of abuse. It is possible that extended time points would produce significant changes, although the available evidence suggests that the plus-maze may not be a suitable model for detection of behavioural dysfunction after neurotoxic MDMA.

An iso-α-acid-rich extract from hops (Humulus lupulus) attenuates acute alcohol-induced liver steatosis in mice.

PubMed

Hege, Marianne; Jung, Finn; Sellmann, Cathrin; Jin, Chengjun; Ziegenhardt, Doreen; Hellerbrand, Claus; Bergheim, Ina

2018-01-01

Results of in vitro and in vivo studies suggest that consumption of beer is less harmful for the liver than consumption of spirits. It also has been suggested that secondary plant compounds derived from hops such as xanthohumol or iso-α-acids may have beneficial effects on the development of liver diseases of various etiologies. The aim of this study was to determine whether iso-α-acids consumed in doses achieved by "normal" beer consumption have beneficial effects on health. Female C57 Bl/6 J mice, pretreated for 4 d with an iso-α-acid-rich extract (∼30% iso-α-acids from hops, 0.75 mg/kg body weight), were fed one bolus of ethanol (6 g/kg body weight intragastric) or an iso-caloric maltodextrin solution. Markers of liver damage, toll-like receptor-4 signaling, and lipid peroxidation were determined. Furthermore, the effect of isohumulone on the lipopolysaccharide-dependent activation of J774 A.1 macrophages, used as a model of Kupffer cells, was determined. In the liver, acute ethanol administration led to a significant accumulation of fat (∼10-fold), which was accompanied by significantly higher inducible nitric oxide synthase protein level, elevated nitric oxide production, and increased plasminogen activator inhibitor 1 protein concentration when compared to controls. In mice pretreated with iso-α-acids, these effects of alcohol were markedly attenuated. Pretreatment of J774 A.1 macrophages with isohumulone significantly attenuated lipopolysaccharide-induced mRNA expression of inducible nitric oxide synthase and interleukin-6 as well as the release of nitric oxide. Taken together, iso-α-acids markedly attenuated the development of acute alcohol-induced damage in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

A comparison of dehydroepiandrosterone and 7-keto dehydroepiandrosterone with other drugs that modulate ethanol intake in rats responding under a multiple schedule

PubMed Central

Amato, Russell J.; Hulin, Mary W.; Winsauer, Peter J.

2012-01-01

Dehydroepiandrosterone (DHEA), 7-keto DHEA, and several comparison drugs (ethanol, chlordiazepoxide, rauwolscine, and RO15-4513) were administered to male rats responding under a multiple schedule of food and ethanol presentation to determine their selectively for decreasing ethanol-maintained responding. DHEA and 7-keto DHEA significantly decreased both ethanol- and food-maintained responding, compared to control, while also decreasing blood ethanol concentration (BEC). Acute ethanol administration also decreased responding for both food and ethanol; however, ethanol-maintained responding was more potently decreased than food-maintained responding. BEC remained relatively stable after increasing ethanol doses. Among the other drugs tested, RO15-4513 was the most selective for decreasing ethanol-maintained responding compared to food-maintained responding, and it decreased BECs as ethanol-maintained responding decreased. The largest dose of rauwolscine significantly decreased responding for food, while not affecting ethanol-maintained responding compared to control. Low to intermediate doses of rauwolscine produced small, non-significant increases in ethanol-maintained responding and BECs. Chlordiazepoxide produced significant decreases in food-maintained responding and the dose of ethanol presented, but only at the highest dose tested. Although DHEA and 7-keto DHEA did not decrease ethanol-maintained responding as selectively as ethanol or RO15-4513 under the multiple schedule, these neurosteroids may be valuable pharmacological tools in the development of new treatments for alcohol abuse and dependence. PMID:22473025

Vasorelaxant and Hypotensive Effects of an Ethanolic Extract of Eulophia macrobulbon and Its Main Compound 1-(4′-Hydroxybenzyl)-4,8-Dimethoxyphenanthrene-2,7-Diol

PubMed Central

Wisutthathum, Sutthinee; Chootip, Krongkarn; Martin, Hélène; Ingkaninan, Kornkanok; Temkitthawon, Prapapan; Totoson, Perle; Demougeot, Céline

2018-01-01

Background: Ethnopharmacological studies demonstrated the potential for Eulophia species to treat inflammation, cancer, and cardio-metabolic diseases. The aim of the study was to investigate the vasorelaxant effect of ethanolic Eulophia macrobulbon (EM) extract and its main phenanthrene on rat isolated mesenteric artery and to investigate the hypotensive effect of EM. Methods: The vasorelaxant effects of EM extract or phenanthrene and the underlying mechanisms were evaluated on second-order mesenteric arteries from Sprague Dawley rats. In addition, the acute hypotensive effect was evaluated in anesthetized rats infused with cumulative concentrations of the EM extract. Results: Both EM extract (10-4–1 mg/ml) and phenanthrene (10-7–10-4 M) relaxed endothelium-intact arteries, an effect that was partly reduced by endothelium removal (p < 0.001). A significant decrease in the relaxant effect of the extract and the phenanthrene was observed with L-NAME and apamin/charybdotoxin in endothelium-intact vessels, and with iberiotoxin in denuded vessels. SNP (sodium nitroprusside)-induced relaxation was significantly enhanced by EM extract and phenanthrene. By contrast, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one), 4-aminopyridine and glibenclamide (endothelium-denuded vessels) and indomethacin (endothelium-intact vessels) had no effect. In calcium-free solution, both the EM extract and phenanthrene inhibited extracellular Ca2+-induced contraction in high KCl and phenylephrine (PE) pre-contracted rings. They also inhibited the intracellular Ca2+ release sensitive to PE. The acute infusion of EM extract (20 and 70 mg/kg) induced an immediate and transient dose-dependent hypotensive effect. Conclusion: The ethanolic extract of EM tubers and its main active compound, 1-(4′-hydroxybenzyl)-4,8-dimethoxyphenanthrene-2,7-diol (phenanthrene) induced vasorelaxant effects on rat resistance vessels, through pleiotropic effects including endothelium-dependent effects (NOS activation, enhanced EDH production) and endothelium-independent effects (opening of KCa channels, inhibition of Ca2+ channels, inhibition of intracellular Ca2+ release and PDE inhibition). PMID:29872393

Effect of ethanolic extract of Carpolobia lutea G. Don (polygalaceae) root on learning and memory in CD1 mice.

PubMed

Ajiwhen, I O; Bisong, S A

2013-12-20

Carpolobia lutea, commonly called cattle stick or poor man's candle, is used by traditional herbalists in eastern Nigeria to treat 'madness'. It has a reported analgesic and anti-nociceptive effect. The effect of its ethanolic root extract on learning and memory was investigated. Thirty mice were divided into three groups of ten each. One group of mice served as the control and was given normal saline (p.o.) while the other two groups were given acute low dose (1500mg/kg, p.o.) and high dose (2500mg/kg, p.o.) (LD50 3338.83mg/kg). The effect of the extract on cognitive memory was investigated using the Novel Object recognition task (NORT) while the effect on visuospatial learning and memory was studied using the Morris Water maze (MWM). The results obtained in the NORT show that the index of habituation was significantly lower following acute treatment with a low dose of C. lutea extract compared to control. However, the index of habituation did not differ following treatment with a high dose of C. lutea compared to control but it was higher compared to the low dose. Following treatment with a low dose of the extract, the index of discrimination was significantly higher compared to control. The index of discrimination in the high dose treatment group did not differ from control, but it was lower compared to the low dose treatment. This indicated that there was improved cognitive memory only in the low dose treatment group. In the MWM there was no significant difference in swim latency during Acquisition and Reversal training. There also was no significant difference in quadrant duration during probe trial. The swim latency during the visible platform test showed that all mice used had good visual acuity. Therefore, the ethanolic extract of C. lutea root enhanced cognitive memory. However it did not affect visuospatial learning and memory.

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice.

PubMed

Truitt, Jay M; Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy; Ponomareva, Olga; Law, Jade; Merriman, Morgan; Horani, Sami; Jameson, Kelly; Lasek, Amy W; Harris, R Adron; Mayfield, R Dayne

2016-01-01

Proinflammatory pathways in neuronal and non-neuronal cells are implicated in the acute and chronic effects of alcohol exposure in animal models and humans. The nuclear factor-κB (NF-κB) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKKβ mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-κB, leading to activation of NF-κB. The role of IKKβ as a potential regulator of excessive alcohol drinking had not previously been investigated. Based on previous findings that the overactivation of innate immune/inflammatory signaling promotes ethanol consumption, we hypothesized that inhibiting IKKβ would limit/decrease drinking by preventing the activation of NF-κB. We studied the systemic effects of two pharmacological inhibitors of IKKβ, TPCA-1 and sulfasalazine, on ethanol intake using continuous- and limited-access, two-bottle choice drinking tests in C57BL/6J mice. In both tests, TPCA-1 and sulfasalazine reduced ethanol intake and preference without changing total fluid intake or sweet taste preference. A virus expressing Cre recombinase was injected into the nucleus accumbens and central amygdala to selectively knock down IKKβ in mice genetically engineered with a conditional Ikkb deletion ( Ikkb F/F ). Although IKKβ was inhibited to some extent in astrocytes and microglia, neurons were a primary cellular target. Deletion of IKKβ in either brain region reduced ethanol intake and preference in the continuous access two-bottle choice test without altering the preference for sucrose. Pharmacological and genetic inhibition of IKKβ decreased voluntary ethanol consumption, providing initial support for IKKβ as a potential therapeutic target for alcohol abuse.

Protective role of ellagitannins from Eucalyptus citriodora against ethanol-induced gastric ulcer in rats: impact on oxidative stress, inflammation and calcitonin-gene related peptide.

PubMed

Al-Sayed, Eman; El-Naga, Reem N

2015-01-15

The gastroprotective activity of an ellagitannin-rich fraction obtained from Eucalyptus citriodora (ECF) was investigated against ethanol-induced gastric ulceration in rats. The rats were pretreated with ECF (25, 50 and 100mg/kg) 1h before the administration of absolute ethanol to induce acute gastric ulceration. The gastric lesions were significantly reduced by all doses of ECF. Notably, pre-treatment with ECF (100mg/kg) conferred 99.6% gastroprotection, which is significantly higher than that produced by omeprazole. Moreover, ECF administration markedly increased the mucin content in a dose-dependent manner. The potent gastroprotective effect of ECF could be partly mediated by attenuating ethanol-induced oxidative stress. ECF-pre-treatment markedly increased the depleted GSH and SOD levels in a dose-dependent manner. Moreover, ECF significantly decreased the elevated MDA tissue levels induced by ethanol administration. The results demonstrated that ECF administration exerted a powerful anti-inflammatory activity as evidenced by the reduction in the pro-inflammatory markers; IL-1β, TNF-α, 5-LO and COX-2. Additionally, the caspase-3 tissue levels were significantly reduced in the groups pre-treated with ECF. These results suggest that ECF could exert a beneficial gastroprotective effect through their antioxidant, anti-inflammatory and anti-apoptotic properties. Furthermore, ECF pre-treatment significantly attenuated the ethanol-induced decrease in CGRP expression, which has a protective role against gastric ulceration. Histopathological examination revealed intact mucosal layer, absence of hemorrhage and necrosis in groups treated with ECF. Ellagitannins were identified as the major active constituents responsible for the marked antioxidant and gastroprotective properties of ECF. The HPLC-PDA-ESI/MS/MS technique was employed to identify the ellagitannins of E. citriodora. Copyright © 2014 Elsevier GmbH. All rights reserved.

Microarray characterization of gene expression changes in blood during acute ethanol exposure

PubMed Central

2013-01-01

Background As part of the civil aviation safety program to define the adverse effects of ethanol on flying performance, we performed a DNA microarray analysis of human whole blood samples from a five-time point study of subjects administered ethanol orally, followed by breathalyzer analysis, to monitor blood alcohol concentration (BAC) to discover significant gene expression changes in response to the ethanol exposure. Methods Subjects were administered either orange juice or orange juice with ethanol. Blood samples were taken based on BAC and total RNA was isolated from PaxGene™ blood tubes. The amplified cDNA was used in microarray and quantitative real-time polymerase chain reaction (RT-qPCR) analyses to evaluate differential gene expression. Microarray data was analyzed in a pipeline fashion to summarize and normalize and the results evaluated for relative expression across time points with multiple methods. Candidate genes showing distinctive expression patterns in response to ethanol were clustered by pattern and further analyzed for related function, pathway membership and common transcription factor binding within and across clusters. RT-qPCR was used with representative genes to confirm relative transcript levels across time to those detected in microarrays. Results Microarray analysis of samples representing 0%, 0.04%, 0.08%, return to 0.04%, and 0.02% wt/vol BAC showed that changes in gene expression could be detected across the time course. The expression changes were verified by qRT-PCR. The candidate genes of interest (GOI) identified from the microarray analysis and clustered by expression pattern across the five BAC points showed seven coordinately expressed groups. Analysis showed function-based networks, shared transcription factor binding sites and signaling pathways for members of the clusters. These include hematological functions, innate immunity and inflammation functions, metabolic functions expected of ethanol metabolism, and pancreatic and hepatic function. Five of the seven clusters showed links to the p38 MAPK pathway. Conclusions The results of this study provide a first look at changing gene expression patterns in human blood during an acute rise in blood ethanol concentration and its depletion because of metabolism and excretion, and demonstrate that it is possible to detect changes in gene expression using total RNA isolated from whole blood. The analysis approach for this study serves as a workflow to investigate the biology linked to expression changes across a time course and from these changes, to identify target genes that could serve as biomarkers linked to pilot performance. PMID:23883607

Anti-ulcerogenic effect of a whey protein isolate and collagen hydrolysates against ethanol ulcerative lesions on oral administration to rats.

PubMed

Castro, G A; Carvalho, J E; Tinti, S V; Possenti, A; Sgarbieri, V C

2010-02-01

The effect of the administration of a whey protein isolate (WPI) and collagen hydrolysates on ethanol-induced ulcerative lesions was studied in rats. WPI and bovine or porcine collagen hydrolysate (BCH and PCH, respectively) were given to rats by gavage. In acute experiments, (single-dose) physiological saline (10 mL/kg of body weight) was used as the negative control, and carbenoxolone (200 mg/kg of body weight) was used as a positive control. Ethanol (1 mL per 250-g rat) was also given by gavage. These treatments reduced the ulcerative lesion index (ULI) in a range of 40-77%, depending on the dosage. Some mixtures of WPI with either PCH or BCH provided results that suggested synergisms between WPI and the collagen hydrolysates. For example, WPI/BCH (in the proportion of 375:375 mg/kg of body weight) decreased ULI by 64%. The mechanism for mucosal protection involved a decrease in plasma gastrin (approximately 40%), a significant increase (50-267%) in mucus production, and a reduction in ULI (percentage) when intragastric administrations were performed after in vivo alkylation by N-ethylmaleimide. Results suggest that gastrin, sulfhydryl substances, and some mechanisms related to mucus production are all involved in gastric ulcer protection against ethanol. The collagen hydrolysates (both PCH and BCH) presented a stronger effect on mucus production; on the other hand, the effect of WPI was also dependent on sulfhydryl compounds, resulting in a more protective effect when the two proteins were administered together.

Lipoic acid protects gastric mucosa from ethanol-induced injury in rat through a mechanism involving aldehyde dehydrogenase 2 activation.

PubMed

Li, Jia-Hui; Ju, Gui-Xia; Jiang, Jun-Lin; Li, Nian-Sheng; Peng, Jun; Luo, Xiu-Ju

2016-11-01

Numerous studies demonstrate that reactive aldehydes are highly toxic and aldehyde dehydrogenase 2 (ALDH2)-mediated detoxification of reactive aldehydes is thought as an endogenous protective mechanism against reactive aldehydes-induced cell injury. This study aims to explore whether lipoic acid, a potential ALDH2 activator, is able to protect gastric mucosa from ethanol-induced injury through a mechanism involving clearance of reactive aldehydes. The rats received 60% of acidified ethanol through intragastric administration and held for 1 h to establish a mucosal injury model. Lipoic acid (10 or 30 mg/kg) or Alda-1 (a positive control, 10 mg/kg) was given 45 min before the ethanol treatment. The gastric tissues were collected for analysis of gastric ulcer index, cellular apoptosis, 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) contents, and ALDH2 activity. The results showed that acute administration of ethanol led to an increase in gastric ulcer index, cellular apoptosis, 4-HNE and MDA contents concomitant with a decrease in ALDH2 activity; these phenomena were reversed by lipoic acid or Alda-1. The gastric protection of lipoic acid was attenuated in the presence of ALDH2 inhibitor. Based on these observations, we conclude that lipoic acid exerts the beneficial effects on ethanol-induced injury through a mechanism involving, at least in part, ALDH2 activation. As a dietary supplement or a medicine already in some countries, lipoic acid can be used to treat the ethanol - induced gastric mucosal injury. Copyright © 2016 Elsevier Inc. All rights reserved.

[Peppermint oil in the acute treatment of tension-type headache].

PubMed

Göbel, H; Heinze, A; Heinze-Kuhn, K; Göbel, A; Göbel, C

2016-06-01

Tension-type headache is the most frequent form of headache. The local topical treatment with peppermint oil (oleum menthae piperitae) has proven to be significantly more effective than placebo in controlled studies. Peppermint oil targets headache pathophysiology in multiple ways. The efficacy is comparable to that of acetylsalicylic acid or paracetamol. Solutions of 10 % peppermint oil in ethanol are licensed for the treatment of tension-type headache in adults and children above 6 years. It is included in treatment recommendations and guidelines by the respective professional societies and is regarded as a standard treatment for the acute therapy of tension-type headaches.

Protective Effect of Origanum majorana L. 'Marjoram' on various models of gastric mucosal injury in rats.

PubMed

Al-Howiriny, Tawfeq; Alsheikh, Abdulmalik; Alqasoumi, Saleh; Al-Yahya, Mohammed; ElTahir, Kamal; Rafatullah, Syed

2009-01-01

'Marjoram,' Origanum majorana L., a culinary aromatic medicinal herb is known to possess various therapeutic properties. We evaluated the antiulcerogenic activity of the ethanol extract in hypothermic restraint stress-, indomethacin-, necrotizing agents- (80% ethanol, 25% NaCl and 0.2 M NaOH) induced ulcers and basal gastric acid secretion using pylorus ligated Shay rat-model. Marjoram at doses of 250 and 500 mg/kg of body weight, significantly decreased the incidence of ulcers, basal gastric secretion and acid output. Furthermore, the extract replenished the ethanol-induced depleted gastric wall mucus and nonprotein sulfhydryls (NP-SH) contents and significantly lowered the increase in the concentration of malondialdehyde (MDA). Ulcer preventing potential was further confirmed by histopathological assessment. An acute toxicity test showed a large margin of safety of the extract in mice. The phytochemical screening of aerial parts of marjoram revealed the presence of volatile oil, flavonoids, tannins, sterols and/or triterpenes.

Angiotensin (1-7) contributes to nitric oxide tonic inhibition of vasopressin release during hemorrhagic shock in acute ethanol intoxicated rodents

PubMed Central

Whitaker, Annie M.; Molina, Patricia E.

2013-01-01

Aims Acute ethanol intoxication (AEI) attenuates the arginine vasopressin (AVP) response to hemorrhage leading to impaired hemodynamic counter-regulation and accentuated hemodynamic stability. Previously we identified that the ethanol-induced impairment of circulating AVP concentrations in response to hemorrhage was the result of augmented central nitric oxide (NO) inhibition. The aim of the current study was to examine the mechanisms underlying ethanol-induced up-regulation of paraventricular nucleus (PVN) NO concentration. Angiotensin (ANG) (1-7) is an important mediator of NO production through activation of the Mas receptor. We hypothesized that Mas receptor inhibition would decrease central NO concentration and thus restore the rise in circulating AVP levels during hemorrhagic shock in AEI rats. Main Methods Conscious male Sprague Dawley rats (300-325 g) received a 15h intra-gastric infusion of ethanol (2.5g/kg + 300mg/kg/h) or dextrose prior to a fixed-pressure (~40mmHg) 60 minute hemorrhage. The Mas receptor antagonist A-779 was injected through an intracerebroventricular (ICV) cannula 15 min prior to hemorrhage. Key Findings PVN NOS activity and NO were significantly higher in AEI compared to DEX-treated controls at the completion of hemorrhage. ICV A-779 administration decreased NOS activity and NO concentration, partially restoring the rise in circulating AVP levels completion of hemorrhage in AEI rats. Significance These results suggest that Mas receptor activation contributes to the NO-mediated inhibitory tone of AVP release in the ethanol-intoxicated hemorrhaged host. PMID:24002017

Lack of relation between drug-seeking behavior in an addiction model and the expression of behavioral sensitization in response to ethanol challenge in mice.

PubMed

Ribeiro, A F; Pigatto, G; Goeldner, F O; Lopes, J F; de Lacerda, R B

2008-01-01

Drug-induced sensitization has been associated with enhanced self-administration and may contribute to addiction. The possible association between sensitization and voluntary ethanol consumption using an addiction model was investigated. Mice (n = 60) were individually housed with ad libitum access to food and had free choice between ethanol (5% and 10%) and water in a four-phase paradigm: free choice (12 weeks), withdrawal (2 weeks), re-exposure (2 weeks), and quinine-adulteration (2 weeks). Control mice (n = 10) had access to water. Mice were characterized as addicted (n = 10, ethanol preference without reducing intake with adulterated ethanol), heavy (n = 22, ethanol preference but reduced intake with adulterated ethanol), and light (n = 21, water preference). Oral ethanol then was withdrawn, and 24 h later mice received a 2 g/kg ethanol (i.p.) challenge dose or saline, and ambulation was evaluated 10 min later. Half of the classified mice received daily 2 g/kg ethanol injections for 14 days, and ambulation was assessed 10 min after the last dose. Acute ethanol increased ambulation in all groups compared to the control group, and chronic ethanol induced sensitization, showing no difference among ethanol-treated mice. The data suggest that independent neural mechanisms are responsible for the development of addiction and sensitization.

Impaired Respiratory Function and Heightened Pulmonary Inflammation in Episodic Binge Ethanol Intoxication and Burn Injury

PubMed Central

Shults, Jill A.; Curtis, Brenda J.; Chen, Michael M.; O'Halloran, Eileen B.; Ramirez, Luis; Kovacs, Elizabeth J.

2015-01-01

Clinical data indicate that cutaneous burn injuries covering greater than ten percent total body surface area are associated with significant morbidity and mortality, where pulmonary complications, including acute respiratory distress syndrome (ARDS), contribute to nearly half of all patient deaths. Approximately 50% of burn patients are intoxicated at the time of hospital admission, which increases days on ventilators by three-fold, and doubles length of hospital admittance, compared to non-intoxicated burn patients. The most common drinking pattern in the United States is binge drinking, where one rapidly consumes alcoholic beverages (4 for women, 5 for men) in 2 hours and an estimated 38 million Americans binge drink, often several times per month. Experimental data demonstrate a single binge ethanol exposure prior to scald injury, impairs innate and adaptive immune responses, thereby enhancing infection susceptibility and amplifying pulmonary inflammation, neutrophil infiltration, and edema, and is associated with increased mortality. Since these characteristics are similar to those observed in ARDS burn patients, our study objective was to determine whether ethanol intoxication and burn injury and the subsequent pulmonary congestion affects physiological parameters of lung function using non-invasive and unrestrained plethysmography in a murine model system. Furthermore, to mirror young adult binge drinking patterns, and to determine the effect of multiple ethanol exposures on pulmonary inflammation, we utilized an episodic binge ethanol exposure regimen, where mice were exposed to ethanol for a total of 6 days (3 days ethanol, 4 days rest, 3 days ethanol) prior to burn injury. Our analyses demonstrate mice exposed to episodic binge ethanol and burn injury have higher mortality, increased pulmonary congestion and neutrophil infiltration, elevated neutrophil chemoattractants, and respiratory dysfunction, compared to burn or ethanol intoxication alone. Overall, our study identifies plethysmography as a useful tool for characterizing respiratory function in a murine burn model and for future identification of therapeutic compounds capable of restoring pulmonary functionality. PMID:26364264

Acute poisonings treated in hospitals in Oslo: a one-year prospective study (I): pattern of poisoning.

PubMed

Hovda, K E; Bjornaas, M A; Skog, K; Opdahl, A; Drottning, P; Ekeberg, O; Jacobsen, D

2008-01-01

Prospective design is mandatory to study pattern of poisoning and suicidal intention of patients. Prospective cross-sectional multi-center study of all patients contacting health care services because of acute poisoning during one year in Oslo, irrespective of intention. Data on the adult hospitalized patients (> or = 16 years) are presented here. Of a total of 3,775 such adult contacts (3,025 episodes), there were 947 (31 %) hospitalizations; annual incidence 1.9 (per 1,000) in males and 2.1 in females. Median age was 36 years (range 16-89); 54% females. Benzodiazepines (18%), ethanol (17%), paracetamol (12%), opioids (7%), and gamma hydroxybutyric acid (GHB) (7%) were most frequently taken. Patients stated suicidal intention in 29% of the admissions; physicians in 10%. Benzodiazepines and ethanol were the most common agents, but newer illicit drugs were frequent, especially GHB. Males often took ethanol and drugs of abuse; females often used prescription drugs with suicidal intention.

Nephroprotective effect of Bauhinia variegata (Linn.) whole stem extract against cisplatin-induced nephropathy in rats

PubMed Central

Pani, Saumya R.; Mishra, Satyaranjan; Sahoo, Sabuj; Panda, Prasana K.

2011-01-01

The nephroprotective activity of the ethanolic extract of Bauhinia variegata (Linn.) whole stem against cisplatin-induced nephropathy was investigated by an in vivo method in rats. Acute nephrotoxicity was induced by i.p. injection of cisplatin (7 mg/kg of body weight (b.w.)). Administration of ethanol extract at dose levels of 400 and 200 mg/kg (b.w.) to cisplatin-intoxicated rats for 14 days attenuated the biochemical and histological signs of nephrotoxicity of cisplatin in a dose-dependent fashion. Ethanol extract at 400 mg/kg decreased the serum level of creatinine (0.65 ± 0.09; P<0.001) and urea (32.86 ± 5.88; P<0.001) associated with a significant increase in body weight (7.16 ± 1.10; P<0.001) and urine volume output (11.95 ± 0.79; P<0.05) as compared to the toxic control group. The ethanol extract of B. variegata at 400 mg/kg (b.w.) exhibited significant and comparable nephroprotective potential to that of the standard polyherbal drug cystone. The statistically (one-way-ANOVA followed by Tukey-Kramer multiple comparison) processed results suggested the protective action of B. variegate whole stem against cisplatin-induced nephropathy. PMID:21572659

Impact of adolescent alcohol use across the lifespan: Long-lasting tolerance to high-dose alcohol coupled with potentiated spatial memory impairments to moderate-dose alcohol.

PubMed

Matthews, Douglas B; Novier, Adelle; Diaz-Granados, Jaime L; Van Skike, Candice E; Ornelas, Laura; Mittleman, G

2017-06-01

Understanding how alcohol exposure during adolescence affects aging is a critical but understudied area. In the present study, male rats were exposed to either alcohol or saline during adolescence, then tested every 4 months following either an ethanol or saline challenge; animals were tested until postnatal day (PD) 532. It was found that long-lasting tolerance to high-dose ethanol exists through the test period, as measured by loss of righting reflex, while tolerance to lower doses of ethanol is not found. In addition, alcohol exposure during adolescence facilitated spatial memory impairments to acute ethanol challenges later in life. The current work demonstrates that exposure to ethanol during adolescent development can produce long-lasting detrimental impairments. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-lasting, experience-dependent alcohol preference in Drosophila

PubMed Central

Peru y Colón de Portugal, Raniero L.; Ojelade, Shamsideen A.; Penninti, Pranav S.; Dove, Rachel J.; Nye, Matthew J.; Acevedo, Summer F.; Lopez, Antonio; Rodan, Aylin R.; Rothenfluh, Adrian

2013-01-01

To understand the molecular and neural mechanisms underlying alcohol addiction, many models ranging from vertebrates to invertebrates have been developed. In Drosophila melanogaster, behavioral paradigms from assaying acute responses to alcohol, to behaviors more closely modeling addiction, have emerged in recent years. However, both the CAFÉ assay, similar to a 2-bottle choice consumption assay, as well as conditioned odor preference, where ethanol is used as the reinforcer, are labor intensive and have low throughput. To address this limitation, we have established a novel ethanol consumption preference assay, called FRAPPÉ, which allows for fast, high throughput measurement of consumption in individual flies, using a fluorescence plate reader. We show that naïve flies do not prefer to consume ethanol, but various pre-exposures, such as ethanol vapor or voluntary ethanol consumption, induce ethanol preference. This ethanol-primed preference is long lasting and is not driven by calories contained in ethanol during the consumption choice. Our novel experience-dependent model of ethanol preference in Drosophila – a highly genetically tractable organism – therefore recapitulates salient features of human alcohol abuse and will facilitate the molecular understanding of the development of alcohol preference. PMID:24164972

Kaempferol protects ethanol-induced gastric ulcers in mice via pro-inflammatory cytokines and NO.

PubMed

Li, Qinchen; Hu, Xinxin; Xuan, Yanhan; Ying, Jianghua; Fei, Yujia; Rong, Jielu; Zhang, Yong; Zhang, Jian; Liu, Chunyan; Liu, Zheng

2018-03-01

Gastric ulcers (GUs) are common pathologies that affect many people around the world. Excessive alcohol consumption is one of the main causes of GUs; however, there are still lack of effective drugs for the prevention or therapy of GUs. In this study, we evaluated the protective effects and possible mechanisms of kaempferol (KAE) against acute ethanol-induced lesions to the gastric mucosa in mice. Fasted mice were orally given vehicle (0.9% saline), omeprazole (20 mg/kg), or KAE (40, 80, or 160 mg/kg) for 1 h in different experimental sets prior to the establishment of the GU model by challenge with absolute ethanol (10 ml/kg). Animals were euthanized 1 h after ethanol intake, and their plasma and stomach tissues were subject to further examination. Macroscopic and microscopic lesions, and immunological and biochemical parameters were observed. The effects of inflammation were investigated using the following indicators: tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, myeloperoxidase (MPO), and nitric oxide (NO). Results showed that KAE significantly decreased the ulcer index, increased the preventive index, completely protected the mucosa from lesions, and preserved gastric mucosal glycoprotein. KAE decreased MPO activity and pro-inflammatory cytokine (TNF-α, and IL-1β) levels, and improved NO levels. The gastroprotective activity of KAE might be attributed to the preservation of gastric mucous glycoproteins levels, thus by inhibiting neutrophil accumulation and MPO activity, adjusting the levels of pro-inflammatory cytokines, and improving NO production.

Effects of acute administration of nicotine, amphetamine, diazepam, morphine, and ethanol on risky decision-making in rats

PubMed Central

Mitchell, Marci R.; Vokes, Colin M.; Blankenship, Amy L.; Simon, Nicholas W.

2011-01-01

Rationale Most individuals can accurately assess the risks and rewards associated with choice alternatives and decide accordingly; however, drug users often display maladaptive decision-making, such that choices are biased toward excessively risky options. Objective The purpose of this study was to investigate the effects of a range of drugs of abuse on risky decision-making. Methods Male Long–Evans rats were trained in the Risky Decision-Making Task, in which they chose between two levers, one which produced a small, “safe” food reward and the other which produced a large, “risky” food reward. The large reward was accompanied by the risk of a mild footshock, the probability of which increased over the course of each test session (0%, 25%, 50%, 75%, and 100%). Results Nicotine (0.6 mg/kg) and amphetamine (1.5 mg/kg) caused a significant decrease in choice of the large risky reward (decreased risk taking). Diazepam (1.0 mg/kg) caused a significant increase in choice of the large risky reward (increased risk taking), whereas morphine (3.0 mg/kg) caused only a trend toward increased choice of the large risky reward. Ethanol had no effect on choice behavior. Conclusions These results show that acute administration of drugs of abuse can modulate risk taking in a drug-specific manner, either increasing or decreasing preference for highly rewarding, but risky, options. PMID:21638222

Silencing of cytosolic NADP+-dependent isocitrate dehydrogenase gene enhances ethanol-induced toxicity in HepG2 cells.

PubMed

Yang, Eun Sun; Lee, Su-Min; Park, Jeen-Woo

2010-07-01

It has been shown that acute and chronic alcohol administrations increase the production of reactive oxygen species, lower cellular antioxidant levels and enhance oxidative stress in many tissues. We recently reported that cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) functions as an antioxidant enzyme by supplying NADPH to the cytosol. Upon exposure to ethanol, IDPc was susceptible to the loss of its enzyme activity in HepG2 cells. Transfection of HepG2 cells with an IDPc small interfering RNA noticeably downregulated IDPc and enhanced the cells' vulnerability to ethanol-induced cytotoxicity. Our results suggest that suppressing the expression of IDPc enhances ethanol-induced toxicity in HepG2 cells by further disruption of the cellular redox status.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Edlich, R.F.; Spyker, D.A.

This book contains over 50 selections. Some of the titles are: Ethanol; Hydrocarbons; Lead; Rubella and Congenital Rubella; Tachycardias; Intracerebral Hemorrhage; Acute Otitis Media; and Diabetic Ketoacidosis and Coma in Adults.

Effects of chronic binge-like ethanol consumption on cocaine self-administration in rhesus monkeys.

PubMed

Czoty, Paul W

2015-08-01

Most cocaine abusers also abuse alcohol, but little is known about interactions that promote co-abuse. These experiments in rhesus monkeys determined the effects of >8 weeks of ethanol (EtOH) consumption on cocaine self-administration (n=6), effects of dopamine (DA) receptor antagonists on cocaine reinforcement (n=3-4 per drug) and the ability of the D2-like DA receptor agonist quinpirole to elicit yawning (n=3). Monkeys self-administered cocaine (0.0-1.0mg/kg/injection, i.v.) under a 300-s fixed-interval schedule and the above-listed variables were measured before EtOH exposure. Next, monkeys consumed a sweetened, 4% EtOH solution in the home cage under binge-like conditions: 1h, 5 days/week with daily intake equaling 2.0g/kg EtOH. After approximately 8 weeks, measures were re-determined, then EtOH drinking was discontinued. Finally, acute effects of EtOH on cocaine self-administration were determined by infusing EtOH (0.0-1.0g/kg. i.v.) prior to cocaine self-administration sessions (n=4). In five of six monkeys, EtOH drinking increased self-administration of low cocaine doses but did not alter reinforcing effects of higher doses. Self-administration returned to baseline after EtOH access was terminated (n=3). Effects of DA receptor antagonists on cocaine self-administration were not consistently altered after EtOH consumption, but the ability of quinpirole to induce yawning was enhanced in two of three monkeys. Acute EtOH infusions only decreased self-administration of lower cocaine doses. Taken together, the data suggest that long-term EtOH exposure can increase sensitivity to cocaine, possibly by increasing D3 receptor sensitivity. Data do not support a role for acute pharmacological interactions in promoting cocaine/EtOH co-abuse. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Mechanisms of Neuroplasticity and Ethanol’s Effects on Plasticity in the Striatum and Bed Nucleus of the Stria Terminalis

PubMed Central

Lovinger, David M.; Kash, Thomas L.

2015-01-01

Long-lasting changes in synaptic function (i.e., synaptic plasticity) have long been thought to contribute to information storage in the nervous system. Although synaptic plasticity mainly has adaptive functions that allow the organism to function in complex environments, it is now clear that certain events or exposure to various substances can produce plasticity that has negative consequences for organisms. Exposure to drugs of abuse, in particular ethanol, is a life experience that can activate or alter synaptic plasticity, often resulting in increased drug seeking and taking and in many cases addiction. Two brain regions subject to alcohol’s effects on synaptic plasticity are the striatum and bed nucleus of the stria terminalis (BNST), both of which have key roles in alcohol’s actions and control of intake. The specific effects depend on both the brain region analyzed (e.g., specific subregions of the striatum and BNST) and the duration of ethanol exposure (i.e., acute vs. chronic). Plastic changes in synaptic transmission in these two brain regions following prolonged ethanol exposure are thought to contribute to excessive alcohol drinking and relapse to drinking. Understanding the mechanisms underlying this plasticity may lead to new therapies for treatment of these and other aspects of alcohol use disorder. PMID:26259092

Chronic Ethanol Intake Alters Circadian Phase Shifting and Free-Running Period in Mice

PubMed Central

Seggio, Joseph A.; Fixaris, Michael C.; Reed, Jeffrey D.; Logan, Ryan W.; Rosenwasser, Alan M.

2011-01-01

Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker—including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli—in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes. PMID:19625732

Chronic ethanol intake alters circadian phase shifting and free-running period in mice.

PubMed

Seggio, Joseph A; Fixaris, Michael C; Reed, Jeffrey D; Logan, Ryan W; Rosenwasser, Alan M

2009-08-01

Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker--including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli--in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes.

A Review of the Interactions between Alcohol and the Endocannabinoid System: Implications for Alcohol Dependence and Future Directions for Research

PubMed Central

Pava, Matthew J.; Woodward, John J.

2012-01-01

Over the past fifty years a significant body of evidence has been compiled suggesting an interaction between the endocannabinoid (EC) system and alcohol dependence. However, much of this work has been conducted only in the past two decades following the elucidation of the molecular constituents of the EC system that began with the serendipitous discovery of the cannabinoid 1 receptor (CB1). Since then, novel pharmacological and genetic tools have enabled researchers to manipulate select components of the EC system, to determine their contribution to the motivation to consume ethanol. From these preclinical studies, it is evident that CB1 contributes the motivational and reinforcing properties of ethanol, and chronic consumption of ethanol alters EC transmitter levels and CB1 expression in brain nuclei associated with addiction pathways. These results are augmented by in vitro and ex vivo studies showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the EC system. This report provides a current and comprehensive review of the literature regarding the interactions between ethanol and the EC system. We begin be reviewing the studies published prior to the discovery of the EC system that compared the behavioral and physiological effects of cannabinoids with ethanol in addition to cross-tolerance between these drugs. Next, a brief overview of the molecular constituents of the EC system is provided as context for the subsequent review of more recent studies examining the interaction of ethanol with the EC system. These results are compiled into a summary providing a scheme for the known changes to the components of the EC system in different stages of alcohol dependence. Finally, future directions for research are discussed. PMID:22459871

Risky choice and brain CRF after adolescent ethanol vapor exposure and social stress in adulthood.

PubMed

Boutros, Nathalie; Der-Avakian, Andre; Semenova, Svetlana; Lee, Soon; Markou, Athina

2016-09-15

Adolescent ethanol exposure increases risky choice and alters corticotropin releasing factor (CRF) systems in adulthood. The impact of stress on risky choice after adolescent intermittent ethanol (AIE) exposure is not known. We investigated time-specific effects of AIE vapor exposure during early adolescence on risky choice after stress or no stress in adulthood. Male Wistar rats were exposed to air or AIE vapor on postnatal days 28-42 (adolescence) and were exposed to 10days of social defeat or no stress on postnatal days 172-181 (adulthood). Risky choice was assessed in the probability discounting task under baseline conditions and after days 1 and 10 of social defeat. CRF and CRF receptor 1 (CRFR1) mRNA levels were assessed in the prefrontal cortex (PFC) and the central nucleus of the amygdala (CeA) 24h post-stress to evaluate persistent effects of stress on the brain. AIE exposure had no effect on risky choice either at baseline or after social defeat. Additionally, neither acute nor chronic social defeat affected risky choice in air-exposed rats. In the PFC, chronic social defeat selectively decreased CRF mRNA levels in air-exposed rats and increased CRFR1 mRNA levels in all rats. AIE exposure increased CRF mRNA levels in the CeA with no effect of social stress. Our results indicate no effect of ethanol exposure via vapor during early adolescence on risky choice, while our previous findings indicated that AIE exposure via gavage affected risky choice. Both AIE exposure and social defeat altered CRF and CRFR1 mRNA levels in the brain. Copyright © 2016 Elsevier B.V. All rights reserved.

Acute administration of vinpocetine, a phosphodiesterase type 1 inhibitor, ameliorates hyperactivity in a mice model of fetal alcohol spectrum disorder.

PubMed

Nunes, Fernanda; Ferreira-Rosa, Kélvia; Pereira, Maurício Dos S; Kubrusly, Regina C; Manhães, Alex C; Abreu-Villaça, Yael; Filgueiras, Cláudio C

2011-12-01

Maternal alcohol use during pregnancy causes a continuum of long-lasting disabilities in the offspring, commonly referred to as fetal alcohol spectrum disorder (FASD). Attention-deficit/hyperactivity disorder (ADHD) is possibly the most common behavioral problem in children with FASD and devising strategies that ameliorate this condition has great clinical relevance. Studies in rodent models of ADHD and FASD suggest that impairments in the cAMP signaling cascade contribute to the hyperactivity phenotype. In this work, we investigated whether the cAMP levels are affected in a long-lasting manner by ethanol exposure during the third trimester equivalent period of human gestation and whether the acute administration of the PDE1 inhibitor vinpocetine ameliorates the ethanol-induced hyperactivity. From postnatal day (P) 2 to P8, Swiss mice either received ethanol (5g/kg i.p.) or saline every other day. At P30, the animals either received vinpocetine (20mg/kg or 10mg/kg i.p.) or vehicle 4h before being tested in the open field. After the test, frontal cerebral cortices and hippocampi were dissected and collected for assessment of cAMP levels. Early alcohol exposure significantly increased locomotor activity in the open field and reduced cAMP levels in the hippocampus. The acute treatment of ethanol-exposed animals with 20mg/kg of vinpocetine restored both their locomotor activity and cAMP levels to control levels. These data lend support to the idea that cAMP signaling system contribute to the hyperactivity induced by developmental alcohol exposure and provide evidence for the potential therapeutic use of vinpocetine in FASD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Impaired TFEB-mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-induced Liver Injury and Steatosis in Mice.

PubMed

Chao, Xiaojuan; Wang, Shaogui; Zhao, Katrina; Li, Yuan; Williams, Jessica A; Li, Tiangang; Chavan, Hemantkumar; Krishnamurthy, Partha; He, Xi C; Li, Linheng; Ballabio, Andrea; Ni, Hong-Min; Ding, Wen-Xing

2018-05-18

Defects in lysosome function and autophagy contribute to pathogenesis of alcoholic liver disease. We investigated the mechanisms by which alcohol consumption affects these processes, evaluating the functions transcription factor EB (TFEB), which regulates lysosomal biogenesis. We performed studies with GFP-LC3 mice, mice with liver-specific deletion of transcription factor EB (TFEB), mice with disruption of the transcription factor E3 gene (TFE3-knockout mice), mice with disruption of the Tefb and Tfe3 genes (TFEB, TFE3 double-knockout mice), and Tfeb flox/flox albumin cre-negative mice (controls). TFEB was overexpressed from adenoviral vectors or knocked down with small interfering RNAs in mouse livers. Mice were placed on diets of chronic ethanol feeding plus an acute binge to induce liver damage (ethanol diet); some mice were also given injections of torin1, an inhibitor of the kinase activity of the mechanistic target of rapamycin (mTOR). Liver tissues were collected and analyzed by immunohistochemistry, immunoblots, and quantitative real-time PCR to monitor lysosome biogenesis. We analyzed levels of TFEB in liver tissues from patients with alcoholic hepatitis and from healthy donors (controls) by immunohistochemistry. Liver tissues from mice on the ethanol diet had lower levels of total and nuclear TFEB, compared with control mice, and hepatocytes had reduced lysosome biogenesis and autophagy. Hepatocytes from mice on the ethanol diet had increased translocation of mTOR into lysosomes, resulting increased mTOR activation. Administration of torin1 increased liver levels of TFEB and reduced steatosis and liver injury induced by ethanol. Mice that overexpressed TFEB in liver developed less-severe ethanol-induced liver injury and had increased lysosomal biogenesis and mitochondrial bioenergetics compared to mice carrying a control vector. Mice with knockdown of TFEB, as well as TFEB, TFE3 double-knockout mice, developed more severe liver injury in response to the ethanol diet than control mice. Liver tissues from patients with alcohol-induced hepatitis had lower nuclear levels of TFEB than control tissues CONCLUSIONS: We found chronic ethanol feeding plus an acute binge to reduce hepatic expression of the transcription factor TFEB, which is required for lysosomal biogenesis and autophagy. Strategies to block mTOR activity or increase levels of TFEB might be developed to protect liver from ethanol-induced damage. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics of ethanol and its metabolite, acetaldehyde, and fetolethality in the third-trimester pregnant guinea pig for oral administration of acute, multiple-dose ethanol.

PubMed

Clarke, D W; Steenaart, N A; Slack, C J; Brien, J F

1986-08-01

The pharmacokinetics of ethanol and its metabolite, acetaldehyde, were determined in the third-trimester pregnant guinea pig (56-59 days gestation) for oral intubation of four doses of 1 g ethanol/kg maternal body weight, administered at 1-h intervals. Animals (n = 4-7) were sacrificed at each of selected times during the 26-h study. Ethanol and acetaldehyde concentrations were determined by headspace gas-liquid chromatography. The maternal and fetal blood ethanol concentration-time curves were virtually superimposable, which indicated unimpeded bidirectional placental transfer of ethanol in the maternal-fetal unit. The blood and brain ethanol concentrations were similar in each of the maternal and fetal compartments during the study, which indicated rapid equilibrium distribution of ethanol. There was accumulation of ethanol in the amniotic fluid resulting in higher ethanol concentration compared with maternal and fetal blood during the elimination phase, which indicated that the amniotic fluid may serve as a reservoir for ethanol in utero. Acetaldehyde was measurable in all the biological fluids and tissues at concentrations that were at least 1,000-fold less than the respective ethanol concentrations and were variable. There was ethanol-induced fetolethality that was delayed and variable among animals, and was 55% at 23 h. At this time interval, the ethanol concentrations in maternal blood and brain, fetal brain, and amniotic fluid were 35- to 53-fold greater and the acetaldehyde concentrations in maternal blood and fetal brain were four- to five-fold higher in the animals with dead fetuses compared with the guinea pigs with live litters. These data indicated that decreased ethanol elimination from the maternal-fetal unit was related temporally to the fetolethality.

Ethanol impedes embryo transport and impairs oviduct epithelium.

PubMed

Xu, Tonghui; Yang, Qiuhong; Liu, Ruoxi; Wang, Wenfu; Wang, Shuanglian; Liu, Chuanyong; Li, Jingxin

2016-05-16

Most studies have demonstrated that alcohol consumption is associated with decreased fertility. The aim of this study was to investigate the effects of alcohol on pre-implantation embryo transport and/or early embryo development in the oviduct. We reported here that ethanol concentration-dependently suppressed the spontaneous motility of isolated human oviduct strips (EC50 50±6mM), which was largely attenuated in the present of L-NAME, a classical nitric oxide synthase(NOS) competitive inhibitor. Notably, either acute or chronic alcohol intake delayed egg transport and retarded early development of the embryo in the mouse oviduct, which was largely rescued by co-administration of L-NAME in a acute alcohol intake group but not in chronic alcohol intake group. It is worth mentioning that the oviductal epithelium destruction was verified by scanning electron microscope (SEM) observations in chronic alcohol intake group. In conclusion, alcohol intake delayed egg transport and retarded early development of the embryo in the oviduct by suppressing the spontaneous motility of oviduct and/or impairing oviductal epithelium. These findings suggested that alcohol abuse increases the incident of ectopic pregnancy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Prevention of experimentally-induced gastric ulcers in rats by an ethanolic extract of "Parsley" Petroselinum crispum.

PubMed

Al-Howiriny, Tawfeq; Al-Sohaibani, Mohammed; El-Tahir, Kamal; Rafatullah, Syed

2003-01-01

An ethanolic extract of Parsley, Petroselinum crispum (Mill.) Nym.ex A.W. Hill (Umbelliferae), was tested for its ability to inhibit gastric secretion and to protect gastric mucosa against the injuries caused by pyloric ligation, hypothermic restraint stress, indomethacin and cytodestructive agents (80% ethanol, 0.2 M NaOH and 25% NaCl) in rats. The extract in doses of 1 and 2 g/kg body weight had a significant antiulcerogenic activity on the models used. Besides, ethanol-induced depleted gastric wall mucus and non-protein sulfhydryl contents were replenished by pretreatment with Parsley extract. Acute toxicity tests showed a large margin of safety for the extract. The phytochemical screening of Parsley leaves revealed the presence of tannins, flavonoids, sterols and/or triterpenes.

Heterogeneity of p53 dependent genomic responses following ethanol exposure in a developmental mouse model of fetal alcohol spectrum disorder.

PubMed

Camargo Moreno, Maria; Mooney, Sandra M; Middleton, Frank A

2017-01-01

Prenatal ethanol exposure can produce structural and functional deficits in the brain and result in Fetal Alcohol Spectrum Disorder (FASD). In rodent models acute exposure to a high concentration of alcohol causes increased apoptosis in the developing brain. A single causal molecular switch that signals for this increase in apoptosis has yet to be identified. The protein p53 has been suggested to play a pivotal role in enabling cells to engage in pro-apoptotic processes, and thus figures prominently as a hub molecule in the intracellular cascade of responses elicited by alcohol exposure. In the present study we examined the effect of ethanol-induced cellular and molecular responses in primary somatosensory cortex (SI) and hippocampus of 7-day-old wild-type (WT) and p53-knockout (KO) mice. We quantified apoptosis by active caspase-3 immunohistochemistry and ApopTag™ labeling, then determined total RNA expression levels in laminae of SI and hippocampal subregions. Immunohistochemical results confirmed increased incidence of apoptotic cells in both regions in WT and KO mice following ethanol exposure. The lack of p53 was not protective in these brain regions. Molecular analyses revealed a heterogeneous response to ethanol exposure that varied depending on the subregion, and which may go undetected using a global approach. Gene network analyses suggest that the presence or absence of p53 alters neuronal function and synaptic modifications following ethanol exposure, in addition to playing a classic role in cell cycle signaling. Thus, p53 may function in a way that underlies the intellectual and behavioral deficits observed in FASD.

Long-term behavioral change as a result of acute ethanol exposure in zebrafish: Evidence for a role for sonic hedgehog but not retinoic acid signaling.

PubMed

Burton, Derek F; Zhang, Chengjin; Boa-Amponsem, Oswald; Mackinnon, Shanta; Cole, Gregory J

2017-05-01

Developmental exposure to ethanol is recognized to produce long-term neurobehavioral impairment in multiple animal models. However, the molecular mechanisms underlying these deficits remain poorly understood. The present study was undertaken to ascertain whether two well-characterized targets of prenatal alcohol exposure, sonic hedgehog (Shh) and retinoic acid (RA), that induce the hallmark morphological phenotypes of fetal alcohol spectrum disorders (FASD), are involved in the generation of behavioral alterations as a result of alcohol exposure. Zebrafish embryos were exposed to ethanol (0%, 1%, 3%) at either 8-10 or 24-27h post-fertilization (hpf) and then evaluated during adolescence in the novel tank dive test to assess anxiety and risk-taking behavior. Overt signs of dysmorphogenesis were also scored and behavioral and morphological changes were compared for embryos treated with alcohol alone or in combination with subthreshold doses of shh or alhh1a3 morpholinos (MOs). Ethanol treated fish displayed altered tank diving behavior that was not exacerbated by combined MO treatment. While treatment of embryos with either shha mRNA or RA prior to ethanol exposure only ameliorated the altered tank diving response in the case of shha mRNA overexpression, dysmorphogenesis was rescued by both treatments. These results suggest that the effects of ethanol exposure on changes in anxiety and risk-taking behavior in adolescent zebrafish is manifested by a blunting of Shh, but not RA, signaling during early development. Copyright © 2017 Elsevier Inc. All rights reserved.

Protective effect of mannitol, glucose-fructose-sucrose-maltose mixture, and natural honey hyperosmolar solutions against ethanol-induced gastric mucosal damage in rats.

PubMed

Gharzouli, K; Gharzouli, A; Amira, S; Khennouf, S

2001-06-01

We have previously shown that natural honey is able to protect the rat stomach against acute ethanol- and indomethacin-induced lesions. The present investigations were undertaken to examine the role of intraluminal osmolality in this protective effect. Mannitol, glucose-fructose-sucrose-maltose mixture (GFSM) and natural honey (300, 600, 1800 mOsmol/kg water) were given orally to rats 30 min before administration of 70% ethanol for a further 15-min period. Lesions area of the excised stomachs were evaluated. Pylorus-ligated stomachs were filled with mannitol, GFSM mixture and honey (1800 mOsmol/kg water) to test the effect of the hyperosmolar solutions on gastric fluid content and acid secretion. The rate of gastric emptying of the three test solutions (1800 mOsmol/kg) was measured by the phenol red method. Intragastric administration of mannitol, GFSM mixture or honey prevented the formation of mucosal lesions in an osmolality-dependent manner. Using the pylorus-ligated stomach model, the test solutions led to a net increase of luminal fluid volume without affecting acid content. Hyperosmolar solutions presented a delayed gastric emptying if compared to a nonnutrient solution made of carboxymethyl cellulose. The observed results suggest that hyperosmolar solutions can prevent the formation of hemorrhagic lesions by luminal dilution of the necrotising agent and acid, an effect which may be potentiated by a lowered gastric emptying rate.

Protective effect of N-acetylcysteine against ethanol-induced gastric ulcer: A pharmacological assessment in mice

PubMed Central

Jaccob, Ausama Ayoob

2015-01-01

Aim: Since there is an increasing need for gastric ulcer therapies with optimum benefit-risk profile. This study was conducted to investigate gastro-protective effects of N-acetylcysteine (NAC) against ethanol-induced gastric ulcer models in mice. Materials and Methods: A total of 41 mice were allocated into six groups consisted of 7 mice each. Groups 1 (normal control) and 2 (ulcer control) received distilled water at a dose of 10 ml/kg, groups 3, 4 and 5 were given NAC at doses 100, 300 and 500 mg/kg, respectively, and the 6th group received ranitidine (50 mg/kg). All drugs administered orally once daily for 7 days, on the 8th day absolute ethanol (7 ml/kg) was administrated orally to all mice to induce the acute ulcer except normal control group. Then 3 h after, all animals were sacrificed then consequently the stomachs were excised for examination. Results: NAC administration at the tested doses showed a dose-related potent gastro-protective effect with significant increase in curative ratio, PH of gastric juice and mucus content viscosity seen with the highest dose of NAC and it is comparable with that observed in ranitidine group. Conclusion: The present findings demonstrate that, oral NAC shows significant gastro-protective effects comparable to ranitidine confirmed by anti-secretory, cytoprotective, histological and biochemical data, but the molecular mechanisms behind such protection are complex. PMID:26401392

Alcohol Intoxication Impact on Outcome from Traumatic Injury

DTIC Science & Technology

2007-05-01

factors for these complications is the severity of the injury, genetic makeup of the individual, the history of alcohol intake of the individual (acute...ethanol as related to trauma in the awake dog. J Trauma 11:76Y86, 1971. 18. Edgarian H, Altura BM: Ethanol and contraction of venous smooth muscle...impact of a 3-day alcohol binge on host responses during trauma/hemorrhage (THem) and following overnight recovery. Methods: Chronically catheterized

Gastroprotective effects and antimicrobial activity of Lithraea molleoides and isolated compounds against Helicobacter pylori.

PubMed

Garro, María Filomena; Salinas Ibáñez, Angel Gabriel; Vega, Alba Edith; Arismendi Sosa, Andrea Celeste; Pelzer, Lilian; Saad, José Roberto; Maria, Alejandra Olivia

2015-12-24

Lithraea molleoides (Vell.) Engl. (Anacardiaceae) is a medicinal plant traditionally used in South America to treat various ailments, including diseases of the digestive system. To evaluate the in vivo antiulcer and antimicrobial activities against Helicobacter pylori of L. molleoides and its isolated compounds. Methanolic extract 250 and 500 mg/kg, (LmE 250 and LmE 500, respectively) and infusions, 10 g and 20 g en 100mL (LmI 10 and LmI 20, respectively) of L. molleoides was evaluated for antiulcer activity against 0.6N HCl, 0.2N NaOH, 200mg/kg acetilsalicilic acid and absolute ethanol-induced gastric ulcers in rats. The degree of erosion in the glandular part of the stomach was assessed from a scoring system. Acute toxicity in mice was also evaluated. The antiulcer effect of the isolated compounds (catechol, mannitol, rutin, gallic acid, ferulic acid and caffeic acid, 100mg/kg) was evaluated against absolute ethanol-induced gastric ulcers in rats. The anti-Helicobacter pylori activity of L. molleoides and isolated compounds was performed using broth dilution methods. The LmE 250, LmE 500, LmI 10 and LmI 20 produced significant inhibition on the ulcer index in 0.6N HCl, 0.2N NaOH, 200mg/kg acetilsalicilic acid and absolute ethanol- induced gastric ulcers in rats. The isolated compounds, catechol, mannitol, rutin, ferulic acid and caffeic acid were active in absolute ethanol- induced gastric ulcers in rats. L. molleoides and different compounds showed antimicrobial activity in all strains tested. The lowest MIC value (0. 5 μg/mL) was obtained with catechol in six of eleven strains assayed. No signs of toxicity were observed with doses up to 2g/kg in an acute toxicity assay. These findings indicate that L. molleoides displays potential antiulcerogenic and antimicrobial activities and the identification of active principles could support the use of this plant for the treatment of digestive affections. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Antioxidant and anti-inflammatory activities of Moroccan Erica arborea L].

PubMed

Amezouar, F; Badri, W; Hsaine, M; Bourhim, N; Fougrach, H

2013-12-01

The present study was carried out to evaluate the antioxidant and anti-inflammatory capacity, and acute toxicity of Moroccan Erica arborea leaves. Antioxidant capacity was assessed by diphenyle-picryl-hydrazyl (DPPH), phosphomolybdate (PPM) and ferric reducing antioxidant power (FRAP) tests and anti-inflammatory capacity was evaluated by hind paw oedema model using carrageenan-induced inflammation in rat. The acute toxicity was evaluated using mice. Acute toxicity of ethanolic extract of E. arborea showed no sign of toxicity at dose of 5 g/kg B.W. Our extracts have important antioxidant properties. The efficient concentration of the ethanolic extract (10.22 μg/ml) required for decreasing initial DPPH concentration by 50% was comparable to that of standard solution butyl-hydroxy-toluene (BHT) (8.87 μg/ml). The administration of ethanolic extract at doses of 200 and 400mg/kg B.W. was able to prevent plantar oedema and exhibited a significant inhibition against carrageenan-induced inflammation when compared to the control group (NaCl 0.9%) but comparable to those of diclofenac (reference drug). Our results show that the leaves of E. arborea may contain some bioactive compounds which are responsible for the antioxidant and anti-inflammatory activities observed here. Our finding may indicate the possibility of using the extracts of this plant to prevent the antioxidant and inflammatory processes. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Rates of Ethanol Metabolism Decrease in Sons of Alcoholics Following a Priming Dose of Ethanol

PubMed Central

Bradford, Blair U.; Jackson, Jennifer K.; Powell, Linda L.; Garbutt, James C.

2007-01-01

Rapid changes in rates of ethanol metabolism in response to acute ethanol administration have been observed in animals and humans. To examine whether this phenomenon might vary by risk for alcoholism, 23 young men with a positive family history of alcoholism (FHP) were compared to 15 young men without a family history of alcoholism (FHN). Rates of ethanol metabolism were measured in all subjects first after an initial ethanol dose (0.85 g/kg) and then, several hours later, a second dose (0.3 g/kg), and the two rates were compared. The two groups of subjects were similar in their histories of ethanol consumption. FHP subjects demonstrated faster initial rates of ethanol metabolism, 148 ± 36 mg/kg/hr, compared to FHN subjects, 124 ± 18 mg/kg/hr, p=.01. However, FHN subjects increased their rate of metabolism by 10 ± 27 percent compared to a decrease of -15 ± 24 percent in FHP subjects, p =.007. Fifty-two percent of the FHP and none of the FHN subjects exhibited a decline in metabolic rate of 20% or more, p=.0008. Since a significant proportion of FHP subjects exhibited a decrease in the second rate of ethanol metabolism, these preliminary data might help to partly explain why FHP individuals differ in their sensitivity to ethanol and are more likely to develop alcohol dependence. PMID:17521843

Alcohols enhance caerulein-induced zymogen activation in pancreatic acinar cells

PubMed Central

LU, ZHAO; KARNE, SURESH; KOLODECIK, THOMAS; GORELICK, FRED S.

2010-01-01

Activation of zymogens within the pancreatic acinar cell is an early feature of acute pancreatitis. Supraphysiological concentrations of cholecystokinin (CCK) cause zymogen activation and pancreatitis. The effects of the CCK analog, caerulein, and alcohol on trypsin and chymotrypsin activation in isolated pancreatic acini were examined. Caerulein increased markers of zymogen activation in a time- and concentration-dependent manner. Notably, trypsin activity reached a peak value within 30 min, then diminished with time, whereas chymotrypsin activity increased with time. Ethanol (35 mM) sensitized the acinar cells to the effects of caerulein (10−10 to 10−7 M) on zymogen activation but had no effect alone. The effects of ethanol were concentration dependent. Alcohols with a chain length of ≥2 also sensitized the acinar cell to caerulein; the most potent was butanol. Branched alcohols (2-propanol and 2-butanol) were less potent than aliphatic alcohols (1-propanol and 1-butanol). The structure of an alcohol is related to its ability to sensitize acinar cells to the effects of caerulein on zymogen activation. PMID:11842000

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

PubMed Central

Cook, Jason B; Nelli, Stephanie M; Neighbors, Mackenzie R; Morrow, Danielle H; O'Buckley, Todd K; Maldonado-Devincci, Antoniette M; Morrow, A Leslie

2014-01-01

The neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP or allopregnanolone) is a positive modulator of GABAA receptors synthesized in the brain, adrenal glands, and gonads. In rats, ethanol activates the hypothalamic–pituitary–adrenal axis and elevates 3α,5α-THP in plasma, cerebral cortex, and hippocampus. In vivo, these effects are dependent on both the pituitary and adrenal glands. In vitro, however, ethanol locally increases 3α,5α-THP in hippocampal slices, in the absence of adrenal influence. Therefore, it is not known whether ethanol can change local brain levels of 3α,5α-THP in vivo, independent of the adrenals. To directly address this controversy, we administered ethanol (2 g/kg) or saline to rats that underwent adrenalectomy (ADX) or received sham surgery and performed immunohistochemistry for 3α,5α-THP. In the medial prefrontal cortex (mPFC), ethanol increased 3α,5α-THP after sham surgery, compared with saline controls, with no ethanol-induced change in 3α,5α-THP following ADX. In subcortical regions, 3α,5α-THP was increased independent of adrenals in the CA1 pyramidal cell layer, dentate gyrus polymorphic layer, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus. Furthermore, ethanol decreased 3α,5α-THP labeling in the nucleus accumbens shore and central nucleus of the amygdala, independent of the adrenal glands. These data indicate that ethanol dynamically regulates local 3α,5α-THP levels in several subcortical regions; however, the adrenal glands contribute to 3α,5α-THP elevations in the mPFC. Using double immunofluorescent labeling we determined that adrenal dependence of 3α,5α-THP induction by ethanol is not due to a lack of colocalization of 3α,5α-THP with the cholesterol transporters steroidogenic acute regulatory protein (StAR) or translocator protein (TSPO). PMID:24566803

Fomepizole versus ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak.

PubMed

Zakharov, Sergey; Pelclova, Daniela; Navratil, Tomas; Belacek, Jaromir; Komarc, Martin; Eddleston, Michael; Hovda, Knut Erik

2015-01-01

Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. During an outbreak of mass poisonings in the Czech Republic in 2012-2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. The study was designed as a cross-sectional case series and quasi-case-control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH < 7.3, serum bicarbonate < 20 mmol/L, and anion gap or AG ≥ 20 mmol/L. Fomepizole was given as a bolus dose of 15 mg/kg i.v. diluted in isotonic saline, followed by 10 mg/kg every 12 h (every 4 h during hemodialysis); ethanol was administered both intravenously as a 10% solution in 5% glucose, and per os in boluses of 20% solution. Multivariate regression was applied to determine the effect of antidote on outcome. Additionally, for a retrospective quasi-case-control study, a control group of patients treated with ethanol, matched carefully on severity of poisoning and other key parameters, was selected. Data were obtained from 100 hospitalized patients with confirmed poisoning: 25 patients treated with fomepizole were compared with 68 patients receiving ethanol (seven patients did not receive any antidote). More severely acidotic (p < 0.001) and late-presenting (>12 h; p = 0.028) patients received fomepizole more often than ethanol, as reflected in the higher number of fomepizole-treated patients being intubated (p = 0.009). No association was found between the type of antidote and the survival in either the case series (p = 0.205) or the quasi-control groups (p = 0.705) in which patients were very closely matched to minimize confounding by allocation. In the multivariate analysis, positive serum ethanol (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.9-39.9) and arterial blood pH (OR, 3.7; 95% CI, 1.3-10.5) on admission were the only independent variables for the survival. The median intensive care unit length of stay was 6 (range, 2-22) days in the fomepizole group and 4 (range, 1-33) days in the ethanol group (p = 0.131). There were no differences in the use of elimination techniques between the two groups (neither in the full material (n = 100), nor the case-control groups (n = 50)). This study on antidotes for methanol poisoning did not show any evidence of different clinical effectiveness. Although ethanol is generally associated with a higher incidence of complications, this study suggests that both antidotes are similarly effective and that ethanol should not be avoided on grounds of effectiveness.

A novel comparative pattern count analysis reveals a chronic ethanol-induced dynamic shift in immediate early NF-κB genome-wide promoter binding during liver regeneration.

PubMed

Kuttippurathu, Lakshmi; Patra, Biswanath; Hoek, Jan B; Vadigepalli, Rajanikanth

2016-03-01

Liver regeneration after partial hepatectomy is a clinically important process that is impaired by adaptation to chronic alcohol intake. We focused on the initial time points following partial hepatectomy (PHx) to analyze the genome-wide binding activity of NF-κB, a key immediate early regulator. We investigated the effect of chronic alcohol intake on immediate early NF-κB genome-wide localization, in the adapted state as well as in response to partial hepatectomy, using chromatin immunoprecipitation followed by promoter microarray analysis. We found many ethanol-specific NF-κB binding target promoters in the ethanol-adapted state, corresponding to the regulation of biosynthetic processes, oxidation-reduction and apoptosis. Partial hepatectomy induced a diet-independent shift in NF-κB binding loci relative to the transcription start sites. We employed a novel pattern count analysis to exhaustively enumerate and compare the number of promoters corresponding to the temporal binding patterns in ethanol and pair-fed control groups. The highest pattern count corresponded to promoters with NF-κB binding exclusively in the ethanol group at 1 h post PHx. This set was associated with the regulation of cell death, response to oxidative stress, histone modification, mitochondrial function, and metabolic processes. Integration with the global gene expression profiles to identify putative transcriptional consequences of NF-κB binding patterns revealed that several of ethanol-specific 1 h binding targets showed ethanol-specific differential expression through 6 h post PHx. Motif analysis yielded co-incident binding loci for STAT3, AP-1, CREB, C/EBP-β, PPAR-γ and C/EBP-α, likely participating in co-regulatory modules with NF-κB in shaping the immediate early response to PHx. We conclude that adaptation to chronic ethanol intake disrupts the NF-κB promoter binding landscape with consequences for the immediate early gene regulatory response to the acute challenge of PHx.

Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood.

PubMed

Kyzar, Evan J; Zhang, Huaibo; Sakharkar, Amul J; Pandey, Subhash C

2017-09-01

Alcohol exposure in adolescence is an important risk factor for the development of alcoholism in adulthood. Epigenetic processes are implicated in the persistence of adolescent alcohol exposure-related changes, specifically in the amygdala. We investigated the role of histone methylation mechanisms in the persistent effects of adolescent intermittent ethanol (AIE) exposure in adulthood. Adolescent rats were exposed to 2 g/kg ethanol (2 days on/off) or intermittent n-saline (AIS) during postnatal days (PND) 28-41 and used for behavioral and epigenetic studies. We found that AIE exposure caused a long-lasting decrease in mRNA and protein levels of lysine demethylase 1(Lsd1) and mRNA levels of Lsd1 + 8a (a neuron-specific splice variant) in specific amygdaloid structures compared with AIS-exposed rats when measured at adulthood. Interestingly, AIE increased histone H3 lysine 9 dimethylation (H3K9me2) levels in the central nucleus of the amygdala (CeA) and medial nucleus of the amygdala (MeA) in adulthood without producing any change in H3K4me2 protein levels. Acute ethanol challenge (2 g/kg) in adulthood attenuated anxiety-like behaviors and the decrease in Lsd1 + 8a mRNA levels in the amygdala induced by AIE. AIE caused an increase in H3K9me2 occupancy at the brain-derived neurotrophic factor exon IV promoter in the amygdala that returned to baseline after acute ethanol challenge in adulthood. These results indicate that AIE specifically modulates epizymes involved in H3K9 dimethylation in the amygdala in adulthood, which are possibly responsible for AIE-induced chromatin remodeling and adult psychopathology such as anxiety. © Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

The C1473G polymorphism in the Tryptophan hydroxylase-2 gene: involvement in ethanol-related behavior in mice.

PubMed

Bazovkina, Darya V; Lichman, Daria V; Kulikov, Alexander V

2015-03-04

Tryptophan hydroxylase-2 (Tph2) is the rate limiting enzyme of serotonin synthesis in the brain. The functional (C1473G) polymorphism in the mouse Tph2 gene affecting the enzymatic activity was suspected to be involved in behavioral actions of ethanol (EtOH). Congenic B6-1473C (C/C) and B6-1473G (G/G) lines bred from C57BL/6 mice were not different in EtOH-induced sleep time and hypothermia. B6-1473C mice displayed increased EtOH preference on the second and third days compared to that of the first day, but no differences in this parameter was found across genotypes. Both lines demonstrated the same responsiveness to hypothermic and hypnotic effect of acute EtOH treatment after repeated alcohol exposure. However, acute EtOH administration led to reduction of locomotor activity in B6-1473C, but not in B6-1473G animals and to increase of time spent in the center of open-field arena in B6-1473G, but not in B6-1473C mice. Thus, the present study indicates the involvement of C1473G polymorphism in mTph2 gene in the regulation of EtOH-induced effects on locomotor activity and anxiety-like behavior in mice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effects of Persea americana Mill (Lauraceae) ["Avocado"] ethanolic leaf extract on blood glucose and kidney function in streptozotocin-induced diabetic rats and on kidney cell lines of the proximal (LLCPK1) and distal tubules (MDBK).

PubMed

Gondwe, M; Kamadyaapa, D R; Tufts, M A; Chuturgoon, A A; Ojewole, J A O; Musabayane, C T

2008-01-01

Extracts of Persea americana Mill (Lauraceae) ("Avocado") have been traditionally used to treat hypertension and diabetes mellitus. Accordingly, we studied the hypoglycaemic and renal function effects of P. americana leaf ethanolic extracts (PAE) in STZ-induced diabetic rats. Oral glucose tolerance responses to various doses of PAE were monitored in fasted rats following a glucose load. Rats treated with deionized water or standard hypoglycaemic drugs acted as untreated and treated positive controls, respectively. Acute renal effects of PAE were investigated in anesthetized rats challenged with 0.077 M NaCl after a 3.5-h equilibration for 4 h comprising 1 h control, 1.5 h treatment and 1.5 h recovery periods. PAE was added to the infusate during the treatment period. Hepatic glycogen concentration was measured after 6 weeks of daily treatment with PAE. PAE induced dose-dependent hypoglycaemic responses in STZ-induced diabetic rats while subchronic PAE treatment additionally increased hepatic glycogen concentrations. Acute PAE infusion decreased urine flow and electrolyte excretion rates, whilst subchronic treatment reduced plasma creatinine and urea concentrations. These results indicate not only the basis of the ethnomedicinal use of P. americana leaf extract in diabetes management, but also of need for further studies to identify and evaluate the safety of PAE's bioactive compounds. (c) 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

Antidiabetic and antihyperlipidemic effects of Thespesia populnea fruit pulp extracts on alloxan-induced diabetic rats

PubMed Central

Belhekar, S. N.; Chaudhari, P. D.; Saryawanshi, J. S.; Mali, K. K.; Pandhare, R. B.

2013-01-01

Present study was carried to find out the antihyperglycemic and antihyperlipidemic activity of ethanol and aqueous extract of Thespesia populnea fruit pulp on alloxan-induced diabetic rats. Diabetes was induced in rats by administration of alloxan (150 mg/kg, i.p.). After the successful induction of experimental diabetes, the rats were divided into five groups each comprising a minimum of six rats. Phytochemical analysis and acute toxicity study of extracts was also done. The effects of extracts and metformin on fasting blood glucose and plasma lipid were examined for 28 days. Statistical analysis was carried out by using analysis of variance followed by Dunnet's multiple comparison test and paired t-test were done as the test of significance using GraphPad Prism. P≤0.05 was considered as the minimal level of statistical significance. Therapeutic dose of extract was found to be 200 mg/kg on the basis of acute toxicity study. Aqueous and alcoholic extract showed a significant reduction in blood glucose levels as well as a lipid profile of diabetic rats at the end of 28th day of treatment. However, in groups treated with plant extract the reduction in the blood glucose and improvement in lipid profile was slightly less than that achieved with the standard group (metformin). From this study, it can be concluded that ethanol and aqueous extract of Thespesia populnea exhibited significant antihyperglycemic and antihyperlipidemic effects on alloxan-induced diabetic rats. PMID:24019572

Influence of chronic ethanol consumption on toxic effects of 1,2-dichloroethane: glycolipoprotein retention and impairment of dolichol concentration in rat liver microsomes and Golgi apparatus.

PubMed

Cottalasso, Damiano; Domenicotti, Cinzia; Traverso, Nicola; Pronzato, Maria; Nanni, Giorgio

2002-09-16

Our previous investigations demonstrated that 1,2-dichloroethane (DCE) and chronic ethanol treatment separately are able to impair glycoprotein metabolism and secretion, and reduce dolichol concentration in liver membranes. The purpose of this study was to investigate whether chronic ethanol consumption can induce potentiation of rat liver damage due to DCE haloalkane used in several chemical processes and in agriculture. Rats were given 36% of their total energy as ethanol in the Lieber-DeCarli liquid diet for 8 weeks (CH group). The pair-fed control group received an isocaloric amount of dextrine-maltose (PF group). "In vitro" experiments: the DCE (6.5 mM) treatment of isolated hepatocytes from CH rats enhanced glycoprotein retention and further reduced glycoprotein secretion and 14C-glucosamine incorporation compared to the hepatocytes from CH or from PF and DCE treated rats. "In vivo" experiments: a marked decrease of dolichol concentration in microsomes (in which dolichyl phosphate is rate-limiting for the initial glycosylation of protein) and in Golgi membranes (in which total dolichol is very important for membrane permeability, fluidity and vesicle fusion) was observed in CH rats acutely treated with 628 mg/kg bw of DCE (CH+DCE) compared with CH or PF+DCE treated rats. These data suggest that chronic ethanol consumption increases DCE liver toxicity by affecting protein glycosylation processes and impairing glycolipoprotein secretion, with a concomitant retention at the level of the Golgi apparatus.

Ascorbic acid supplementation enhances recovery from ethanol induced inhibition of Leydig cell steroidogenesis than abstention in male guinea pigs.

PubMed

Radhakrishnakartha, Harikrishnan; Appu, Abhilash Puthuvelvippel; Indira, Madambath

2014-01-15

The impact of ascorbic acid supplementation against ethanol induced Leydig cell toxicity was studied in guinea pigs. Male guinea pigs were exposed to ethanol (4g/kgb.wt.) for 90 days. After 90 days, ethanol administration was completely stopped and animals in the ethanol group were divided into abstention group and ascorbic acid supplemented group (25mg/100gb.wt.) and those in control group were maintained as control and control+ascorbic acid group. Ethanol administration reduced the serum testosterone and LH (luteinising hormone) levels and elevated estradiol levels. Cholesterol levels in Leydig cell were increased whereas the mRNA and protein expressions of StAR (steroidogenic acute regulatory) protein, cytochrome P450scc (cytochrome p450side chain cleavage enzyme), 3β-HSD (3β-hydroxysteroid dehydrogenase), 17β-HSD (17β-hydroxysteroid dehydrogenase) and LH receptor were drastically reduced. Administration of ascorbic acid resulted in alteration of all these parameters indicating enhanced recovery from ethanol induced inhibition of Leydig cell steroidogenesis. Although abstention could also reduce the inhibition of steroidogenesis, this was lesser in comparison with ascorbic acid supplemented group. © 2013 Published by Elsevier B.V.

Contrasting influences of Drosophila white/mini-white on ethanol sensitivity in two different behavioral assays

PubMed Central

Chan, Robin F.; Lewellyn, Lara; DeLoyht, Jacqueline M.; Sennett, Kristyn; Coffman, Scarlett; Hewitt, Matthew; Bettinger, Jill C.; Warrick, John M.; Grotewiel, Mike

2014-01-01

Background The fruit fly Drosophila melanogaster has been used extensively to investigate genetic mechanisms of ethanol-related behaviors. Many past studies in flies, including studies from our laboratory, have manipulated gene expression using transposons carrying the genetic-phenotypic marker mini-white, a derivative of the endogenous gene white. Whether the mini-white transgenic marker or the endogenous white gene influence behavioral responses to acute ethanol exposure in flies has not been systematically investigated. Methods We manipulated mini-white and white expression via (i) transposons marked with mini-white, (ii) RNAi against mini-white and white and (iii) a null allele of white. We assessed ethanol sensitivity and tolerance using a previously described eRING assay (based on climbing in the presence of ethanol) and an assay based on ethanol-induced sedation. Results In eRING assays, ethanol-induced impairment of climbing correlated inversely with expression of the mini-white marker from a series of transposon insertions. Additionally, flies harboring a null allele of white or flies with RNAi-mediated knockdown of mini-white were significantly more sensitive to ethanol in eRING assays than controls expressing endogenous white or the mini-white marker. In contrast, ethanol sensitivity and rapid tolerance measured in the ethanol sedation assay were not affected by decreased expression of mini-white or endogenous white in flies. Conclusions Ethanol sensitivity measured in the eRING assay is noticeably influenced by white and mini-white, making eRING problematic for studies on ethanol-related behavior in Drosophila using transgenes marked with mini-white. In contrast, the ethanol sedation assay described here is a suitable behavioral paradigm for studies on ethanol sedation and rapid tolerance in Drosophila including those that use widely available transgenes marked with mini-white. PMID:24890118

Pregnane X Receptor-Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity.

PubMed

Spruiell, Krisstonia; Gyamfi, Afua A; Yeyeodu, Susan T; Richardson, Ricardo M; Gonzalez, Frank J; Gyamfi, Maxwell A

2015-09-01

Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females. U.S. Government work not protected by U.S. copyright.

Acute corticosterone sexually dimorphically facilitates social learning and inhibits feeding in mice.

PubMed

Choleris, Elena; Cazzin, Laura; Lymer, Jennifer M; Amor, Talya R; Lu, Ray; Kavaliers, Martin; Valsecchi, Paola

2013-12-01

In numerous species social learning is predominant and adaptive, yet, we know little of its neurobiological mechanisms. Social learning is modulated by motivations and emotions, in a manner that is often sexually dimorphic. Additionally, stress hormones acutely modulate the related social cognitive process of social recognition. Whether this is true even for social learning is currently unknown. We investigated the acute effects of the stress hormone corticosterone (CORT) on the social transmission of food preferences (STFP) in male and female mice. During a brief social interaction an observer (OBS) acquires a food preference from a same-sex demonstrator (DEM). CORT (1.0, 2.5, 5.0 mg/kg), its ethanol vehicle (0.1%), and saline solution (0.9%) were administered intraperitoneally to the OBS, 10 min before a 30-min social interaction. Levels of plasma CORT were assessed in other mice that had received the same doses of CORT and either had or had not gone through a 30 min social interaction 10 min post-treatment. Exogenous CORT elicited levels of plasma level comparable to those seen at the peak of the circadian cycle and facilitated the STFP with males responding more than females both in terms of the duration of the food preference and the minimum effective dose. CORT also sexually dimorphically inhibited feeding, with females showing a greater dose-response than males. Saline solution and ethanol vehicles also sexually dimorphically facilitated the STFP and reduced feeding, but less than CORT did. These results indicate that CORT facilitates social learning, like social recognition. Hence, CORT may generally increase social information processing. Copyright © 2013 Elsevier Ltd. All rights reserved.

CYP2E1 Potentiates Ethanol-induction of Hypoxia and HIF-1α in vivo

PubMed Central

Wang, Xiaodong; Wu, Defeng; Yang, Lili; Gan, Lixia; Cederbaum, Arthur I

2013-01-01

Ethanol induces hypoxia and elevates HIF-1α in the liver. CYP2E1 plays a role in the mechanisms by which ethanol generates oxidative stress, fatty liver and liver injury. The current study evaluated whether CYP2E1 contributes to ethanol-induced hypoxia and activation of HIF-1α in vivo and whether HIF-1α protects against or promotes CYP2E1-dependent toxicity in vitro. Wild type (WT), CYP2E1-knockin (KI) and CYP2E1 knockout (KO) mice were fed ethanol chronically; pair fed controls received isocaloric dextrose. Ethanol produced liver injury in the KI mice to a much greater extent than in the WT and KO mice. Protein levels of HIF-1α and downstream targets of HIF-1α activation were elevated in the ethanol-fed KI mice compared to the WT and KO mice. Levels of HIF prolylhydroxlase 2 which promotes HIF-1α degradation were decreased in the ethanol-fed KI mice in association with the increases in HIF-1α. Hypoxia occurred in the ethanol-fed CYP2E1 KI mice as shown by an increased area of staining using the hypoxia-specific marker pimonidazole. Hypoxia was lower in the ethanol-fed WT mice and lowest in the ethanol fed KO mice and all the dextrose-fed mice. In situ double staining showed that pimonidazole and CYP2E1 were co-localized to the same area of injury in the hepatic centrilobule. Increased protein levels of HIF-1α were also found after acute ethanol treatment of KI mice. Treatment of HepG2 E47 cells which express CYP2E1 with ethanol plus arachidonic (AA) acid or ethanol plus buthionine sulfoximine (BSO) which depletes GSH caused loss of cell viability to greater extent than in HepG2 C34 cells which do not express CYP2E1. These treatments elevated protein levels of HIF-1α to a greater extent in E47 cells than C34 cells. 2-Methoxyestradiol, an inhibitor of HIF-1α, blunted the toxic effects of ethanol plus AA and ethanol plus BSO in the E47 cells in association with inhibition of HIF-1α. The HIF-1α inhibitor also blocked the elevated oxidative stress produced by ethanol/AA or ethanol/BSO in the E47 cells. These results suggest that CYP2E1 plays a role in ethanol-induced hypoxia, oxidative stress and activation of HIF-1α and that HIF-1α contributes to CYP2E1-dependent ethanol-induced toxicity. Blocking HIF-1α activation and actions may have therapeutic implications for protection against ethanol/CYP2E1-induced oxidative stress, steatosis and liver injury. PMID:23669278

Ethanol teratogenesis in the C57BL/6J, DBA/2J, and A/J inbred mouse strains.

PubMed

Boehm, S L; Lundahl, K R; Caldwell, J; Gilliam, D M

1997-01-01

Research has shown variations in susceptibility to alcohol-related birth defects in humans. Genetic differences are one reason for this variability. This study compared three inbred mouse strains to determine whether they differ in their susceptibilities to ethanol teratogenesis because previous studies have generated conflicting data. Pregnant C57BL/6J (B6), DBA/2J (D2), and A/J (A) dams were intubated intragastrically with either an acute dose of ethanol (5.8 g/kg) or an isocaloric amount of maltose-dextrine on day 9 of pregnancy. Litters were removed on day 18 of pregnancy and examined for gross, soft-tissue, and skeletal malformations. Results showed that ethanol-exposed B6 litters had a higher percentage of digit (19%), kidney (24%), and skeletal (32%, mostly vertebral) malformations than their maltose-exposed controls (7% or below). Prenatal exposure to ethanol increased skeletal (68%, both rib and vertebral) malformations for A litters when compared to their maltose-exposed controls (4%), but did not increase digit or kidney malformations. Ethanol-exposed D2 litters did not differ from maltose-exposed controls. Maternal blood ethanol levels did not differ among the B6, D2, and A strains. These results provide additional evidence suggesting a genetic component to ethanol teratogenesis.

Piper umbellatum L.: A medicinal plant with gastric-ulcer protective and ulcer healing effects in experimental rodent models.

PubMed

da Silva Junior, Iberê Ferreira; Balogun, Sikiru Olaitan; de Oliveira, Ruberlei Godinho; Damazo, Amílcar Sabino; Martins, Domingos Tabajara de Oliveira

2016-11-04

Piper umbellatum L. (Piperaceae) is a shrub found in the Amazon, Savannah and Atlantic Forest region of Brazil. It is widely used in folk medicine in many countries primarily for the treatment of gastric disorders. The aim of this study was to evaluate the gastroprotective and anti-ulcer effects of hydroethanolic extract of P. umbellatum (HEPu) leaves in experimental rodents. In addition, the anti-Helicobacter pylori activity of the extract was assessed. The leaves of P. umbellatum were macerated in 75% (1:3w/v) hydroethanolic solution to obtain HEPu. The gastroprotective and ulcer healing activities of HEPu were evaluated using acidified ethanol (acute) and acetic acid (chronic) gastric ulcer models in rodents. The anti-H. pylori activity was evaluated by in vitro broth microdilution assay using H. pylori cagA + and vacA + strain. The probable mechanism of action of HEPu was evaluated by determining gastric secretory parameters, antioxidant enzyme (catalase), non-protein sulfhydryl (glutathione) and malondialdehyde levels in gastric tissue, including pro-inflammatory (IL-1β, TNF-a, IL -17, RANTES, IFN-γ and MIP-2) and anti-inflammatory (IL-10) cytokines. HEPu demonstrated potent gastroprotection against acute ulcer induced by acidified ethanol and excellent healing effect of the chronic ulcer induced by acetic acid. The gastroprotective activity in acidified ethanol is partly attributed to the antioxidant mechanisms, while anti-secretory, anti-inflammatory and regeneration of the gastric mucosa are evoked as part of its antiulcer mechanism of action. The gastric ulcer healing of HEPu also involves restoration of the altered cytokines levels to near normal. However, it has no in vitro anti-H. pylori activity. The results of this study showed that HEPu possesses preventive and curative effects in experimental models of gastric ulcers in animals. These effects are partially dependent on antioxidant, antisecretory, anti-inflammatory and mucosa regeneration. It is independent of anti-H. pylori activity, with substances probably responsible for the pharmacological activity being flavonoids, quercetin and rutin. These results support the popular use of P. umbellatum leaves in the treatment of peptic ulcers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Phytochemistry, Brine shrimp lethality and mice acute oral toxicity studies on seed extracts of Vernonia anthelmintica.

PubMed

Jamil, Subia; Khan, Rafeeq Alam; Afroz, Syeda; Ahmed, Shadab

2016-11-01

Despite the widespread use of Vernonia anthelmintica seeds in traditional medicine, the need to establish the safety of the Vernonia anthelmintica is required to ascertain the safe use of this herbal medicine. The aim of the present study is to establish the acute toxicity profile of different extracts of Vernonia anthelmintica. Hexane and ethanol extract of Vernonia Anthelmintica has been studied for its brine shrimp lethality potential. Water decoction (WDVA), Hexane (HEVA) and Ethanol (EEVA) extracts of Vernonia anthelmintica has also been evaluated for their in-vivo acute oral toxicity in mice by Lorke's method. Phytochemistry of all three extracts was also evaluated for the presence of their secondary metabolites. All three extracts showed the presence of flavonoids and terpenoids, while alkaloids, tannins and fixed oils were present in HEVA and EEVA. Furthermore EEVA also showed presence of carbohydrates and HEVA also showed the presence of cardiac glycosides. Ethanol and hexane extracts of Vernonia anthelmintica showed a positive cytotoxicity in brine shrimp lethality test at 24 hours with LC50 104.16 (224.0-48.05)μg/ml and 216.11μg/ml (378.2-128.7) respectively as compared to standard drug etoposide LC50 7.46μg/ml. The oral LD50 for EEVA, HEVA and WDVA in mice by Lorke's method was greater than 5000mg/kg. The result of brine shrimp lethality test clearly exhibited the presence of bioactive compounds with cytotoxic potential; however seems to be safe for oral use since LD50 was higher than 5000mg/kg and thus safety of acute dosing in vivo practices is justified.

[Carbohydrate metabolism in acute poisoning with xenobiotics].

PubMed

Pach, Dorota; Szurkowska, Magdalena; Szafraniec, Krystyna; Targosz, Dorota; Sułek, Monika; Kamenczak, Aleksandra; Huszno, Bohdan

2007-01-01

The aim of the study was to evaluate carbohydrate metabolism in patients hospitalised because of acute intoxication with xenobiotics. An analysis of 3628 patients (1553 females and 2075 males; age: 40.6 +/- 15.9 y) hospitalized at the Ward of Toxicology and Environmental Diseases because of acute poisoning in 2004-2006 was done. The patients with diabetes mellitus diagnosed prior to hospitalisation were excluded from the analysis. The blood ethanol concentration was measured, medication drugs and/or psychoactive substance screening test were performed in all patients on admission. Fasting glucose level on admission and control level on second or third day of hospitalisation were determined. Risk ratio of hyperglycaemia according to toxic agent was assessed using multiple regression model considering age, gender, and the patient education. In 18.2% (398 males and 254 females) of the patients the blood glucose level on admission was > or = 7.8 mmol/l; in u 3.6% (78 males and 50 females) > or = 11.1 mmol/l. In 24 (0.6%) of the patients glycaemia on admission was < or = 3.5 mmol/l. Control fasting glucose level of > or = 7.0 mmol/l was determined in 115 males and 76 female patients. 42% elevation in risk of hyperglycaemia was noted in acute carbon monoxide poisoning (OR = 1.42; 95% PU: 1.11-1.82). In ethanol intoxicated patients 12% drop in risk of hyperglycaemia was noted (OR = 0.88; 95% PU: 0.72-1.07). Benzodiazepine poisoning diminished risk of hyperglycaemia in 36% (OR=0.64; 95%PU: 0.48-0.84). Risk of hyperglycaemia in poisoning by medicines co-ingested with ethanol was always lower compared to poisoning with the single agent. A higher risk of hyperglycaemia was related to acute carbon monoxide poisoning whereas lower risk of hyperglycaemia was attributed to benzodiazepines and alcohol. A frequency of hypoglycaemia in the group of poisoned patients was much more lower compared to hyperglycaemia.

The anesthetic action of ethanol analyzed by genetics in Caenorhabditis elegans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Mingi; Choi, Myung Kyu; Lee, Junho

2008-02-29

Acute exposure to ethanol causes paralysis at high concentrations in the nematode Caenorhabditis elegans. We set out to elucidate the mechanism of the anesthetic action of ethanol by genetic approaches. We identified nine mutations that conferred reduced sensitivity to ethanol after chemical, irradiation, or transposon insertion mutagenesis. Of these nine, we further characterized five mutations that defined four genes, jud-1-jud-4. Analysis of the phenotypes of the animals heterozygous for two unlinked genes revealed that jud-1 and jud-3 act synergistically in a gene dose-dependent manner. We cloned jud-4 and found that it encodes a protein with limited homology to human Homermore » proteins. jud-4 was expressed in the hypodermis and vulva muscles, suggesting that this gene acts in tissues directly exposed to the external environment. Characterization of the other mutations identified in this study will facilitate the elucidation of the molecular mechanism for the anesthetic action of ethanol.« less

Ocimum basilicum ethanolic extract decreases cholesterol synthesis and lipid accumulation in human macrophages.

PubMed

Bravo, Elena; Amrani, Souliman; Aziz, Mohammed; Harnafi, Hicham; Napolitano, Mariarosaria

2008-12-01

Macrophage lipid accumulation induced by low density lipoproteins (LDL) plays a pivotal role in atherosclerotic plaque development. Previous work showed that Ocimum basilicum extract, used as hypocholesterolemic agent by traditional medicine in Morocco, has hypolipidemic activity in rat acute hyperlipimidemia. This study investigated the effects of ethanolic extract of O. basilicum on lipid accumulation in human macrophages. As modification of LDL increase atherogenicity of the particles we evaluated the effects of the extract on LDL oxidation. The extract caused a dose-related increase of LDL-resistance to Cu(2+)-induced oxidation. Furthermore, at the dose of 60 microg/ml, significantly decreases the accumulation of macrophage lipid droplets induced by modified LDL evaluated as by red-oil staining. Cholesterol esterification and triacylglycerol synthesis in the cells were not affected. Macrophage treatment with 60 microg/ml, but not 20 microg/ml, of the extract reduced newly synthesized unesterified cholesterol by about 60% and decreased scavenger receptors activity by about 20-30%, evaluated by the internalization of cholesterol carried by [(3)H]CE-aggregated-LDL. The results suggest that O. basilicum ethanolic extract has the capability to reduce foam cell formation through the reduction of cholesterol synthesis and the modulation of the activity of surface scavenger receptors.

Alcohol reversibly disrupts TNF-α/TACE interactions in the cell membrane

PubMed Central

Song, Kejing; Zhao, Xue-Jun; Marrero, Luis; Oliver, Peter; Nelson, Steve; Kolls, Jay K

2005-01-01

Background Alcohol abuse has long been known to adversely affect innate and adaptive immune responses and pre-dispose to infections. One cellular mechanism responsible for this effect is alcohol-induced suppression of TNF-α (TNF) by mononuclear phagocytes. We have previously shown that alcohol in part inhibits TNF-α processing by TNF converting enzyme (TACE) in human monocytes. We hypothesized that the chain length of the alcohol is critical for post-transcriptional suppression of TNF secretion. Methods Due to the complex transcriptional and post-transcriptional regulation of TNF in macrophages, to specifically study TNF processing at the cell membrane we performed transient transfections of A549 cells with the TNF cDNA driven by the heterologous CMV promoter. TNF/TACE interactions at the cell surface were assessed using fluorescent resonance energy transfer (FRET) microscopy. Results The single carbon alcohol, methanol suppressed neither TNF secretion nor FRET efficiency between TNF and TACE. However, 2, 3, and 4 carbon alcohols were potent suppressors of TNF processing and FRET efficiency. The effect of ethanol, a 2-carbon alcohol was reversible. Conclusion These data show that inhibition of TNF-α processing by acute ethanol is a direct affect of ethanol on the cell membrane and is reversible upon cessation or metabolism. PMID:16246259

Heterogeneity of p53 dependent genomic responses following ethanol exposure in a developmental mouse model of fetal alcohol spectrum disorder

PubMed Central

Mooney, Sandra M.; Middleton, Frank A.

2017-01-01

Prenatal ethanol exposure can produce structural and functional deficits in the brain and result in Fetal Alcohol Spectrum Disorder (FASD). In rodent models acute exposure to a high concentration of alcohol causes increased apoptosis in the developing brain. A single causal molecular switch that signals for this increase in apoptosis has yet to be identified. The protein p53 has been suggested to play a pivotal role in enabling cells to engage in pro-apoptotic processes, and thus figures prominently as a hub molecule in the intracellular cascade of responses elicited by alcohol exposure. In the present study we examined the effect of ethanol-induced cellular and molecular responses in primary somatosensory cortex (SI) and hippocampus of 7-day-old wild-type (WT) and p53-knockout (KO) mice. We quantified apoptosis by active caspase-3 immunohistochemistry and ApopTag™ labeling, then determined total RNA expression levels in laminae of SI and hippocampal subregions. Immunohistochemical results confirmed increased incidence of apoptotic cells in both regions in WT and KO mice following ethanol exposure. The lack of p53 was not protective in these brain regions. Molecular analyses revealed a heterogeneous response to ethanol exposure that varied depending on the subregion, and which may go undetected using a global approach. Gene network analyses suggest that the presence or absence of p53 alters neuronal function and synaptic modifications following ethanol exposure, in addition to playing a classic role in cell cycle signaling. Thus, p53 may function in a way that underlies the intellectual and behavioral deficits observed in FASD. PMID:28723918

Ethanol affects acylated and total ghrelin levels in peripheral blood of alcohol-dependent rats.

PubMed

Szulc, Michal; Mikolajczak, Przemyslaw L; Geppert, Bogna; Wachowiak, Roman; Dyr, Wanda; Bobkiewicz-Kozlowska, Teresa

2013-07-01

There is a hypothesis that ghrelin could take part in the central effects of alcohol as well as function as a peripheral indicator of the changes which occur during long-term alcohol consumption. The aim of this study was to determine a correlation between alcohol concentration and acylated and total form of ghrelin after a single administration of alcohol (intraperitoneal, i.p.) (experiment 1) and prolonged ethanol consumption (experiment 2). The study was performed using Wistar alcohol preferring (PR) and non-preferring (NP) rats and rats from inbred line (Warsaw High Preferring, WHP; Warsaw Low Preferring, WLP). It was found that ghrelin in ethanol-naive WHP animals showed a significantly lower level when compared with the ethanol-naive WLP or Wistar rats. After acute ethanol administration in doses of 1.0; 2.0 and 4.0 g/kg, i.p., the simple (WHP) or inverse (WLP and Wistar) relationship between alcohol concentration and both form of ghrelin levels in plasma were found. Chronic alcohol intake in all groups of rats led to decrease of acylated ghrelin concentration. PR and WHP rats, after chronic alcohol drinking, had lower levels of both form of ghrelin in comparison with NP and WLP rats, respectively, and the observed differences in ghrelin levels were in inverse relationship with their alcohol intake. In conclusion, it is suggested that there is a strong relationship between alcohol administration or intake, ethanol concentration in blood and both active and total ghrelin level in the experimental animals, and that ghrelin plasma concentration can be a marker of alcohol drinking predisposition. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.

A study of antimicrobial activity, acute toxicity and cytoprotective effect of a polyherbal extract in a rat ethanol-HCl gastric ulcer model

PubMed Central

2012-01-01

Background The decoction of the aerial parts of Rhynchosia recinosa (A.Rich.) Bak. [Fabaceae] is used in combination with the stem barks of Ozoroa insignis Del. (Anacardiaceae), Maytenus senegalensis (Lam.) Excell. [Celastraceae] Entada abyssinica Steud. ex A.Rich [Fabaceae] and Lannea schimperi (Hochst.)Engl. [Anacardiaceae] as a traditional remedy for managing peptic ulcers. However, the safety and efficacy of this polyherbal preparation has not been evaluated. This study reports on the phytochemical profile and some biological activities of the individual plant extracts and a combination of extracts of the five plants. Methods A mixture of 80% ethanol extracts of R. recinosa, O. insignis, M. senegalensis, E. abyssinica and L. schimperi at doses of 100, 200, 400 and 800 mg/kg body wt were evaluated for ability to protect Sprague Dawley rats from gastric ulceration by an ethanol-HCl mixture. Cytoprotective effect was assessed by comparison with a negative control group given 1% tween 80 in normal saline and a positive control group given 40 mg/kg body wt pantoprazole. The individual extracts and their combinations were also tested for antibacterial activity against four Gram negative bacteria; Escherichia coli (ATCC 25922), Salmonella typhi (NCTC 8385), Vibrio cholerae (clinical isolate), and Klebsiella pneumoniae (clinical isolate) using the microdilution method. In addition the extracts were evaluated for brine shrimp toxicity and acute toxicity in mice. Phytochemical tests were done using standard methods to determine the presence of tannins, saponins, steroids, cardiac glycosides, flavonoids, alkaloids and terpenoids in the individual plant extracts and in the mixed extract of the five plants. Results The combined ethanolic extracts of the 5 plants caused a dose-dependent protection against ethanol/HCl induced ulceration of rat gastric mucosa, reaching 81.7% mean protection as compared to 87.5% protection by 40 mg/kg body wt pantoprazole. Both the individual plant extracts and the mixed extracts of 5 plants exhibited weak to moderate antibacterial activity against four G-ve bacteria. Despite Ozoroa insignis being toxic to mice at doses above 1000 mg/kg body wt, the other plant extracts and the combined extract of the 5 plants were tolerated by mice up to 5000 mg/kg body wt. The brine shrimp test results showed the same pattern of toxicity with Ozoroa insignis being the most toxic (LC50 = 10.63 μg/ml). Phytochemical tests showed that the combined extract of the five plants contained tannins, saponins, steroids, cardiac glycosides, flavonoids and terpenoids. Flavonoids, tannins and terpenoids are known to have antioxidant activity. Conclusion The combined extract of the five plants exhibited a dose-dependent protective activity in the rat ethanol-HCl gastric ulcer model. The extracts also exhibited weak antibacterial activity against four Gram negative bacteria and low acute toxicity in mice and brine shrimps. Although the results support claims by traditional healers who use a decoction of the five plants for treatment of peptic ulcers, more models of gastric ulceration and proper animal toxicity studies are needed to validate possible clinical use of the polyherbal extract. It is also evident that the doses of the crude extracts showing protection of the gastric mucosa are too large for realistic translation to direct clinical application, but further studies using bioassay guided fractionation are important to either identify more practical fractions or active compound/s. PMID:23031266

Design of ultra-compact composite plasmonic Mach-Zehnder interferometer for chemical vapor sensing

NASA Astrophysics Data System (ADS)

Ghosh, Souvik; Rahman, B. M. A.

2018-02-01

Following the Industrial advancements in the last few decades, highly flammable chemicals, such as ethanol (CH3CH2OH) and methanol (CH3OH) are widely being used in daily life. Ethanol have some degrees of carcinogenic effects in human whereas acute and chronic exposer of methanol results blurred vision and nausea. Therefore, accurate and efficient sensing of these two vapors in industrial environment are of high priorities. We have designed a novel, ultra-compact chemical vapor sensor based on composite plasmonic horizontal slot waveguide (CPHSW) where a low-index porous-ZnO (P-ZnO) layer is sandwiched in between top silver metal and lower silicon layers. Different P-ZnO templates, such as nano-spheres, nano-sheets and nanoplates could be used for high-selectivity of ethanol and methanol at different temperatures. The Lorentz-Lorenz model is used to determine the variation of P-ZnO refractive index (RI) with porosity and equivalent RI of P-ZnO layer for capillary condensation of different percentage of absorbed vapor. An in-house, new divergence modified finite element method is used to calculate effective index and attenuation sensitivity. Plasmonic modal analyses of dominant quasi-TM mode shows a high 42% power confinement in the slot. Next, an ultra-compact MZI incorporating a few micrometres long CPHSW is designed and analysed as a transducer device for accurate detection of effective index change. The device performance has been studied for different percentage of ethanol into P-ZnO with different porosity and a maximum phase sensitivity of >0.35 a.u. is achieved for both the chemical vapors at a mid-IR operating wavelength of 1550 nm.

Disentangling the role of astrocytes in alcohol use disorder

PubMed Central

Adermark, Louise; Bowers, M. Scott

2016-01-01

Several laboratories recently identified that astrocytes are critical regulators of addiction machinery. It is now known that astrocyte pathology is a common feature of ethanol exposure in both humans and animal models, as even brief ethanol exposure is sufficient to elicit long-lasting perturbations in astrocyte gene expression, activity, and proliferation. Astrocytes were also recently shown to modulate the motivational properties of ethanol and other strongly reinforcing stimuli. Given the role of astrocytes in regulating glutamate homeostasis, a crucial component of alcohol use disorder, astrocytes might be an important target for the development of next generation alcoholism treatments. This review will outline some of the more prominent features displayed by astrocytes, how these properties are influenced by acute and long term ethanol exposure, and future directions that may help to disentangle astrocytic from neuronal functions in the etiology of alcohol use disorder. PMID:27476876

Schiff base metal derivatives enhance the expression of HSP70 and suppress BAX proteins in prevention of acute gastric lesion.

PubMed

Golbabapour, Shahram; Gwaram, Nura Suleiman; Al-Obaidi, Mazen M Jamil; Soleimani, A F; Ali, Hapipah Mohd; Abdul Majid, Nazia

2013-01-01

Schiff base complexes have appeared to be promising in the treatment of different diseases and disorders and have drawn a lot of attention to their biological activities. This study was conducted to evaluate the regulatory effect of Schiff base metal derivatives on the expression of heat shock proteins (HSP) 70 and BAX in protection against acute haemorrhagic gastric ulcer in rats. Rats were assigned to 6 groups of 6 rats: the normal control (Tween 20 5% v/v, 5 mL/kg), the positive control (Tween 20 5% v/v, 5 mL/kg), and four Schiff base derivative groups named Schiff_1, Schiff_2, Schiff_3, and Schiff_4 (25 mg/kg). After 1 h, all of the groups received ethanol 95% (5 mL/kg) but the normal control received Tween 20 (Tween 20 5% v/v, 5 mL/kg). The animals were euthanized after 60 min and the stomachs were dissected for histology (H&E), immunohistochemistry, and western blot analysis against HSP70 and BAX proteins. The results showed that the Schiff base metal derivatives enhanced the expression of HSP70 and suppressed the expression of BAX proteins during their gastroprotection against ethanol-induced gastric lesion in rats.

Schiff Base Metal Derivatives Enhance the Expression of HSP70 and Suppress BAX Proteins in Prevention of Acute Gastric Lesion

PubMed Central

Gwaram, Nura Suleiman; Al-Obaidi, Mazen M. Jamil; Soleimani, A. F.; Ali, Hapipah Mohd; Abdul Majid, Nazia

2013-01-01

Schiff base complexes have appeared to be promising in the treatment of different diseases and disorders and have drawn a lot of attention to their biological activities. This study was conducted to evaluate the regulatory effect of Schiff base metal derivatives on the expression of heat shock proteins (HSP) 70 and BAX in protection against acute haemorrhagic gastric ulcer in rats. Rats were assigned to 6 groups of 6 rats: the normal control (Tween 20 5% v/v, 5 mL/kg), the positive control (Tween 20 5% v/v, 5 mL/kg), and four Schiff base derivative groups named Schiff_1, Schiff_2, Schiff_3, and Schiff_4 (25 mg/kg). After 1 h, all of the groups received ethanol 95% (5 mL/kg) but the normal control received Tween 20 (Tween 20 5% v/v, 5 mL/kg). The animals were euthanized after 60 min and the stomachs were dissected for histology (H&E), immunohistochemistry, and western blot analysis against HSP70 and BAX proteins. The results showed that the Schiff base metal derivatives enhanced the expression of HSP70 and suppressed the expression of BAX proteins during their gastroprotection against ethanol-induced gastric lesion in rats. PMID:24298554

Antimicrobial activity, acute toxicity and cytoprotective effect of Crassocephalum vitellinum (Benth.) S. Moore extract in a rat ethanol-HCl gastric ulcer model

PubMed Central

2014-01-01

Background A decoction of Crassocephallum vitellinum (Benth.) S. Moore (Asteraceae) is used in Kagera Region to treat peptic ulcers. This study seeks to evaluate an aqueous ethanol extract of aerial parts of the plant for safety and efficacy. Methods An 80% ethanolic extract of C. vitellinum at doses of 100, 200, 400 and 800 mg/kg body wt was evaluated for ability to protect Sprague Dawley rats from acidified ethanol gastric ulceration in comparison with 40 mg/kg body wt pantoprazole. The extract and its dichloromethane, ethyl acetate, and aqueous fractions were also evaluated for acute toxicity in mice, brine shrimp toxicity, and antibacterial activity against four Gram negative bacteria; Escherichia coli (ATCC 25922), Salmonella typhi (NCTC 8385), Vibrio cholera (clinical isolate), and Streptococcus faecalis (clinical isolate). The groups of phytochemicals present in the extract were also determined. Results The ethanolic extract of C. vitellinum dose-dependently protected rat gastric mucosa against ethanol/HCl insult to a maximum of 88.3% at 800 mg/kg body wt, affording the same level of protection as by 40 mg/kg body wt pantoprazole. The extract also exhibited weak antibacterial activity against S. typhi and E. coli, while its ethyl acetate, dichloromethane and aqueous fractions showed weak activity against K. pneumonia, S.typhi, E. coli and V. cholera. The extract was non-toxic to mice up to 5000 mg/kg body wt, and the total extract (LC50 = 37.49 μg/ml) and the aqueous (LC50 = 87.92 μg/ml), ethyl acetate (LC50 = 119.45 μg/ml) and dichloromethane fractions (88.79 μg/ml) showed low toxicity against brine shrimps. Phytochemical screening showed that the extract contains tannins, saponins, flavonoids, and terpenoids. Conclusion The results support the claims by traditional healers that a decoction of C.vitellinum has antiulcer activity. The mechanism of cytoprotection is yet to be determined but the phenolic compounds present in the extract may contribute to its protective actions. However, the dose conferring gastro-protection in the rat is too big to be translated to clinical application; thus bioassay guided fractionation to identify active compound/s or fractions is needed, and use of more peptic ulcer models to determine the mechanism for the protective action. PMID:24552147

The BIOSAFEPAPER project for in vitro toxicity assessments: preparation, detailed chemical characterisation and testing of extracts from paper and board samples.

PubMed

Bradley, E L; Honkalampi-Hämäläinen, U; Weber, A; Andersson, M A; Bertaud, F; Castle, L; Dahlman, O; Hakulinen, P; Hoornstra, D; Lhuguenot, J-C; Mäki-Paakkanen, J; Salkinoja-Salonen, M; Speck, D R; Severin, I; Stammati, A; Turco, L; Zucco, F; von Wright, A

2008-07-01

Nineteen food contact papers and boards and one non-food contact board were extracted following test protocols developed within European Union funded project BIOSAFEPAPER. The extraction media were either hot or cold water, 95% ethanol or Tenax, according to the end use of the sample. The extractable dry matter content of the samples varied from 1200 to 11,800 mg/kg (0.8-35.5 mg/dm2). According to GC-MS the main substances extracted into water were pulp-derived natural products such as fatty acids, resin acids, natural wood sterols and alkanols. Substances extracted into ethanol particularly, were diisopropylnaphthalenes, alkanes and phthalic acid esters. The non-food contact board showed the greatest number and highest concentrations of GC-MS detectable compounds. The extracts were subjected to a battery of in vitro toxicity tests measuring both acute and sublethal cytotoxicity and genotoxic effects. None of the water or Tenax extracts was positive in cytotoxicity or genotoxicity assays. The ethanol extract of the non-food contact board gave a positive response in the genotoxicity assays, and all four ethanol extracts gave positive response(s) in the cytotoxicity assays to some extent. These responses could not be pinpointed to any specific compound, although there appeared a correlation between the total amount of extractables and toxicity.

Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain

PubMed Central

Saito, Mitsuo; Chakraborty, Goutam; Shah, Relish; Mao, Rui-Fen; Kumar, Asok; Yang, Dun-Sheng; Dobrenis, Kostantin; Saito, Mariko

2012-01-01

GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase-3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase-3 activation in the 7-day–old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration. PMID:22372857

Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice.

PubMed

Stragier, E; Martin, V; Davenas, E; Poilbout, C; Mongeau, R; Corradetti, R; Lanfumey, L

2015-12-15

Acute or chronic administrations of high doses of ethanol in mice are known to produce severe cognitive deficits linked to hippocampal damage. However, we recently reported that chronic and moderate ethanol intake in C57BL/6J mice induced chromatin remodeling within the Bdnf promoters, leading to both enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal neurogenesis under free-choice protocol. We performed here a series of cellular and behavioral studies to analyze the consequences of these modifications. We showed that a 3-week chronic free-choice ethanol consumption in C57BL/6J mice led to a decrease in DNA methylation of the Bdnf gene within the CA1 and CA3 subfields of the hippocampus, and upregulated hippocampal BDNF signaling pathways mediated by ERK, AKT and CREB. However, this activation did not affect long-term potentiation in the CA1. Conversely, ethanol intake impaired learning and memory capacities analyzed in the contextual fear conditioning test and the novel object recognition task. In addition, ethanol increased behavioral perseveration in the Barnes maze test but did not alter the mouse overall spatial capacities. These data suggested that in conditions of chronic and moderate ethanol intake, the chromatin remodeling leading to BDNF signaling upregulation is probably an adaptive process, engaged via epigenetic regulations, to counteract the cognitive deficits induced by ethanol.

Cardio-pulmonary effects of inhaled solvents: computer-assisted measurement and analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Engwall, M.J.

The physiological effects of the inhalation of three solvent vapors were measured on anesthetized dogs. The tested solvents were: acetone, ethanol, and toluene. Measurements of respiratory mechanics, pulmonary and systemic hemodynamics, cardiac output, and gas-exchange were taken while exposing the animals to the vaporized solvents. After the exposures, the animals were terminated and lung tissue and alveolar lining material (ALM) were collected. The ALM was analyzed by high performance liquid chromatography for the amounts of component phospholipids. The tissues were inspected under light microscopy for evidence of acute damage associated with the solvent exposures.

Immunomodulatory effect of Moringa peregrina leaves, ex vivo and in vivo study

PubMed Central

Al-Oran, Sawsan Atallah; Hassuneh, Mona Rushdie; Al-Qaralleh, Haitham Naief; Rayyan, Walid Abu; Al-Thunibat, Osama Yosef; Mallah, Eyad; Abu-Rayyan, Ahmed; Salem, Shadi

2017-01-01

This study was conducted to assess the in vivo and ex vivo immunomodulatory effect of the ethanol leaves extract of Moringa peregrina in Balb/c mice. For this study, five groups of 5 Balb/c mice were given a single acute subtoxic oral dose of the ethanolic extract at 1.13, 11.30, 23.40 and 113.4 mg/kg and the immunomodulatory effect was assessed on the 6th day following the ingestion. In the (non-functional) assessment, the effect of the extract on the body weight, relative lymphoid organ weight, splenic cellularity and peripheral blood hematologic parameters were evaluated. While in the immunomodulation assessment (functional), we investigated the effect of the extract on the proliferative capacity of splenic lymphocytes and peripheral T and B lymphocytes using mitogen blastogenesis, mixed allogeneic MLR and IgM-Plaque forming cells assays. The ingestion of M. peregrina extract caused a significant increase in the body weight, weight and number of cells of spleen and lymph nodes of the treated mice. Furthermore, the count of RBCs, WBCs, platelets, hemoglobin concentration and PCV % were increased by the extract treatment in a dose-dependent manner. M. peregrina enhanced the proliferative responses of splenic lymphocytes for both T cell and B-cell mitogens. Likewise, the mixed lymphocyte reaction MLR assay has revealed a T-cell dependent proliferation enhancement in the extract treated mice. Moreover, the oral administration of M. peregrina leaves extracts significantly increased PFCs/106 splenocytes in a dose-dependent manner. In conclusion, subtoxic acute doses of M. peregrina extract demonstrated significant potential as an immunomodulatory agent even at the lowest dose of 1.13 mg/kg. PMID:29204086

[The influence of alcohol on the oral cavity, salivary glands and saliva].

PubMed

Waszkiewicz, Napoleon; Zalewska, Anna; Szulc, Agata; Kepka, Alina; Konarzewska, Beata; Zalewska-Szajda, Beata; Chojnowska, Sylwia; Waszkiel, Danuta; Zwierz, Krzysztof

2011-01-01

Ethanol diffuses rapidly into saliva during the drinking, and immediately after its salivary concentration is temporarily much higher than in plasma. Within 30 minutes, salivary ethanol concentration equilibrates with the plasma level, thus suggesting that ethanol easily penetrates the whole body, including oral cavity tissues and salivary glands. After alcohol intake, the level of acetaldehyde in saliva strikingly exceeds the level in systemic blood. From saliva, acetaldehyde and ethanol easily reach all local tissues. Damage to the oral tissues seems to be ascribed mostly to the action of acetaldehyde, although some acute effects depend on a direct action of ethanol and formation of reactive oxygen species (ROS) and fatty acid ethyl esters (FAEEs). It is known that the oral mucosal surface is the home of numerous normal flora microorganisms and is the portal of entry for the majority of pathogens. The oral cavity and salivary antimicrobial immune defense systems eliminate pathogens and prevent massive overgrowth of microorganisms. An oral defense system participate in the protection of not only oral tissues, but also in the protection of upper digestive and respiratory tracts, against a number of microbial pathogens. Saliva plays the role in the oral cavity lubrication, maintenance of mucosal and tooth integrity, esophageal physiology, digestion and gastric cytoprotection. As alcohol abuse affects the structure and function of oral cavity mucosa, salivary glands and saliva, the maintenance of oral and general health under normal conditions is seriously impaired during the drinking. The severe tissue damage occurs in particular when alcohol abuse coincides with smoking.

Zingiber officinale Roscoe prevents acetaminophen-induced acute hepatotoxicity by enhancing hepatic antioxidant status.

PubMed

Ajith, T A; Hema, U; Aswathy, M S

2007-11-01

A large number of xenobiotics are reported to be potentially hepatotoxic. Free radicals generated from the xenobiotic metabolism can induce lesions of the liver and react with the basic cellular constituents - proteins, lipids, RNA and DNA. Hepatoprotective activity of aqueous ethanol extract of Zingiber officinale was evaluated against single dose of acetaminophen-induced (3g/kg, p.o.) acute hepatotoxicity in rat. Aqueous extract of Z. officinale significantly protected the hepatotoxicity as evident from the activities of serum transaminase and alkaline phosphatase (ALP). Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and ALP activities were significantly (p<0.01) elevated in the acetaminophen alone treated animals. Antioxidant status in liver such as activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase and glutathione-S-transferase (GST), a phase II enzyme, and levels of reduced glutathione (GSH) were declined significantly (p<0.01) in the acetaminophen alone treated animals (control group). Hepatic lipid peroxidation was enhanced significantly (p<0.01) in the control group. Administration of single dose of aqueous extract of Z. officinale (200 and 400mg/kg, p.o.) prior to acetaminophen significantly declines the activities of serum transaminases and ALP. Further the hepatic antioxidant status was enhanced in the Z. officinale plus acetaminophen treated group than the control group. The results of the present study concluded that the hepatoprotective effect of aqueous ethanol extract of Z. officinale against acetaminophen-induced acute toxicity is mediated either by preventing the decline of hepatic antioxidant status or due to its direct radical scavenging capacity.

Effects of Ethanol on Phosphorylation Site Mutants of Recombinant NMDA Receptors

PubMed Central

Xu, Minfu; Smothers, Corigan T.; Woodward, John J.

2010-01-01

N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels activated by the neurotransmitter glutamate. These channels are highly expressed by brain neurons and are critically involved in excitatory synaptic transmission. Results from previous studies show that both native and recombinant NMDA receptors are inhibited by ethanol at concentrations associated with signs of behavioral impairment and intoxication. Given the important role that NMDA receptors play in synaptic transmission and brain function, it is important to understand the factors that regulate the ethanol inhibition of these receptors. One dynamic mechanism for regulating ethanol action may be via phosphorylation of NMDA subunits by serine-threonine and tyrosine kinases. Both NR1 and NR2 subunits contain multiple sites of phosphorylation and in the NR1 subunit, most of these are contained within the C1 domain, a carboxy-terminal cassette that is subject to alternative splicing. While results from our previous studies suggest that single phosphorylation sites do not greatly affect ethanol sensitivity of NMDA receptors, it is likely that in vivo, these subunits are phosphorylated at multiple sites by different kinases. In the present study, we constructed a series of NMDA receptor mutants at serine (S) or threonine (T) residues proposed to be sites of phosphorylation by PKA and various isoforms of PKC. Ethanol (100 mM) inhibited currents from wild-type NR1/2A and NR1/2B receptors expressed in HEK293 cells by approximately 25% and 30% respectively. This inhibition was not different in single site mutants expressing alanine (A) or aspartate/glutamate (D/E) at positions T879, S896 or T900. The mutant NR1(S890D) showed greater ethanol inhibition than NR1(890A) containing receptors although this was only observed when it was combined with the NR2A subunit. Ethanol inhibition was not altered by aspartate substitution at four serines (positions 889, 890, 896, 897) or when T879D was added to the four serine-substituted mutant. Ethanol inhibition was increased when T900E was added to the five serine/threonine substituted mutant but again this was selective for NR2A containing receptors. Together with previously published data, these findings suggest that modification of putative phosphorylation sites could contribute to the overall acute ethanol sensitivity of recombinant NMDA receptors. Supported by R37 AA009986. PMID:21163614

Interaction between different extracts of Hypericum perforatum L. from Serbia and pentobarbital, diazepam and paracetamol.

PubMed

Rašković, Aleksandar; Cvejić, Jelena; Stilinović, Nebojša; Goločorbin-Kon, Svetlana; Vukmirović, Saša; Mimica-Dukić, Neda; Mikov, Momir

2014-03-28

Herb-drug interactions are an important safety concern and this study was conducted regarding the interaction between the natural top-selling antidepressant remedy Hypericum perforatum (Hypericaceae) and conventional drugs. This study examined the influence of acute pretreatment with different extracts of Hypericum perforatum from Serbia on pentobarbital-induced sleeping time, impairment of motor coordination caused by diazepam and paracetamol pharmacokinetics in mice. Ethanolic extract, aqueous extract, infusion, tablet and capsule of Hypericum perforatum were used in this experiment. The profile of Hypericum perforatum extracts as well as paracetamol plasma concentration was determined using RP-HPLC analysis. By quantitative HPLC analysis of active principles, it has been proven that Hypericum perforatum ethanolic extract has the largest content of naphtodianthrones: hypericin (57.77 µg/mL) and pseudohypericin (155.38 µg/mL). Pretreatment with ethanolic extract of Hypericum perforatum potentiated the hypnotic effect of pentobarbital and impairment of motor coordination caused by diazepam to the greatest extent and also increased paracetamol plasma concentration in comparison to the control group. These results were in correlation with naphtodianthrone concentrations. The obtained results have shown a considerable influence of Hypericum perforatum on pentobarbital and diazepam pharmacodynamics and paracetamol pharmacokinetics.