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Sample records for acute ethanol administration

  1. The effects of acute ethanol administration on ethanol withdrawal-induced anxiety-like syndrome in rats: A biochemical study.

    PubMed

    Kumar, Jaya; Hapidin, Hermizi; Get Bee, Yvonne-Tee; Ismail, Zalina

    2016-02-01

    Withdrawal from long-term ethanol consumption results in overexcitation of glutamatergic neurotransmission in the amygdala, which induces an anxiety-like syndrome. Most alcoholics that suffer from such symptoms frequently depend on habitual drinking as self-medication to alleviate their symptoms. Metabotropic glutamate receptor subtype 5 (mGlu5) and protein kinase C (PKC) epsilon have been reported to mediate acute and chronic effects of ethanol. This study explores the changes in mGlu5 and PKC epsilon in the amygdala following acute administration of ethanol during ethanol withdrawal (EW) induced anxiety. Male Wistar rats were fed a modified liquid diet containing low-fat cow milk, sucrose, and maltodextrin, with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days. Six hours into EW, the rats were intraperitoneally injected with normal saline and ethanol (2.5 g/kg, 20% v/v), and exposed to open-field and elevated plus maze tests. Then, amygdala tissue was dissected from the rat brain for Western blot and gene expression studies. EW-induced anxiety was accompanied by a significant increase in mGlu5, total PKC epsilon, and phosphorylated PKC epsilon protein levels, and also of mRNA of mGlu5 (GRM5) in the amygdala. Acute administration of ethanol significantly attenuated EW-induced anxiety as well as an EW-induced increase in GRM5. The acute challenge of ethanol to EW rats had little effect on the phosphorylated and total protein levels of PKC epsilon in the amygdala. Our results demonstrate that amygdala PKC epsilon may not be directly involved in the development of anxiety following EW.

  2. 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.

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

    SciTech Connect

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

    1988-01-01

    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 effect 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.

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

    PubMed Central

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

    2008-01-01

    Rationale 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. Objective 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. Materials and methods 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‰ by an ethanol infusion regime. Results 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. Conclusions 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. PMID:18305926

  5. Increased loss and decreased synthesis of hepatic glutathione after acute ethanol administration. Turnover studies.

    PubMed Central

    Speisky, H; MacDonald, A; Giles, G; Orrego, H; Israel, Y

    1985-01-01

    The effect of acute ethanol administration on rates of synthesis and utilization of hepatic glutathione (GSH) was studied in rats after a pulse of [35S]cysteine. A 35% decrease in hepatic GSH content 5h after administration of 4 g of ethanol/kg body wt. was accompanied by a 33% increase in the rate of GSH utilization. The decrease occurred without increases in hepatic oxidized glutathione (GSSG) or in the GSH/GSSG ratio. The rate of non-enzymic condensation of GSH with acetaldehyde could account for only 6% of the rate of hepatic GSH disappearance. The increased loss of [35S]GSH induced by ethanol was not accompanied by an increased turnover; rather, a 30% inhibition of GSH synthesis balanced the increased rate of loss, leaving the turnover rate unchanged. The rate of acetaldehyde condensation with cysteine in vitro occurred at about one-third of the rate of GSH loss in ethanol-treated animals. However, ethanol induced only a minor decrease in liver cysteine content, which did not precede, but followed, the decrease in GSH. The characteristics of 2-methylthiazolidine-4-carboxylic acid, the condensation product between acetaldehyde and cysteine, were studied and methodologies were developed to determine its presence in tissues. It was not found in the liver of ethanol-treated animals. Ethanol administration led to a marked increase (47%) in plasma GSH in the post-hepatic inferior vena cava, but not in its pre-hepatic segment. Data suggest that an increased loss of GSH from the liver constitutes an important mechanism for the decrease in GSH induced by ethanol. In addition, an inhibition of GSH synthesis is observed. PMID:3977847

  6. Acute psychomotor effects of MDMA and ethanol (co-) administration over time in healthy volunteers.

    PubMed

    Dumont, G J H; Schoemaker, R C; Touw, D J; Sweep, F C G J; Buitelaar, J K; van Gerven, J M A; Verkes, R J

    2010-02-01

    In Western societies, a considerable percentage of young people use 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'). The use of alcohol (ethanol) in combination with ecstasy is common. The aim of the present study was to assess the acute psychomotor and subjective effects of (co-) administration of MDMA and ethanol over time and in relation to the pharmacokinetics. We performed a four-way, double blind, randomized, crossover, placebo-controlled study in 16 healthy volunteers (nine men, seven women) between the ages of 18 and 29. MDMA (100 mg) was given orally while blood alcohol concentration was maintained at pseudo-steady state levels of approximately 0.6 per thousand for 3 h by a 10% intravenous ethanol clamp. MDMA significantly increased psychomotor speed but did not affect psychomotor accuracy and induced subjective arousal. Ethanol impaired both psychomotor speed and accuracy and induced sedation. Coadministration of ethanol and MDMA improved psychomotor speed but impaired psychomotor accuracy compared with placebo and reversed ethanol-induced sedation. Pharmacokinetics and pharmacodynamics showed maximal effects at 90-150 min after MDMA administration after which drug effects declined in spite of persisting MDMA plasma concentration, with the exception of ethanol-induced sedation, which manifested itself fully only after the infusion was stopped. In conclusion, results show that subjects were more aroused when intoxicated with both substances combined compared with placebo, but psychomotor accuracy was significantly impaired. These findings may have implications for general neuropsychological functioning as this may provide a sense of adequate performance that does not agree with a significant reduction in psychomotor accuracy.

  7. 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. PMID:26314628

  8. 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...

  9. Conditioned place aversion to the "hangover" phase of acute ethanol administration in the rat.

    PubMed

    Morse, A C; Schulteis, G; Holloway, F A; Koob, G F

    2000-08-01

    The purpose of this study was to examine ethanol's delayed effects (termed hangover) using conditioned place testing. Four groups of rats received a single pairing of a distinctive environment (tactile and visual) 10 h after injection with ethanol (0, 2, 3, 4 g/kg, i.p. ) or saline in a counterbalanced design. Rats receiving 3 and 4 g/kg ethanol showed a conditioned place aversion to ethanol hangover. Conditioning 10 h after 0 or 2 g/kg ethanol did not produce a significant place preference or aversion. The results suggest that the hangover following an acute injection of high doses of ethanol (3-4 g/kg) produces a significant and dose-related conditioned place aversion in the rat.

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

    SciTech Connect

    Sato, Tomoki; Morita, Akihito; Mori, Nobuko; Miura, Shinji

    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, the 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.

  11. Mechanics of the carotid artery wall and baroreflex sensitivity after acute ethanol administration in young healthy volunteers.

    PubMed

    Fazio, M; Bardelli, M; Macaluso, L; Fiammengo, F; Mattei, P L; Bossi, M; Fabris, B; Fischetti, F; Pascazio, L; Candido, R; Carretta, R

    2001-09-01

    The effects of ethanol administered orally (300 mg/kg in 250 ml of water) or intravenously (7.5 mg.min(-1).kg(-1) in 250 ml of saline over 40 min) on common carotid haemodynamics, wall mechanics and baroreflex sensitivity were compared with the effects of the intravenous infusion of 250 ml of saline. Ethanol or saline was administered to 10 healthy volunteers after 30 min of supine rest, and measurements were obtained 40 min (median; range 34-46 min) after administration. After ethanol administration, the plasma alcohol level rose from 0 to 0.3+/-0.07 g/l. Mean arterial blood pressure had risen slightly at 20 min, but was normalized by 40 min, the time at which the haemodynamic study was performed. Heart rate decreased after infusion of either saline or alcohol, but was unchanged after oral ethanol administration. Both oral and intravenous ethanol administration were associated with significant decreases in baroreflex sensitivity, carotid shear stress and blood velocity, compared with resting values, while the mean carotid artery diameter was increased, and blood viscosity and mean blood flow were unchanged. No changes were observed in these parameters after saline administration. Ethanol, administered either intravenously or orally, increased the stiffness of the carotid artery and decreased the pulsatility (systo-diastolic changes) of its diameter. A direct, statistically significant correlation was found between the decrease in shear stress and the decrease in baroreflex heart rate control sensitivity after both modes of alcohol administration, while no such correlation was found between the increase in the Peterson elastic modulus and the decrease in carotid diameter pulsatility on the one hand or the decrease in baroreflex sensitivity on the other. In conclusion, reduced shear stress associated with vasodilatation of the carotid artery wall may contribute to the decrease in baroreflex sensitivity observed after acute ethanol administration.

  12. 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. PMID:15381050

  13. Glutathione Depletion and Recovery After Acute Ethanol Administration in the Aging Mouse

    PubMed Central

    Vogt, Barbara L.; Richie, John P.

    2007-01-01

    Glutathione (GSH) plays an important role in the detoxification of ethanol (EtOH) and acute EtOH administration leads to GSH depletion in the liver and other tissues. Aging is also associated with a progressive decline in GSH levels and impairment in GSH biosynthesis in many tissues. Thus, the present study was designed to examine the effects of aging on EtOH-induced depletion and recovery of GSH in different tissues of the C57Bl/6NNIA mouse. EtOH (2-5 g/kg) or saline was administered i.p. to mice of ages 6 mo (young), 12 mo (mature), and 24 mo (old); and GSH and cyst(e)ine concentrations were measured 0-24 hours thereafter. EtOH administration (5g/kg) depleted hepatic GSH levels >50% by 6 hr in all animals. By 24 hr, levels remained low in both young and old mice, but recovered to baseline levels in mature mice. At 6 hr, the decrease in hepatic GSH was dose-dependent up to 3 g/kg EtOH, but not at higher doses. The extent of depletion at the 3 g/kg dose was dependent upon age, with old mice demonstrating significantly lower GSH levels than mature mice (P<0.001). Altogether these results indicate that aging was associated with a greater degree of EtOH and fasting-induced GSH depletion and subsequent impaired recovery in liver. An impaired ability to recover was also observed in young animals. Further studies are required to determine if an inability to recover from GSH depletion by EtOH is associated with enhanced toxicity. PMID:17343832

  14. Comparative studies of oral administration of marine collagen peptides from Chum Salmon (Oncorhynchus keta) pre- and post-acute ethanol intoxication in female Sprague-Dawley rats.

    PubMed

    Liang, Jiang; Li, Qiong; Lin, Bing; Yu, Yongchao; Ding, Ye; Dai, Xiaoqian; Li, Yong

    2014-09-01

    The present study aimed to evaluate the effect of an oral administration of marine collagen peptides (MCPs) pre- and post-acute ethanol intoxication in female Sprague-Dawley (SD) rats. MCPs were orally administered to rats at doses of 0 g per kg bw, 2.25 g per kg bw, 4.5 g per kg bw and 9.0 g per kg bw, prior to or after the oral administration of ethanol. Thirty minutes after ethanol treatment, the effect of MCPs on motor incoordination and hypnosis induced by ethanol were investigated using a screen test, fixed speed rotarod test (5 g per kg bw ethanol) and loss of righting reflex (7 g per kg bw ethanol). In addition, the blood ethanol concentrations at 30, 60, 90, and 120 minutes after ethanol administration (5 g per kg bw ethanol) were measured. The results of the screen test and fixed speed rotarod test suggested that treatment with MCPs at 4.5 g per kg bw and 9.0 g per kg bw prior to ethanol could attenuate ethanol-induced loss of motor coordination. Moreover, MCP administered both pre- and post-ethanol treatment had significant potency to alleviate the acute ethanol induced hypnotic states in the loss of righting reflex test. At 30, 60, 90 and 120 minutes after ethanol ingestion at 5 g per kg bw, the blood ethanol concentration (BEC) of control rats significantly increased compared with that in the 4.5 g per kg bw and 9.0 g per kg bw MCP pre-treated groups. However, post-treatment with MCPs did not exert a significant inhibitory effect on the BEC of the post-treated groups until 120 minutes after ethanol administration. Therefore, the anti-inebriation effect of MCPs was verified in SD rats with the possible mechanisms related to inhibiting ethanol absorption and facilitating ethanol metabolism. Moreover, the efficiency was better when MCPs were administered prior to ethanol.

  15. Effects of acute administration of ethanol on cerebral glucose utilization in adult alcohol-preferring and alcohol-nonpreferring rats.

    PubMed

    Strother, Wendy N; McBride, William J; Lumeng, Lawrence; Li, Ting-Kai

    2005-02-01

    Local cerebral glucose utilization (LCGU) rates, as determined by the [(14)C]-2-deoxyglucose (2-DG) technique, were examined after acute ethanol administration within selected brain regions of alcohol-preferring (P) and alcohol-nonpreferring (NP) rats. Adult male P and NP rats were injected with saline, 0.25 g/kg, or 1.0 g/kg ethanol, intraperitoneally (ip), 10 min before an intravenous bolus of [(14)C]2-DG (125 microCi/kg). Timed arterial blood samples were collected over 45 min and assayed for plasma glucose, ethanol, and [(14)C]2-DG levels. Image densities were determined using quantitative autoradiography and LCGU values calculated. Data were collected from several key limbic, basal ganglionic, cortical, and subcortical structures. Low-dose ethanol (0.25 g/kg) significantly decreased LCGU rates in several brain regions including the medial prefrontal cortex, olfactory tubercles, and the CA1 subregion of the hippocampus of P rats. Low-dose ethanol had no significant effects on LCGU rates in the NP rats. Moderate-dose ethanol (1.0 g/kg) also significantly lowered LCGU rates in many brain regions of P rats, including key limbic structures, such as the medial prefrontal cortex, olfactory tubercles, ventral tegmental area, basolateral nucleus of the amygdala, lateral septum, and ventral pallidum. Moderate-dose ethanol also significantly lowered LCGU rates in the medial prefrontal cortex as well as in the habenula of NP rats. All other regions were unaffected in the NP rats. These findings support the suggestion that certain central nervous system regions of P rats may be more sensitive than those of NP rats to the effects of low to intermediate doses of ethanol.

  16. 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

  17. Spin-trapping studies of hepatic free radicals formed following the acute administration of ethanol to rats: In vivo detection of 1-hydroxyethyl radicals with PBN

    SciTech Connect

    Reinke, L.A.; Kotake, Y.; McCay, P.B.; Janzen, E.G. )

    1991-01-01

    The generation of free radicals in rat liver following the acute oral administration of ethanol was studied with the spin-trapping method, using a deuterated derivative of phenyl-N-tert-butylnitrone (PBN-d14) as the spin-trapping agent. After administration of ethanol and PBN-d14 to rats, organic extracts of the liver were prepared and subjected to ESR spectroscopy. In the case of ethanol-treated rats, the ESR spectra indicated that mixtures of radicals had been trapped, while spectra from control rats were essentially negative. The predominant spin adduct detected after ethanol treatment is proposed to be from a carbon-centered, primary alkyl radical, based on gamma-hydrogen hyperfine splitting patterns observed with PBN-d14. Oxygen-centered radicals also contributed to the ESR spectra. Liver extracts also contained low concentrations of the 1-hydroxyethyl radical spin adduct, which was indicated by weak spectral lines corresponding to those of the 1-13C-ethanol adduct. These data confirm previous suggestions that ethanol is metabolized to a free radical metabolite in rat liver. In addition, some information on types of lipid radicals generated during alcohol intoxication has been obtained.

  18. Liver, plasma and erythrocyte levels of thiamine and its phosphate esters in rats with acute ethanol intoxication: a comparison of thiamine and benfotiamine administration.

    PubMed

    Portari, Guilherme Vannucchi; Vannucchi, Helio; Jordao, Alceu Afonso

    2013-03-12

    Thiamine and benfotiamine are vitamin B1 and pro-vitamin B1 substances, respectively. Vitamin B1 plays an essential role in energy metabolism, and its deficiency leads to neurologic and cardiovascular pathologies, as seen in alcoholics. This study presents new data about the effects of thiamine hydrochloride or benfotiamine treatment given to rats with acute alcohol intoxication, on the distribution of thiamine and its phosphate esters in liver, plasma and erythrocytes. The treatments were effective in increasing thiamine levels in plasma, erythrocytes and liver cells. The benfotiamine-treated group had its total plasma thiamine increased by 100%. In erythrocytes, thiamine levels were 4- and 25-fold higher in the groups treated with thiamine and benfotiamine, respectively, compared with the untreated groups. Liver thiamine was increased by 60% in the treated groups compared with the untreated groups. Thus, we verified the high bioavailability especially of benfotiamine within 6h of ethanol administration.

  19. Operant ethanol self-administration in ethanol dependent mice.

    PubMed

    Lopez, Marcelo F; Becker, Howard C

    2014-05-01

    While rats have been predominantly used to study operant ethanol self-administration behavior in the context of dependence, several studies have employed operant conditioning procedures to examine changes in ethanol self-administration behavior as a function of chronic ethanol exposure and withdrawal experience in mice. This review highlights some of the advantages of using operant conditioning procedures for examining the motivational effects of ethanol in animals with a history of dependence. As reported in rats, studies using various operant conditioning procedures in mice have demonstrated significant escalation of ethanol self-administration behavior in mice rendered dependent via forced chronic ethanol exposure in comparison to nondependent mice. This paper also presents a summary of these findings, as well as suggestions for future studies.

  20. Acute and chronic effect of ethanol on hepatic albumin synthesis in rat liver in vitro

    SciTech Connect

    Ohtake, H.; Kato, S.; Murawaki, Y.; Kishimoto, Y.; Wakushima, T.; Hirayama, C.

    1986-08-01

    To study the effects of ethanol and its metabolite on albumin metabolism, we examined the hepatic albumin synthesis and secretion in male Wistar rats in vitro, following acute and chronic ethanol administration. After acute ethanol administration, proalbumin synthesis in rat liver in vitro, declined to 47% of the control level at 4 hrs, the lowest level, and increased thereafter to slightly higher than the control level at 16 hrs. On the other hand, chronic ethanol administration for 4 weeks, increased proalbumin synthesis to 1.5 times that of the control level. In the acute ethanol group, a significant negative correlation was observed between proalbumin radioactivity and the concentration of hepatic ethanol and acetaldehyde. The variation between proalbumin radioactivity and hepatic ethanol concentration was wider than the variation between proalbumin and hepatic acetaldehyde. In the chronic ethanol group, ethanol was not detected in the liver. No significant differences from the proalbumin/albumin ratio were seen at any time point after acute or chronic ethanol administration. These findings suggest that the effects of ethanol on hepatic albumin synthesis differ with the method of ethanol administration, and acetaldehyde and/or ethanol is involved in the reduction in albumin synthesis, however, proalbumin-albumin conversion is not disturbed.

  1. Effect of ethanol administration and withdrawal on GABA receptor binding in rat cerebral cortex

    SciTech Connect

    Volicer, L.; Biagioni, T.M.

    1982-01-01

    Sodium independent GABA receptor binding was measured in synaptosomes prepared from cerebral cortex of rats made ethanol dependent by three daily ethanol administrations. In rats sacrificed 1 hour after the last ethanol dose there was a lower number of low affinity binding sites and lower affinity of the high affinity binding than in controls. The decreased affinity was present only in rats who showed symptoms of ethanol withdrawal during the course of ethanol administration. In rats sacrificed during ethanol withdrawal the affinity of the high affinity binding was lower than in controls and other binding characteristics were unchanged. This decreased binding was normalized by repeated Triton X-100 incubations indicating involvement of an endogenous inhibitor in this ethanol effect. Acute ethanol administration did not change GABA receptor binding.

  2. Acute effects of ethanol on renal folate clearance in rats

    SciTech Connect

    Eisenga, B.H.; McMartin, K.E.

    1986-03-05

    Studies of the renal clearance of folic acid in primates demonstrate net reabsorption of folate by a saturable system. The acute administration of ethanol to rats causes a significant increase in urinary folate excretion. The mechanism for this effect is unknown and thus the effect of acute administration of ethanol on the renal absorption and urinary clearance of folate was studied in rats. Folic acid was administered to male Sprague-Dawley rats via continuous intravenous infusion in doses ranging from 3-75 micromoles/kg and renal clearance relative to inulin was determined. The effects of various dose levels of ethanol on these parameters were then determined. At a dose of 15 micromoles/kg, the renal clearance of folate relative to that of inulin was about 0.65 mg/min. At a plasma ethanol level about 100 mg/dl, the renal clearance of folate was not markedly altered. These results suggests that there is net reabsorption of folate in the rat kidney and that moderate doses of ethanol have little effect on renal effect on renal folate reabsorption.

  3. Evaluation of acute effects of melatonin on ethanol drinking in ethanol naïve rats

    PubMed Central

    Rather, Zahoor Ahmad; Chowta, Mukta N.; Bolumbu, Ganaraja; Rakesh, K. B.

    2015-01-01

    Objective: The objective was to evaluate the acute effect of melatonin on ethanol drinking in ethanol naïve rats and to determine the specificity of the effect of melatonin on ethanol intake as compared to an intake of plain tap water or sugar water. Materials and Methods: A total of three experiments (2 weeks duration each) using different drinking solutions (ethanol, plain tap water, sugar water) was conducted in individually housed male wistar rats of 5 weeks age. Each animal had access to bottles containing drinking solutions for 2 h a day. In each experiment, on day 1, day 2, day 4, day 5, day 8, day 9, day 11, day 12 rats received drinking solutions. Each individual rat received single doses of saline, melatonin (50 mg and 100 mg/kg), and naltrexone on day 2, 5, 9, and 12, 1-h before receiving drinking solution. The order of drug administration is permuted such a way that each animal received the drugs in a different order in different experiments. Results: Melatonin has significantly decreased ethanol consumption by the rats and effect is dose-dependent. Naltrexone also has caused a significant reduction in the ethanol consumption. The maximum reduction in ethanol consumption was seen with melatonin 100 mg/kg dose compared to melatonin 50 mg/kg and naltrexone. There was no statistically significant effect of melatonin on plain water and sugar solution intake. Conclusions: Melatonin decreases ethanol consumption in ethanol naïve rats. The effect of melatonin is similar to naltrexone affecting selectively ethanol consumption, but not plain water and sugar water consumption. PMID:26288469

  4. Interactions between methaqualone and ethanol in rats and mice during acute and chronic states.

    PubMed

    Ho, C C; Ho, A K

    1978-01-01

    1. The effects of acute and chronic treatment of methaqualone on ethanol preference, the rate of disappearance of ethanol and on toxicity were studied in mice and rats. 2. Acute treatment with methaqualone showed a dose-dependent suppression in the voluntary intake of ethanol in C57Bl/6J mice in rats. No significant change in ethanol intake was observed during chronic methaqualone treatment and withdrawal. 3. Methaqualone pretreatment significantly (P less than 0.005) delayed the disappearance of ethanol in the blood and brain over a period of 50 and 200 min after a loading dose of 2.0 g/kg, i.p., of ethanol. 4. Methaqualone pretreatment at doses of 140 and 200 mg/kg significantly increased ethanol toxicity by 11% and 28%, respectively. Co-administration of ethanol using 6.0, 7.0 and 8.0 g/kg also reduced the LD50 of methaqualone by 19%, 24% and 40%, respectively. 5. Chronic administration with ethanol decreased the toxicity due to methaqualone. Potentiation of ethanol toxicity by methaqualone may be of clinical importance in view of the narrow range of safety margin of ethanol.

  5. Operant self-administration of ethanol in infant rats.

    PubMed

    Pautassi, Ricardo Marcos; Miranda-Morales, Roberto Sebastián; Nizhnikov, Michael

    2015-09-01

    The review focuses on operant self-administration of ethanol in immature, infant rats. Several methods for the analysis of ethanol intake in infants are available, yet only oral self-administration models the typical pattern of ethanol consumption found in humans. The study of ethanol intake in infants is important for our understanding of how early alcohol experiences facilitate subsequent engagement with alcohol. It seems that sensitivity to ethanol-induced operant reinforcement is found very early in life, a few hours after birth, and throughout the first three weeks of life. Most of the studies reviewed complied with most, albeit not all, of the criteria for operant behavior (e.g., greater responding than yoked controls and persistence of this difference after withholding the reinforcer). Operant self-administration of ethanol in infant rats seems to be, at least partially, mediated by endogenous opioid transmission and can be enhanced by prior exposure to ethanol. Furthermore, acquisition of ethanol-mediated operant learning seems to facilitate drug self-administration during adolescence. Relative to older subjects, infants exhibit lower sensitivity to ethanol's sedative, hypnotic and motor impairing effects. On the other hand, they exhibit increased sensitivity to the motor stimulant and rewarding effects of ethanol. We suggest that this pattern of response to ethanol may favor the rapid acquisition of operant self-administration in infant rats.

  6. Flavor preference conditioning by oral self-administration of ethanol.

    PubMed

    Cunningham, C L; Niehus, J S

    1997-12-01

    Oral self-administration and operant tasks have been used successfully to confirm ethanol's positive reinforcing effects in rats. However, in flavor conditioning tasks, ethanol is typically found to have aversive effects. The present studies explored this apparent paradox by examining the change in value of a flavor paired with orally self-administered ethanol in two different limited-access procedures. Rats were food-deprived and trained to drink (experiment 1) or to barpress for (experiment 2) 10% (v/v) ethanol during daily 30-min sessions using prandial initiation techniques. All rats were then exposed to a differential flavor conditioning procedure in which banana or almond extract was added to the drinking solution. One flavor (counterbalanced) was always mixed with ethanol (CS+), whereas the other flavor was mixed with water (CS-). By the end of conditioning, rats in both experiments drank more flavored ethanol than flavored water, confirming ethanol's efficacy as a reinforcer. Moreover, barpress rates for CS+ exceeded those for CS- in the operant task. Ethanol doses self-administered in final sessions averaged about 1 g/kg. The effect of the flavor-ethanol contingency was assessed in preference tests that offered a choice between the two flavor solutions without ethanol. In both experiments, subjects developed a preference for the flavor that had been paired with ethanol. Thus, the outcome of flavor conditioning was consistent with that of the oral self-administration tasks in providing evidence of ethanol's rewarding effects. These experiments confirm and extend previous studies showing that flavor aversion is not the inevitable result of flavor-ethanol association in rats. It seems likely that ethanol's nutrient and pharmacological effects both contributed to the development of conditioned flavor preference.

  7. The Effects of Chronic Ethanol Administration on Amygdala Neuronal Firing and Ethanol Withdrawal Seizures

    PubMed Central

    Feng, Hua-Jun; Faingold, Carl L.

    2008-01-01

    Summary Physical dependence on ethanol results in an ethanol withdrawal (ETX) syndrome including susceptibility to audiogenic seizures (AGS) in rodents after abrupt cessation of ethanol. Chronic ethanol administration and ETX induce functional changes of neurons in several brain regions, including the amygdala. Amygdala neurons are requisite elements of the neuronal network subserving AGS propagation during ETX induced by a subacute “binge” ethanol administration protocol. However, the effects of chronic ethanol administration on amygdala neuronal firing and ETX seizure behaviors are unknown. In the present study ethanol (5 g/kg) was administered intragastrically in Sprague-Dawley rats once daily for 28 days [chronic intermittent ethanol (CIE) protocol]. One week later the rats began receiving ethanol intragastrically 3 times daily for 4 days (binge protocol). Microwire electrodes were implanted prior to CIE or on the day after CIE ended day 29 to record extracellular action potentials in lateral amygdala (LAMG) neurons. The first dose of ethanol administered in the binge protocol following CIE treatment did not alter LAMG neuronal firing, which contrasts with firing suppression seen previously in the binge protocol alone. These data indicate that CIE induces neuroadaptive changes in the ETX network which reduce LAMG response to ethanol. LAMG neuronal responses to acoustic stimuli prior to AGS were significantly decreased during ETX as compared to those before ethanol treatment. LAMG neurons fired tonically throughout the tonic convulsions during AGS. CIE plus binge treatment resulted in a significantly greater mean seizure duration and a significantly elevated incidence of death than was seen previously with the binge protocol alone, indicating an elevated seizure severity following chronic ethanol administration. PMID:18614185

  8. ACUTE ETHANOL DISRUPTS PHOTIC AND SEROTONERGIC CIRCADIAN CLOCK PHASE-RESETTING IN THE MOUSE

    PubMed Central

    Brager, Allison J.; Ruby, Christina L.; Prosser, Rebecca A.; Glass, J. David

    2011-01-01

    Background Alcohol abuse is associated with impaired circadian rhythms and sleep. Ethanol administration disrupts circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on the circadian timing system. In this study, we extend previous work in C57BL/6J mice to: 1) characterize the SCN pharmacokinetics of acute systemic ethanol administration; 2) explore the effects of acute ethanol on photic and non-photic phase-resetting; and 2) determine if the SCN is a direct target for photic effects. Methods First, microdialysis was used to characterize the pharmacokinetics of acute i.p. injections of 3 doses of ethanol (0.5, 1.0 and 2.0 g/kg) in the mouse suprachiasmatic (SCN) circadian clock. Second, the effects of acute i.p. ethanol administration on photic phase-delays and serotonergic ([+]8-OH-DPAT-induced) phase-advances of the circadian activity rhythm were assessed. Third, the effects of reverse-microdialysis ethanol perfusion of the SCN on photic phase-resetting were characterized. Results Peak ethanol levels from the 3 doses of ethanol in the SCN occurred within 20–40 min post-injection with half-lives for clearance ranging from 0.6–1.8 hr. Systemic ethanol treatment dose-dependently attenuated photic and serotonergic phase-resetting. This treatment also did not affect basal SCN neuronal activity as assessed by Fos expression. Intra-SCN perfusion with ethanol markedly reduced photic phase-delays. Conclusions These results confirm that acute ethanol attenuates photic phase-delay shifts and serotonergic phase-advance shifts in the mouse. This dual effect could disrupt photic and non-photic entrainment mechanisms governing circadian clock timing. It is also significant that the SCN clock is a direct target for disruptive effects of ethanol on photic shifting. Such actions by ethanol could underlie the disruptive effects of alcohol abuse on behavioral, physiological, and endocrine rhythms associated with alcoholism. PMID:21463340

  9. Maternal metallothionein and zinc after acute ethanol exposure during gestation in the rat

    SciTech Connect

    Harris, J.E. )

    1992-02-26

    Acute exposure of the rat fetus to ethanol at critical periods can cause growth retardation and brain damage; the mechanism(s) is not known. Ethanol may cause redistribution of maternal zinc which results in fetal zinc deficiency and subsequent interruption of growth and development. The purpose was to determine if acute ethanol administration to the pregnant rat alters Zn and the Zn binding protein metallothionein (MT) in selected tissues. On gestational day (gd) 14, eighteen pregnant Sprague-Dawley rats were divided into groups. By intragastric tube, ethanol treated dams were given ethanol and pairfed controls were given a 0.85% NaCl solution. On gd 15, intragastric feedings were repeated. Throughout, the Lieber-DeCarli control diet was fed (adlibitum to untreated controls and ethanol treated dams and in appropriate quantities to pair fed controls). Blood ethanol concentrations at 90 minutes after the ethanol dose were 154 {plus minus} 46 and 265 {plus minus} 110 mg% on gd 14 and 15, respectively.

  10. Effects of chronic ethanol administration on hepatic glycoprotein secretion in the rat

    SciTech Connect

    Sorrell, M.F.; Nauss, J.M.; Donohue, T.M. Jr.; Tuma, D.J.

    1983-03-01

    The effects of chronic ethanol feeding on protein and glycoprotein synthesis and secretion were studied in rat liver slices. Liver slices from rats fed ethanol for 4-5 wk showed a decreased ability to incorporate (/sup 14/C)glucosamine into medium trichloracetic acid-precipitable proteins when compared to the pair-fed controls; however, the labeling of hepatocellular glycoproteins was unaffected by chronic ethanol treatment. Immunoprecipitation of radiolabeled secretory (serum) glycoproteins with antiserum against rat serum proteins showed a similar marked inhibition in the appearance of glucosamine-labeled proteins in the medium of slices from ethanol-fed rats. Minimal effects, however, were noted in the labeling of intracellular secretory glycoproteins. Protein synthesis, as determined by measuring (/sup 14/C)leucine incorporation into medium and liver proteins, was decreased in liver slices from ethanol-fed rats as compared to the pair-fed controls. This was the case for both total proteins as well as immunoprecipitable secretory proteins, although the labeling of secretory proteins retained in the liver slices was reduced to a lesser extent than total radiolabeled hepatic proteins. When the terminal sugar, (/sup 14/C)fucose, was employed as a precursor in order to more closely focus on the final steps of hepatic glycoprotein secretion, liver slices obtained from chronic ethanol-fed rats exhibited impaired secretion of fucose-labeled proteins into the medium. When ethanol (5 or 10 mM) was added to the incubation medium containing liver slices from the ethanol-fed rats, the alterations in protein and glycoprotein synthesis and secretion caused by the chronic ethanol treatment were further potentiated. The results of this study indicate that liver slices prepared from chronic ethanol-fed rats exhibit both impaired synthesis and secretion of proteins and glycoproteins, and these defects are further potentiated by acute ethanol administration.

  11. Protective Effects of the Traditional Herbal Formula Oryeongsan Water Extract on Ethanol-Induced Acute Gastric Mucosal Injury in Rats

    PubMed Central

    Jeon, Woo-Young; Lee, Mee-Young; Shin, In-Sik; Lim, Hye-Sun; Shin, Hyeun-Kyoo

    2012-01-01

    This study was performed to evaluate the protective effect and safety of Oryeongsan water extract (OSWE) on ethanol-induced acute gastric mucosal injury and an acute toxicity study in rats. Acute gastric lesions were induced via intragastric oral administration of absolute ethanol at a dose of 5 mL/kg. OSWE (100 and 200 mg/kg) was administered to rats 2 h prior to the oral administration of absolute ethanol. The stomach of animal models was opened and gastric mucosal lesions were examined. Gastric mucosal injuries were evaluated by measuring the levels of malondialdehyde (MDA), glutathione (GSH), and the activity of antioxidant enzymes. In the acute toxicity study, no adverse effects of OSWE were observed at doses up to 2000 mg/kg/day. Administration of OSWE reduced the damage by conditioning the gastric mucosa against ethanol-induced acute gastric injury, which included hemorrhage, hyperemia, and loss of epithelial cells. The level of MDA was reduced in OSWE-treated groups compared with the ethanol-induced group. Moreover, the level of GSH and the activity of antioxidant enzymes were significantly increased in the OSWE-treated groups. Our findings suggest that OSWE has a protective effect on the gastric mucosa against ethanol-induced acute gastric injury via the upregulation of antioxidant enzymes. PMID:23118790

  12. Sex-dependent effects of maternal separation on plasma corticosterone and brain monoamines in response to chronic ethanol administration.

    PubMed

    Kawakami, S E; Quadros, I M H; Machado, R B; Suchecki, D

    2013-12-01

    Prolonged and repeated periods of maternal separation produce behavioral phenotype of increased vulnerability to neuropsychiatric disorders and drug abuse. Most of the changes in behavior, corticosterone (CORT) and monoamine levels induced by long maternal separation (LMS) are observed after a challenge, but not in basal conditions. LMS increases ethanol-induced locomotor response and self-administration, possibly due to changes in CORT release and/or monoamine concentrations. This study examined the effects of LMS in association with chronic ethanol treatment on plasma CORT and brain monoamine concentrations in male and female Swiss mice, which were kept undisturbed (animal facility rearing - AFR) or separated from their mothers for 3h/day, from 2 to 14 days of age (LMS). As adults, one set of male and female mice received no drug treatment to assess the effect of LMS per se. Another set of animals received saline injections for 20 days and one ethanol injection (2.2g/kg, i.p.) on day 21 (acute) or ethanol for 21 days (chronic). Locomotor activity, plasma CORT levels and monoamines in the frontal cortex, striatum and hippocampus of AFR and LMS mice were evaluated in non-treated, acute and chronic ethanol-treated animals. In non-treated mice, no differences were found in CORT or locomotor activity, with small changes in monoamines content. In LMS females, chronic ethanol increased dopamine and serotonin concentrations in the frontal cortex, relative to acute ethanol LMS and to chronic ethanol-treated AFR groups (p<0.05). In LMS males, chronic ethanol increased hippocampal noradrenaline, dopamine, serotonin and metabolites when compared to respective AFR controls, as well as acute LMS. Moreover, chronic ethanol treatment resulted in higher CORT concentrations in LMS than in AFR males. Overall, these results indicate that LMS mice were more susceptible to the effects of chronic ethanol administration on CORT and brain monoamine concentrations, and that these effects

  13. Peripheral oxytocin administration reduces ethanol consumption in rats.

    PubMed

    MacFadyen, Kaley; Loveless, Rebecca; DeLucca, Brandon; Wardley, Krystal; Deogan, Sumeet; Thomas, Cameron; Peris, Joanna

    2016-01-01

    The neuropeptide oxytocin interacts with mesolimbic dopamine neurons to mediate reward associated with filial behaviors, but also other rewarding behaviors such as eating or taking drugs of abuse. Based on its efficacy to decrease intake of other abused substances, oxytocin administration is implicated as a possible treatment for excessive alcohol consumption. We tested this hypothesis by measuring ethanol intake in male Sprague-Dawley rats injected with oxytocin or saline using two different ethanol self-administration paradigms. First, a dose-response curve was constructed for oxytocin inhibition of fluid intake using a modified drinking-in-the-dark model with three bottles containing .05% saccharine, 10% ethanol in saccharine, and 15% ethanol in saccharine. Doses of oxytocin tested were 0.05, 0.1, 0.3, and 0.5mg/kg (I.P.). Next, rats received 0.3mg/kg oxytocin preceding operant sessions in which they were trained to lever-press for either plain gelatin or ethanol gelatin in order to compare oxytocin inhibition of ethanol intake versus caloric intake. For the three-bottle choice study, rats consumed significantly less ethanol when treated with the three higher doses of oxytocin on the injection day. In the operant study, 0.3mg/kg oxytocin significantly decreased ethanol gel consumption to a greater extent than plain gel consumption, both in terms of the amount of gel eaten and calories consumed. These data affirm oxytocin's efficacy for decreasing ethanol intake in rats, and confirm clinical studies suggesting oxytocin as a potential treatment for alcoholism.

  14. Peripheral oxytocin administration reduces ethanol consumption in rats

    PubMed Central

    MacFadyen, Kaley; Loveless, Rebecca; DeLucca, Brandon; Wardley, Krystal; Deogan, Sumeet; Thomas, Cameron; Peris, Joanna

    2016-01-01

    The neuropeptide oxytocin interacts with mesolimbic dopamine neurons to mediate reward associated with filial behaviors, but also other rewarding behaviors such as eating or taking drugs of abuse. Based on its efficacy to decrease intake of other abused substances, oxytocin administration is implicated as a possible treatment for excessive alcohol consumption. We tested this hypothesis by measuring ethanol intake in male Sprague–Dawley rats injected with oxytocin or saline using two different ethanol self-administration paradigms. First, a dose–response curve was constructed for oxytocin inhibition of fluid intake using a modified drinking-in-the-dark model with three bottles containing .05% saccharine, 10% ethanol in saccharine, and 15% ethanol in saccharine. Doses of oxytocin tested were 0.05, 0.1, 0.3, and 0.5 mg/kg (I.P.). Next, rats received 0.3 mg/kg oxytocin preceding operant sessions in which they were trained to lever-press for either plain gelatin or ethanol gelatin in order to compare oxytocin inhibition of ethanol intake versus caloric intake. For the three-bottle choice study, rats consumed significantly less ethanol when treated with the three higher doses of oxytocin on the injection day. In the operant study, 0.3 mg/kg oxytocin significantly decreased ethanol gel consumption to a greater extent than plain gel consumption, both in terms of the amount of gel eaten and calories consumed. These data affirm oxytocin's efficacy for decreasing ethanol intake in rats, and confirm clinical studies suggesting oxytocin as a potential treatment for alcoholism. PMID:26519603

  15. Acute effects of ethanol on left ventricular diastolic function.

    PubMed Central

    Kupari, M; Koskinen, P; Hynynen, M; Salmenperä, M; Ventilä, M

    1990-01-01

    Transmitral flow velocities were measured by Doppler echocardiography in nine healthy men who ingested 1 g/kg of ethanol within one hour. The measurements were made before the first drink and every hour thereafter for three hours. The peak mean (SE) blood ethanol concentration was 21.4 (1.0) mmol/l. Each man was also studied after drinking fruit juice. Ethanol increased the heart rate but did not change the peak transmitral velocities, the normalised peak filling rate, the deceleration of early flow, or the duration of relaxation as measured from the second heart sound to the peak early diastolic velocity. The ratio of the peak atrial to the peak early diastolic velocity rose from 0.41 (0.03) to 0.44 (0.03) after ethanol but remained unchanged after juice. The difference between juice and ethanol was independent of changes in heart rate. The fluid balance was more negative in the ethanol experiment (-727 (114) ml v -107 (70) ml), suggesting a reduction in preload, and the ethanol-induced net loss of fluid correlated with the concomitant change in the velocity ratio. A moderate dose of ethanol causes a small acute increase of the ratio of the peak atrial to the peak early diastolic velocity of mitral flow in healthy subjects. Although this change indicates altered diastolic function of the left ventricle, most of it may result from the diuretic effect of ethanol. Any major impairment of ventricular relaxation seems unlikely. PMID:2393610

  16. Sucrose administration to partially hepatectomized rats: a possible model to study ethanol-induced inhibition of liver regeneration.

    PubMed

    Gutiérrez-Salinas, J; Aranda-Fraustro, A; Paredes-Díaz, R; Hernández-Muñoz, R

    1996-09-01

    Although acute ethanol treatment drastically inhibits liver regeneration after partial hepatectomy, the exact mechanisms involved remain obscure. On the other hand, it is known that early carbohydrate administration promotes a more successful restoration of the liver mass. Therefore, carbohydrate administration could be an experimental approach for studying ethanol action on the regenerating liver. In rats subjected to two-thirds partial hepatectomy, ethanol was administered alone or in combination with a variety of carbohydrates (glucose, fructose, glucose plus fructose, sucrose and maltose). In liver samples, regeneration parameters and histological assessment were performed. Blood ethanol and metabolites reflecting liver function were assayed. Ethanol intake strongly decreased the incorporation of [3H]thymidine into liver DNA, the concentration of DNA/g of tissue, and thymidine kinase activity. In this group, severe alterations in cell structure (i.e. abundant fat droplets and abnormal mitochondria) were found. Carbohydrates readily improved the survival rate of ethanol-intoxicated hepatectomized rats. Sucrose was effective in reverting the ethanol-induced alterations in liver structure and the parameters of liver regeneration, and partially blocked the ethanol-induced alterations in serum levels of albumin, triacylglycerols and ammonia without modifying the blood levels and clearance of ethanol. Data suggest that the beneficial action of sucrose might be related to an adequate supply of energetic sources at early times of liver regeneration, rather than altering ethanol bioavailability. Thus, the present model could be an experimental approach for studying the metabolic alterations involved in the ethanol-induced inhibition of the liver regeneration.

  17. A practical method of chronic ethanol administration in mice.

    PubMed

    Coleman, Ruth A; Young, Betty M; Turner, Lucas E; Cook, Robert T

    2008-01-01

    Mice provide a useful model for the study of immune deficiency caused by chronic alcohol abuse. Their suitability is related to several factors, including in particular the extensive knowledge base in the immunology of mice already existing in the literature. Specific modeling of the immunodeficiency of the chronic human alcoholic requires that ethanol must be administered to the model for a significant portion of its life span. In mice, it has proven to be necessary to administer ethanol daily for up to 32 wk or longer to observe all the immune abnormalities that occur in middle-aged alcoholic humans. Such time spans are problematic with many of the common protocols for ethanol administration. It has been shown by others and confirmed by our group that the most practical way of accomplishing such long protocols is by administering ethanol in water as the only choice of water. Details of management of the chronic ethanol mouse colony are described here that are necessary for the success of such studies, including methods for initiating ethanol administration, maintenance of barrier protection, monitoring weight gain, strain differences and fetal alcohol exposure.

  18. Male adolescent rats display blunted cytokine responses in the CNS after acute ethanol or lipopolysaccharide exposure.

    PubMed

    Doremus-Fitzwater, Tamara L; Gano, Anny; Paniccia, Jacqueline E; Deak, Terrence

    2015-09-01

    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 (P31-33days of age) and adult (69-71days 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 (250μg/kg), or ethanol (4-g/kg), and then trunk blood and brain tissue were collected 3h later for measurement of blood ethanol 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. ethanol challenge, IL-6 and IκBα expression was 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 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

  19. Acute tolerance to rate-decreasing effects of single doses of ethanol.

    PubMed

    Ginsburg, Brett C; Martinez, Gerardo; Friesenhahn, Gregory; Javors, Martin; Lamb, R J

    2008-06-01

    Acute tolerance occurs when behavioral impairment is greater at a given blood ethanol concentration (BAC) on the ascending versus descending limb of the BAC-time curve following administration of a single dose of ethanol, however studies utilizing learned behaviors have not been widely reported. We assessed acute tolerance to single doses of ethanol in five Lewis rats responding under a fixed-ratio (FR8) schedule of food presentation. Response rates for food during 1-min components (ending 2, 4, 11, 18, 33, and 57 min after ethanol administration) were determined, and BAC was measured immediately after each component using a rat breathalyzer. Ethanol (0.4, 0.6, 0.8, and 1.2 g/kg, i.p.) produced dose-related decreases in responding for food that tended to recover over time for all but the highest dose tested. Similarly, dose-related increases in BAC were also observed. Using either an analysis that expressed impairment per unit BAC on the ascending limb versus the descending limb (by assessing the area under the curve (AUC) for behavior and BAC on each limb), the slope of the function that relates the behavioral effect to BAC (each expressed as percent maximum effect), or a variant of the Mellanby method (hysteresis), acute tolerance was observed following a dose of 0.4 g/kg ethanol. Though behavior appeared to recover on the descending limb following higher doses (especially 0.6 and 0.8 g/kg), acute tolerance to these doses was not present. PMID:18328511

  20. Acute ethanol effects on focal cerebral ischemia in fasted rats.

    PubMed

    Zhao, Y J; Yang, G Y; Ben-Joseph, O; Ross, B D; Chenevert, T L; Domino, E F

    1998-05-01

    The effects of acute ethanol intoxication were investigated in a rat model of unilateral middle cerebral artery occlusion. Groups of 5 to 8 male Sprague-Dawley rats were subjected to 4 hr of left middle cerebral artery occlusion. All groups were deprived of food overnight and were pretreated intraperitoneally with 5% dextrose solution (10 ml/kg), 20% ethyl alcohol in 5% dextrose solution (2 g/kg), or 30% ethyl alcohol in a 5% dextrose solution (3 g/kg) 1 hr before middle cerebral artery occlusion. Regional cerebral blood flow during ipsilateral occlusion was approximately 9.1 to 10% of baseline in all groups. The mean % brain water content in control, 2 g/kg ethanol-treated groups, and 3 g/kg ethanol-treated groups were: in the ischemic core--81.6, 81.2, and 82.4; intermediate zone--80.5, 80.6, and 81.7; and outer zone--79.7, 79.7, and 80.8, respectively. Brain Na+ and K+ content in the three groups was related to water content, but much greater with ethanol pretreatment. The water content of the intermediate zones in the 3 g/kg ethanol-treated animals was significantly greater than in the control (p < 0.01 and 0.001) and the 2 g/kg ethanol-treated groups. One-way analysis of variance indicated a significant dose-effect relationship in which the lower dose of ethanol tended to reduce ischemic core water content, and the larger dose increased ischemic core water, compared with the control. None of the overnight fasted groups had any significant hyperglycemia. The group given 3 g/kg i.p. ethanol 1 hr before had exacerbated edema formation with a mean whole blood level of ethanol of approximately 230 mg/dl. The neurotoxic effects of high concentrations of ethanol were unrelated to any change in plasma glucose concentrations.

  1. Anxiety in mice following acute aspartame and ethanol exposure.

    PubMed

    LaBuda, C J; Hale, R L

    2000-01-01

    The purpose of the present study was to look at the effect of aspartame on the anxiolytic actions of ethanol. Previous research has shown that ethanol reliably produces an anxiolytic effect on rodent's plus-maze performance. There have been anecdotal reports that aspartame increases anxiety. CD-1 male mice were given i.p. aspartame doses of vehicle, 1000, or 2000 mg/kg, followed 30 min later by i.p. ethanol doses of 1.6 g/kg or vehicle. Animals were then placed in an open field, then tested in the plus-maze. Results determined that the aspartame condition had no significant effect on anxiety-related behavior, nor did it alter the anxiolytic actions of ethanol. Thus, acute high dose exposure to aspartame does not appear to affect anxiety-related behaviors.

  2. Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: A role for angiotensin type 1 receptor

    SciTech Connect

    Yogi, Alvaro; Callera, Glaucia E.; Mecawi, André S.; Batalhão, Marcelo E.; Carnio, Evelin C.; Antunes-Rodrigues, José; Queiroz, Regina H.; Touyz, Rhian M.; Tirapelli, Carlos R.

    2012-11-01

    Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin–angiotensin system (RAS) activation. Ethanol (1 g/kg; p.o. gavage) effects were assessed within 30 min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10 mg/kg; p.o. gavage), a selective AT{sub 1} receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase‐mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT{sub 1}-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage. -- Highlights: ► Acute ethanol intake stimulates RAS activity and vascular oxidative stress. ► RAS plays a role in acute ethanol-induced oxidative damage via AT{sub 1} receptor activation.

  3. 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

  4. Increased brain nitric oxide levels following ethanol administration.

    PubMed

    Finnerty, Niall; O'Riordan, Saidhbhe L; Klamer, Daniel; Lowry, John; Pålsson, Erik

    2015-05-01

    Nitric oxide is a ubiquitous messenger molecule, which at elevated concentrations has been implicated in the pathogenesis of several neurological disorders. Its role in oxidative stress, attributed in particular to the formation of peroxynitrite, proceeds through its high affinity for the superoxide radical. Alcoholism has recently been associated with the induction of oxidative stress, which is generally defined as a shift in equilibrium between pro-oxidant and anti-oxidant species in the direction of the former. Furthermore, its primary metabolite acetaldehyde, has been extensively associated with oxidative damage related toxic effects following alcohol ingestion. The principal objective of this study was the application of long term in vivo electrochemistry (LIVE) to investigate the effect of ethanol (0.125, 0.5 and 2.0 g kg(-1)) and acetaldehyde (12.5, 50 and 200 mg kg(-1)) on NO levels in the nucleus accumbens of freely moving rats. Systemic administrations of ethanol and acetaldehyde resulted in a dose-dependent increases in NO levels, albeit with very differing time courses. Subsequent to this the effect on accumbal NO levels, of subjecting the animal to different drug combinations, was also elucidated. The nitric oxide synthase inhibitor L-NAME (20 mg kg(-1)) and acetaldehyde sequestering agent D-penicillamine (50 mg kg(-1)) both attenuated the increase in NO levels following ethanol (1 g kg(-1)) administration. Conversely, the alcohol dehydrogenase inhibitor 4-methylpyrazole (25 mg kg(-1)) and catalase inhibitor sodium azide (10 mg kg(-1)) potentiated the increase in NO levels following ethanol administration. Finally, dual inhibition of aldehyde dehydrogenase and catalase by cyanamide (25 mg kg(-1)) caused an attenuation of ethanol effects on NO levels. Taken together these data highlight a robust increase in brain NO levels following systemic alcohol administration which is dependent on NO synthase activity and may involve both alcohol- and acetaldehyde

  5. 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.

  6. Cocaethylene formation following ethanol and cocaine administration by different routes.

    PubMed

    Herbst, Ellen D; Harris, Debra S; Everhart, E Thomas; Mendelson, John; Jacob, Peyton; Jones, Reese T

    2011-04-01

    Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d₅) was administered in all conditions. Oral cocaine-d₅ 2.0 mg/kg, intravenous cocaine-d₅ 1.0 mg/kg, and smoked cocaine-d₅ (200 mg) were administered after oral ethanol 1.0 g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d₃) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d₅, cocaethylene-d₅, cocaethylene-d₃, and benzoylecgonine-d₅ were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs. PMID:21463066

  7. 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

  8. The discriminative stimulus properties of ethanol and acute ethanol withdrawal states in rats.

    PubMed

    Gauvin, D V; Harland, R D; Criado, J R; Michaelis, R C; Holloway, F A

    1989-10-01

    Twelve male Sprague-Dawley rats were trained in a standard two-choice Drug 1-Drug 2 discrimination task utilizing 3.0 mg/kg chlordiazepoxide (CDP, an anxiolytic drug) and 20 mg/kg pentylenetetrazol (PTZ, an anxiogenic drug) as discriminative stimuli under a VR 5-15 schedule of food reinforcement. Saline tests conducted at specific time points after acute high doses of ethanol (3.0 and 4.0 g/kg) indicated a delayed rebound effect, evidenced by a shift to PTZ-appropriate responding. Insofar as such a shift in lever selection indexes a delayed anxiety-like state, this acute 'withdrawal' reaction can be said to induce an affective state similar to that seen with chronic ethanol withdrawal states. Ethanol generalization tests: (1) resulted in a dose- and time-dependent biphasic generalization to CDP, (2) failed to block the PTZ stimulus and (3) failed to block the time- and dose-dependent elicitation of an ethanol-rebound effect. These data suggest that ethanol's anxiolytic effects are tenuous. PMID:2791886

  9. Activation of adenosine A1 receptors reduces anxiety-like behavior during acute ethanol withdrawal (hangover) in mice.

    PubMed

    Prediger, Rui D S; da Silva, George E; Batista, Luciano C; Bittencourt, Alvorita L; Takahashi, Reinaldo N

    2006-10-01

    Elevated signs of anxiety are observed in both humans and rodents during withdrawal from chronic as well as acute ethanol exposure, and it represents an important motivational factor for ethanol relapse. Several reports have suggested the involvement of brain adenosine receptors in different actions produced by ethanol such as motor incoordination and hypnotic effects. In addition, we have recently demonstrated that adenosine A1 receptors modulate the anxiolytic-like effect induced by ethanol in mice. In the present study, we evaluated the potential of adenosine A1 and A2A receptor agonists in reducing the anxiety-like behavior during acute ethanol withdrawal (hangover) in mice. Animals received a single intraperitoneal administration of saline or ethanol (4 g/kg) and were tested in the elevated plus maze after an interval of 0.5-24 h. The results indicated that hangover-induced anxiety was most pronounced between 12 and 18 h after ethanol administration, as indicated by a significant reduction in the exploration of the open arms of the maze. At this time interval, ethanol was completely cleared. The acute administration of 'nonanxiolytic' doses of adenosine and the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), but not the adenosine A2A receptor agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA), at the onset of peak withdrawal (18 h), reduced this anxiogenic-like response. In addition, the effect of CCPA on the anxiety-like behavior of ethanol hangover was reversed by pretreatment with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). These results reinforce the notion of the involvement of adenosine receptors in the anxiety-like responses and indicate the potential of adenosine A1 receptor agonists to reduce the anxiogenic effects during ethanol withdrawal.

  10. Acute Ethanol Does Not Always Affect Delay Discounting in Rats Selected to Prefer or Avoid Ethanol

    PubMed Central

    Wilhelm, Clare J.; Mitchell, Suzanne H.

    2012-01-01

    Aims: 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. Methods: 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. Results: 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. Conclusion: 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. PMID:22645038

  11. Ethanol Self-Administration in Mice under a Second-Order Schedule

    PubMed Central

    Lamb, Richard J.; Pinkston, Jonathan W.; Ginsburg, Brett C.

    2015-01-01

    Long Fixed-Interval (FI) schedules, particularly second-order schedules, can engender substantial responding before drug or ethanol delivery that is uninfluenced by the direct effects of the drug or ethanol. Thus, these schedules can be used to study the effects of medications upon drug- or ethanol-seeking, uninfluenced by the direct effects of the self-administered drug or ethanol. Long FI second-order schedules are frequently used in primates and occasionally in rats. Under second-order schedules, completion of one response requirement, e.g., a Fixed Ratio 10 (FR10:S), produces a brief stimulus presentation, e.g., a 1-sec 80-dB 4-kHZ tone, and this FR10:S serves as the response unit under another schedule, e.g., a FI 1800-sec. Thus, the first FR10 completed after 1800 sec would result in delivery both of the tone and of reinforcement, e.g., 10 × 0.01 mL 16% (w/v) ethanol. To examine if such schedules could be effectively used in mice, which have advantages in neurobiological and genetic studies, we trained eight C57BL/6J mice to respond under the schedule just described. This schedule maintained substantial responding. The temporal pattern of behavior was typical of an FI schedule with responding accelerating across the interval. We also examined the effects of acute and chronic administration of fluvoxamine on this responding, and these were modest. Finally, we examined responding when alcohol and/or tone deliveries were withheld, and found that extinction occurred most rapidly when both were withheld. This work demonstrates that long FI schedules of ethanol delivery may be useful in studying ethanol seeking in mice. PMID:26254963

  12. Ethanol self-administration in mice under a second-order schedule.

    PubMed

    Lamb, Richard J; Pinkston, Jonathan W; Ginsburg, Brett C

    2015-09-01

    Long Fixed-Interval (FI) schedules, particularly second-order schedules, can engender substantial responding before drug or ethanol delivery that is uninfluenced by the direct effects of the drug or ethanol. Thus, these schedules can be used to study the effects of medications upon drug- or ethanol-seeking, uninfluenced by the direct effects of the self-administered drug or ethanol. Long FI second-order schedules are frequently used in primates and occasionally in rats. Under second-order schedules, completion of one response requirement, e.g., a Fixed Ratio 10 (FR10:S), produces a brief stimulus presentation, e.g., a 1-s 80-dB 4-kHZ tone, and this FR10:S serves as the response unit under another schedule, e.g., an FI 1800-s. Thus, the first FR10 completed after 1800 s would result in delivery both of the tone and of reinforcement, e.g., 10 × 0.01 mL 16% (w/v) ethanol. To examine if such schedules could be effectively used in mice, which have advantages in neurobiological and genetic studies, we trained eight C57BL/6J mice to respond under the schedule just described. This schedule maintained substantial responding. The temporal pattern of behavior was typical of an FI schedule with responding accelerating across the interval. We also examined the effects of acute and chronic administration of fluvoxamine on this responding, and these were modest. Finally, we examined responding when alcohol and/or tone deliveries were withheld, and found that extinction occurred most rapidly when both were withheld. This work demonstrates that long FI schedules of ethanol delivery may be useful in studying ethanol seeking in mice.

  13. In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses.

    PubMed

    Shukla, Shivendra D; Aroor, Annayya R; Restrepo, Ricardo; Kharbanda, Kusum K; Ibdah, Jamal A

    2015-11-20

    Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.

  14. Neuroprotective effect of small heat shock protein, Hsp27, after acute and chronic alcohol administration.

    PubMed

    Toth, Melinda Erzsebet; Gonda, Szilvia; Vigh, Laszlo; Santha, Miklos

    2010-11-01

    Alcohol induces degeneration of neurons and inhibits neurogenesis in the brain. Small heat shock proteins are able to protect neurons in cerebral ischemia and oxidative stress. In this study, we investigated the neuroprotective effect of small heat shock protein, Hsp27, after acute and chronic ethanol administrations using transgenic mice overexpressing the human Hsp27 protein. Transgenic mice and wild-type littermates were injected with 2 g/kg ethanol intraperitoneally, and then motor coordination and muscle strength were analyzed using different behavioral tests, such as footprint analysis, balance beam, and inverted screen tests. Ethanol-injected transgenic mice showed similar footprints to control saline-injected mice, did not fall of the beam, and were able to climb to the top of the inverted screen, while wild-type mice showed ataxia and incoordination after ethanol injection. The effect of Hsp27 on chronic ethanol consumption was also investigated. Drinking water of mice was replaced by a 20% ethanol solution for 5 weeks, and then brain sections were stained with Fluoro Jade C staining. We found significantly lesser amount of degenerating neurons in the brain of ethanol-drinking transgenic mice compared to wild-type mice. We conclude that Hsp27 can protect neurons against the acute and chronic toxic effects of ethanol.

  15. Neuroprotective effect of small heat shock protein, Hsp27, after acute and chronic alcohol administration

    PubMed Central

    Toth, Melinda Erzsebet; Gonda, Szilvia; Vigh, Laszlo

    2010-01-01

    Alcohol induces degeneration of neurons and inhibits neurogenesis in the brain. Small heat shock proteins are able to protect neurons in cerebral ischemia and oxidative stress. In this study, we investigated the neuroprotective effect of small heat shock protein, Hsp27, after acute and chronic ethanol administrations using transgenic mice overexpressing the human Hsp27 protein. Transgenic mice and wild-type littermates were injected with 2 g/kg ethanol intraperitoneally, and then motor coordination and muscle strength were analyzed using different behavioral tests, such as footprint analysis, balance beam, and inverted screen tests. Ethanol-injected transgenic mice showed similar footprints to control saline-injected mice, did not fall of the beam, and were able to climb to the top of the inverted screen, while wild-type mice showed ataxia and incoordination after ethanol injection. The effect of Hsp27 on chronic ethanol consumption was also investigated. Drinking water of mice was replaced by a 20% ethanol solution for 5 weeks, and then brain sections were stained with Fluoro Jade C staining. We found significantly lesser amount of degenerating neurons in the brain of ethanol-drinking transgenic mice compared to wild-type mice. We conclude that Hsp27 can protect neurons against the acute and chronic toxic effects of ethanol. PMID:20461564

  16. Acute and chronic tianeptine treatments attenuate ethanol withdrawal syndrome in rats.

    PubMed

    Uzbay, Tayfun; Kayir, Hakan; Celik, Turgay; Yüksel, Nevzat

    2006-05-01

    Effects of acute and chronic tianeptine treatments on ethanol withdrawal syndrome were investigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Acute or chronic (twice daily) tianeptine (5, 10 and 20 mg/kg) and saline were administered to rats intraperitoneally. Acute and last chronic tianeptine injections and saline were done 30 min before ethanol withdrawal testing. After 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, tremor, wet dog shakes, stereotyped behavior and audiogenic seizures were recorded or rated. Locomotor activity in naive (no ethanol-dependent rats) was also tested after acute tianeptine treatments. Acute but not chronic tianeptine treatment attenuated locomotor hyperactivity and agitation in ethanol-dependent rats. Both acute and chronic tianeptine treatment produced some significant inhibitory effects on tremor, wet dog shakes, stereotyped behaviors and audiogenic seizures during the ethanol withdrawal. Our results suggest that acute or chronic tianeptine treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

  17. The contribution of electrophysiology to knowledge of the acute and chronic effects of ethanol.

    PubMed

    Little, H J

    1999-12-01

    This review describes the effects of ethanol on the components of neuronal transmission and the relationship of such effects to the behavioural actions of ethanol. The concentrations of ethanol with acute actions on voltage-sensitive ion channels are first described, then the actions of ethanol on ligand-gated ion channels, including those controlled by cholinergic receptors, 5-hydroxytryptamine receptors, the various excitatory amino acid receptors, and gamma-aminobutyric acid receptors. Acute effects of ethanol are then described on brain areas thought to be involved in arousal and attention, the reinforcing effects of ethanol, the production of euphoria, the actions of ethanol on motor control, and the amnesic effects of ethanol; the acute effects of ethanol demonstrated by EEG studies are also discussed. Chronic effects of alcohol on neuronal transmission are described in the context of the various components of the ethanol withdrawal syndrome, withdrawal hyperexcitability, dysphoria and anhedonia, withdrawal anxiety, craving, and relapse drinking. Electrophysiological studies on the genetic influences on the effects of ethanol are discussed, particularly the acute actions of ethanol and electrophysiological differences reported in individuals predisposed to alcoholism. The conclusion notes the concentration of studies on the classical transmitters, with relative neglect of the effects of ethanol on peptides and on neuronal interactions between brain areas and integrated patterns of neuronal activity. PMID:10665833

  18. Effects of acute caffeine administration on adolescents.

    PubMed

    Temple, Jennifer L; Dewey, Amber M; Briatico, Laura N

    2010-12-01

    Acute caffeine administration has physiological, behavioral, and subjective effects. Despite its widespread use, few studies have described the impact of caffeine consumption in children and adolescents. The purpose of this study was to investigate the effects of acute caffeine administration in adolescents. We measured cardiovascular responses and snack food intake after acute administration of 0 mg, 50 mg, 100 mg, and 200 mg of caffeine. We also compared usual food intake and subjective effects of caffeine between high- and low-caffeine consumers. Finally, we conducted a detailed analysis of caffeine sources and consumption levels. We found main effects of caffeine dose on heart rate (HR) and diastolic blood pressure (DBP), with HR decreasing and DBP increasing with increasing caffeine dose. There were significant interactions among gender, caffeine use, and time on DBP. High caffeine consumers (>50 mg/day) reported using caffeine to stay awake and drinking coffee, tea, soda, and energy drinks more than low consumers (<50 mg/day). Boys were more likely than girls to report using getting a rush, more energy, or improved athletic performance from caffeine. Finally, when we examined energy and macronutrient intake, we found that caffeine consumption was positively associated with laboratory energy intake, specifically from high-sugar, low-fat foods and also positively associated with protein and fat consumption outside of the laboratory. When taken together, these data suggest that acute caffeine administration has a broad range of effects in adolescents and that the magnitude of these effects is moderated by gender and chronic caffeine consumption. PMID:21186925

  19. Evaluation of the antinociceptive activity and acute oral toxicity of standardized ethanolic extract of the rhizome of Curcuma xanthorrhiza Roxb.

    PubMed

    Devaraj, Sutha; Esfahani, Azadeh Sabetghadam; Ismail, Sabariah; Ramanathan, Surash; Yam, Mun Fei

    2010-04-22

    Ethanolic extract of Curcuma xanthorrhiza was used to evaluate the analgesic and toxicity effects in vivo. The extract was standardized using GC-MS, which showed that 1 mg of Curcuma xanthorrhiza ethanolic extract contains 0.1238 mg of xanthorrhizol. The analgesic activity was studied in rats using three different models, namely the hot plate test, tail flick test and formalin-induced pain test. The acute oral toxicity was examined by the oral administration of standardized Curcuma xanthorrhiza ethanolic extract in mice at doses ranging from 300-5,000 mg/kg and observation for 14 days. Standardized Curcuma xanthorrhiza ethanolic extract did not show significant analgesic effect in the hot plate and tail flick tests. However, in the formalin-induced pain test, Curcuma xanthorrhiza ethanolic extract significantly (P < 0.05) suppressed the paw licking time of rats in both early and late phases at doses 200 and 400 mg/kg of the extract, respectively. In the acute oral toxicity study, Curcuma xanthorrhiza ethanolic extract did not show any toxic effects in mice at 5 g/kg. These experimental results suggest that the standardized Curcuma xanthorrhiza ethanolic extract showed peripheral and central antinociceptive activity associated with neurogenic pain as well as a relative absence of toxic effects which could compromise the medicinal use of this plant in folk medicine.

  20. Effects of isoflurane and ethanol administration on c-Fos immunoreactivity in mice.

    PubMed

    Smith, M L; Li, J; Cote, D M; Ryabinin, A E

    2016-03-01

    Noninvasive functional imaging holds great promise for the future of translational research, due to the ability to directly compare between preclinical and clinical models of psychiatric disorders. Despite this potential, concerns have been raised regarding the necessity to anesthetize rodent and monkey subjects during these procedures, because anesthetics may alter neuronal activity. For example, in studies on drugs of abuse and alcohol, it is not clear to what extent anesthesia can interfere with drug-induced neural activity. Therefore, the current study investigated whole-brain c-Fos activation following isoflurane anesthesia as well as ethanol-induced activation of c-Fos in anesthetized mice. In the first experiment, we examined effects of one or three sessions of gaseous isoflurane on c-Fos activation across the brain in male C57BL/6J mice. Isoflurane administration led to c-Fos activation in several areas, including the piriform cortex and lateral septum. Lower or similar levels of activation in these areas were detected after three sessions of isoflurane, suggesting that multiple exposures may eliminate some of the enhanced neuronal activation caused by acute isoflurane. In the second experiment, we investigated the ability of ethanol injection (1.5 or 2.5g/kgi.p.) to induce c-Fos activation under anesthesia. Following three sessions of isoflurane, 1.5g/kg of ethanol induced c-Fos in the central nucleus of amygdala and the centrally-projecting Edinger-Westphal nucleus (EWcp). This induction was lower after 2.5g/kg of ethanol. These results demonstrate that ethanol-induced neural activation can be detected in the presence of isoflurane anesthesia. They also suggest, that while habituation to isoflurane helps reduce neuronal activation, interaction between effects of anesthesia and alcohol can occur. Studies using fMRI imaging could benefit from using habituated animals and dose-response analyses.

  1. Effects of isoflurane and ethanol administration on c-Fos immunoreactivity in mice.

    PubMed

    Smith, M L; Li, J; Cote, D M; Ryabinin, A E

    2016-03-01

    Noninvasive functional imaging holds great promise for the future of translational research, due to the ability to directly compare between preclinical and clinical models of psychiatric disorders. Despite this potential, concerns have been raised regarding the necessity to anesthetize rodent and monkey subjects during these procedures, because anesthetics may alter neuronal activity. For example, in studies on drugs of abuse and alcohol, it is not clear to what extent anesthesia can interfere with drug-induced neural activity. Therefore, the current study investigated whole-brain c-Fos activation following isoflurane anesthesia as well as ethanol-induced activation of c-Fos in anesthetized mice. In the first experiment, we examined effects of one or three sessions of gaseous isoflurane on c-Fos activation across the brain in male C57BL/6J mice. Isoflurane administration led to c-Fos activation in several areas, including the piriform cortex and lateral septum. Lower or similar levels of activation in these areas were detected after three sessions of isoflurane, suggesting that multiple exposures may eliminate some of the enhanced neuronal activation caused by acute isoflurane. In the second experiment, we investigated the ability of ethanol injection (1.5 or 2.5g/kgi.p.) to induce c-Fos activation under anesthesia. Following three sessions of isoflurane, 1.5g/kg of ethanol induced c-Fos in the central nucleus of amygdala and the centrally-projecting Edinger-Westphal nucleus (EWcp). This induction was lower after 2.5g/kg of ethanol. These results demonstrate that ethanol-induced neural activation can be detected in the presence of isoflurane anesthesia. They also suggest, that while habituation to isoflurane helps reduce neuronal activation, interaction between effects of anesthesia and alcohol can occur. Studies using fMRI imaging could benefit from using habituated animals and dose-response analyses. PMID:26742790

  2. Differential response of GFAP-positive astrocytes in the rat prefrontal cortex following ethanol self-administration

    PubMed Central

    Bull, Cecilia; Syed, Wahab A.; Minter, Sabrina C.; Bowers, M. Scott

    2015-01-01

    Background Prefrontal cortex (PFC) dysfunction is believed to contribute to the transition from controlled substance use to abuse. Because astrocytes have been suggested to play a key role in the development and maintenance of drug-seeking behaviors, we sought to determine if PFC astrocytes are affected by ethanol self-administration. Methods Ethanol consumption was modeled in rats by three self-administration paradigms where ethanol was made concurrently available with water in the home cage either continuously (CEA) or intermittently (IEA). In the third paradigm, ethanol was only available in the operant chamber (OEA). To avoid the potential confound of acute ethanol effects, all rats were sacrificed either 24 h or 3 wks abstinence. In all groups, the effect of ethanol consumption on PFC astrocytes was measured using unbiased stereological counting of cells expressing the astrocyte marker glial fibrillary acidic protein (GFAP). GFAP immunoreactivity commonly changes in response to pharmacological insult or injury. Results GFAP-positive astrocyte number increased in the prelimbic and anterior cingulate cortex regions of the PFC after IEA. No change was found in the infralimbic or orbitofrontal cortex after IEA. After 3 weeks abstinence, there was a reduction of astrocytes in the prelimbic and orbitofrontal cortex of the CEA cohort as well as a reduction in the orbitofrontal cortex of the OEA cohort. Conclusion These findings demonstrate that discrete PFC subregions contain GFAP-positive astrocyte populations that respond differentially to distinct ethanol consumption paradigms. A better understanding of how specific astrocyte populations uniquely adapt to ethanol consumption could provide insight for targeted therapeutic interventions. PMID:25833026

  3. Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: a role for angiotensin type 1 receptor.

    PubMed

    Yogi, Alvaro; Callera, Glaucia E; Mecawi, André S; Batalhão, Marcelo E; Carnio, Evelin C; Antunes-Rodrigues, José; Queiroz, Regina H; Touyz, Rhian M; Tirapelli, Carlos R

    2012-11-01

    Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin-angiotensin system (RAS) activation. Ethanol (1 g/kg; p.o. gavage) effects were assessed within 30 min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10 mg/kg; p.o. gavage), a selective AT₁ receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase-mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT₁-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage.

  4. Gastroprotective Effects of PMK-S005 against Ethanol-Induced Acute Gastric Damage in Rats

    PubMed Central

    Choi, Yoon Jeong; Kim, Nayoung; Lee, Ju Yup; Nam, Ryoung Hee; Seo, Ji Hyung; Lee, Seonmin; Kim, Hee Jin; Choi, Yoon Jin; Lee, Hye Seung; Lee, Dong Ho

    2016-01-01

    Background/Aims This study aimed to examine the gastroprotective effects of PMK-S005, which is a synthetic S-allyl-l-cysteine (SAC; a sulfur-containing amino acid), against acute ethanol-induced gastric damage in rats. Methods Sprague-Dawley rats were divided into six groups, including a nonethanol group, groups treated with absolute ethanol 1 hour after pretreatment with various doses of PMK-S005 (1, 5, and 10 mg/kg) or rebamipide (50 mg/kg), and an absolute ethanol-only group. Ethanol-induced gross ulcer and mucus levels were measured. Myeloperoxidase, tumor necrosis factor α, interleukin 1β, PGE2, LTB4, cPLA2, COX-1, and COX-2 levels were estimated by enzyme-linked immunosorbent assay or Western blot analysis. Furthermore, the protein expression levels of antioxidant enzymes, including heme oxygenase-1 (HO-1), NAD(P)H:quinine oxidoreductase 1 (NQO-1), GCLC, and GCLM, were assessed. Results PMK-S005 significantly attenuated the ethanol-induced gastric damage; it reduced mucosal inflammatory cytokine production and increased mucus levels. The expression levels of cPLA2, COX-1, and COX-2 were decreased by PMK-S005. PMK-S005 did not affect PGE2 synthesis, but LTB4 production was significantly suppressed. In addition, long-term administration of PMK-S005 significantly increased the expression of HO-1, NQO-1, GCLC, and GCLM. Conclusions These results strongly suggest that PMK-S005 prevents gastric mucosal damage and that these gastroprotective activities are due to anti-inflammatory effects and enhancement of the gastric defense system, including antioxidant enzymes. PMID:26347516

  5. Neurobehavioral and neurochemical effects of prenatal ethanol administration in rats

    SciTech Connect

    Pradhan, S.; Briggs, F. )

    1992-01-01

    Effects of prenatal ethanol exposure in rats on the behavior and on the levels of multiple neurotransmitters in the brain have been investigated. Timed pregnant Sprague-Dawley rats were divided into three groups: ethanol-exposed, pair-fed control and nutritional control. Ethanol was administered through Leiber-DeCarli liquid diet containing 6% ethanol (v/v) throughout the gestation period in ethanol-exposed rats. Male offspring were tested for alternations in neurobehavioral and neurochemical parameters. Animals exposed to ethanol in utero exhibited lower birth weights, delayed motor development, delayed learning and no catch-up growth, as well as significant alterations in levels of dopamine, norepinephrine, serotonin and GABA in discrete brain areas.

  6. Acute ethanol preexposure promotes liver regeneration after partial hepatectomy in mice by activating ALDH2.

    PubMed

    Ding, Xiang; Beier, Juliane I; Baldauf, Keegan J; Jokinen, Jenny D; Zhong, Hai; Arteel, Gavin E

    2014-01-01

    It is known that chronic ethanol significantly impairs liver regeneration. However, the effect of acute ethanol exposure on liver regeneration remains largely unknown. To address this question, C57Bl6/J mice were exposed to acute ethanol (6 g/kg intragastrically) for 3 days, and partial hepatectomy (PHx) was performed 24 h after the last dose. Surprisingly, acute ethanol preexposure promoted liver regeneration. This effect of ethanol did not correlate with changes in expression of cell cycle regulatory genes (e.g., cyclin D1, p21, and p27) but did correlate with protection against the effect of PHx on indices of impaired lipid and carbohydrate metabolism. Ethanol preexposure protected against inhibition of the oxidant-sensitive mitochondrial enzyme, aconitase. The activity of aldehyde dehydrogenase 2 (ALDH2) was significantly increased by ethanol preexposure. The effect of ethanol was blocked by inhibiting (Daidzin) and was mimicked by activating (Alda-1) ALDH2. Lipid peroxides are also substrates for ALDH2; indeed, alcohol preexposure blunted the increase in lipid peroxidation (4OH-nonenal adducts) caused by PHx. Taken together, these data suggest that acute preoperative ethanol exposure "preconditions" the liver to respond more rapidly to regenerate after PHx by activating mitochondrial ALDH2, which prevents oxidative stress in this compartment.

  7. Effects of chronic binge-like ethanol consumption on cocaine self-administration in rhesus monkeys

    PubMed Central

    Czoty, Paul W.

    2015-01-01

    Background 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). Methods Monkeys self-administered cocaine (0.0–1.0 mg/kg/injection, i.v.) under a 300-second 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: one hour, 5 days/week with daily intake equaling 2.0 g/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 (0.0–1.0 g/kg. i.v.) prior to cocaine self-administration sessions (n=4). Results In 5 of 6 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 2 of 3 monkeys. Acute EtOH infusions only decreased self-administration of lower cocaine doses. Conclusions 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. PMID:26048636

  8. Hepatoprotective effect of carob against acute ethanol-induced oxidative stress in rat.

    PubMed

    Souli, Abdelaziz; Sebai, Hichem; Chehimi, Latifa; Rtibi, Kaïs; Tounsi, Haifa; Boubaker, Samir; Sakly, Mohsen; El-Benna, Jamel; Amri, Mohamed

    2015-09-01

    The present study was undertaken to determine whether subacute treatment with aqueous extract of carob (Ceratonia siliqua L.) pods (AECPs) protects against ethanol (EtOH)-induced oxidative stress in rat liver. Animals were divided into four groups: control, carob, EtOH and EtOH + carob. Wistar rats were intraperitoneally pretreated with AECP (600 mg/kg body weight (bw)) during 7 days and intoxicated for 6 h by acute oral administration of EtOH (6 g/kg bw) 24 h after the last injection. We found that acute administration of EtOH leads to hepatotoxicity as monitored by the increase in the levels of hepatic marker aspartate aminotransferase and alanine aminotransferase as well as hepatic tissue injury. EtOH also increased the formation of malondialdehyde in the liver, indicating an increase in lipid peroxidation and depletion of antioxidant enzyme activities as superoxide dismutase, catalase and glutathione peroxidase. Subacute carob pretreatment prevented all the alterations induced by EtOH and returned their levels to near normal. Importantly, we showed that acute alcohol increased hepatic and plasmatic hydrogen peroxide and free iron levels. The carob pretreatment reversed EtOH effects to near control levels. These data suggest that carob could have a beneficial effect in inhibiting the oxidative damage induced by acute EtOH administration and that its mode of action may involve an opposite effect on plasma and tissue-free iron accumulation. Indeed, carob can be offered as a food additive to protect against EtOH-induced oxidative damage.

  9. Depression of contraction and the calcium transient in single cardiomyocytes with acute ethanol exposure

    SciTech Connect

    Rozanski, D.J.; Delaville, F.J.; Thomas, A.P. )

    1992-01-01

    The mechanism by which acute ethanol (ET) exposure causes reversible myocardial dysfunction is unknown. The purpose of this study was to examine the effects of ET exposure on contraction and cytosolic free Ca[sup 2+] ([Ca[sup 2+

  10. Model studies for evaluating the acute neurobehavioral effects of complex hydrocarbon solvents I. Validation of methods with ethanol.

    PubMed

    McKee, R H; Lammers, J H C M; Hoogendijk, E M G; Emmen, H H; Muijser, H; Barsotti, D A; Owen, D E; Kulig, B M

    2006-12-01

    As a preliminary step to evaluating the acute neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, joint neurobehavioral/toxicokinetic studies were conducted which involved administering ethanol to rats and volunteers. The specific objectives of the present studies were to evaluate the acute central nervous system (CNS) effects of ethanol in rats and humans and to assess relationships between internal levels of exposure and behavioral effects. A more general objective was to validate a battery of neurobehavioral tests that could be used to carry out comparative studies in both species. Accordingly, a range of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute CNS effects. Groups of rats were given ethanol at levels of approximately 0.5, 1.0 or 2.0g/kg, with blood level measurements to verify internal doses. In a volunteer study, 12 healthy male subjects were given 0.65g/kg ethanol, a level approximating the limit for motor vehicle operation in The Netherlands, and neurobehavioral effects were measured prior to and 1 and 3h after ethanol administration, with a computerized neurobehavioral test battery. Blood and air measurements were made to quantify internal doses. Results of the behavioral tests in rats provided evidence of ethanol-induced changes in neuromuscular, sensori-motor, and activity domains. There were also significant changes in visual discrimination, particularly in the areas of general measures of responding and psychomotor speed. In humans there were small but statistically significant effects on learning and memory, psychomotor skills and attention. However, the effects were subtle and not all parameters within given domains were affected. These studies demonstrated a qualitative similarity in response between rats and humans.

  11. ACUPUNCTURE INHIBITS GABA NEURON ACTIVITY IN THE VENTRAL TEGMENTAL AREA AND REDUCES ETHANOL SELF-ADMINISTRATION

    PubMed Central

    Yang, Chae Ha; Yoon, Seong Shoon; Hansen, David M.; Wilcox, Jeffrey D.; Blumell, Bryan R; Park, Jung Jae; Steffensen, Scott C.

    2010-01-01

    Background Withdrawal from chronic ethanol enhances ventral tegmental area (VTA) GABA neuron excitability and reduces mesolimbic dopamine (DA) neurotransmission, which is suppressed by acupuncture at Shenmen (HT7) points (Zhao et al., 2006). The aim of this study was to evaluate the effects of HT7 acupuncture on VTA GABA neuron excitability, ethanol inhibition of VTA GABA neuron firing rate, and ethanol self-administration. A role for opioid receptors (ORs) in ethanol and acupuncture effects is also explored. Methods Using electrophysiological methods in mature rats, we evaluated the effects of HT7 stimulation and opioid antagonists on VTA GABA neuron firing rate. Using behavioral paradigms in rats, we evaluated the effects of HT7 stimulation and opioid antagonists on ethanol self-administration using a modification of the sucrose fading procedure. Results HT7 stimulation produced a biphasic modulation of VTA GABA neuron firing rate characterized by transient enhancement followed by inhibition and subsequent recovery in 5 min. HT7 inhibition of VTA GABA neuron firing rate was blocked by systemic administration of the non-selective μ-opioid receptor (MOR) antagonist naloxone. HT7 stimulation significantly reduced ethanol suppression of VTA GABA neuron firing rate, which was also blocked by naloxone. HT7 acupuncture reduced ethanol self-administration without affecting sucrose consumption. Systemic administration of the δ-opioid receptor (DOR) antagonist naltrindole blocked ethanol suppression of VTA GABA neuron firing rate and significantly reduced ethanol self-administration without affecting sucrose consumption. Conclusions These findings suggest that DOR-mediated opioid modulation of VTA GABA neurons may mediate acupuncture’s role in modulating mesolimbic DA release and suppressing the reinforcing effects of ethanol. PMID:20860620

  12. Acute and chronic ethanol exposure differentially alters alcohol dehydrogenase and aldehyde dehydrogenase activity in the zebrafish liver.

    PubMed

    Tran, Steven; Nowicki, Magda; Chatterjee, Diptendu; Gerlai, Robert

    2015-01-01

    Chronic ethanol exposure paradigms have been successfully used in the past to induce behavioral and central nervous system related changes in zebrafish. However, it is currently unknown whether chronic ethanol exposure alters ethanol metabolism in adult zebrafish. In the current study we examine the effect of acute ethanol exposure on adult zebrafish behavioral responses, as well as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activity in the liver. We then examine how two different chronic ethanol exposure paradigms (continuous and repeated ethanol exposure) alter behavioral responses and liver enzyme activity during a subsequent acute ethanol challenge. Acute ethanol exposure increased locomotor activity in a dose-dependent manner. ADH activity was shown to exhibit an inverted U-shaped curve and ALDH activity was decreased by ethanol exposure at all doses. During the acute ethanol challenge, animals that were continuously housed in ethanol exhibited a significantly reduced locomotor response and increased ADH activity, however, ALDH activity did not change. Zebrafish that were repeatedly exposed to ethanol demonstrated a small but significant attenuation of the locomotor response during the acute ethanol challenge but ADH and ALDH activity was similar to controls. Overall, we identified two different chronic ethanol exposure paradigms that differentially alter behavioral and physiological responses in zebrafish. We speculate that these two paradigms may allow dissociation of central nervous system-related and liver enzyme-dependent ethanol induced changes in zebrafish.

  13. Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration

    PubMed Central

    Ramaker, Marcia J.; Strong, Moriah N.; Ford, Matthew M.; Finn, Deborah A.

    2013-01-01

    Recent evidence suggests that GABAA receptor ligands may regulate ethanol intake via effects at both synaptic and extrasynaptic receptors. For example, the endogenous neurosteroid, allopregnanolone (ALLO) has a similar pharmacological profile as ethanol, and it alters ethanol intake in rodent models. Additionally, recent evidence suggests that δ-subunit containing extrasynaptic GABAA receptors may confer high sensitivity to both ethanol and neurosteroids. The purpose of the present study was to determine the effects of ganaxolone (GAN; an ALLO analogue) and gaboxadol (THIP; a GABAA receptor agonist with selectivity for the extrasynaptic δ-subunit) on ethanol intake, drinking patterns, and bout characteristics in operant and limited access self-administration procedures. In separate studies, the effects of GAN (0 – 10 mg/kg) and THIP (2 – 16 mg/kg) were tested in C57BL/6J male mice provided with two-hour access to a two-bottle choice of water or 10% ethanol or trained to respond for 30 minutes of access to 10% ethanol. GAN had no overall significant effect on operant ethanol self-administration, but tended to decrease the latency to consume the first bout. In the limited-access procedure, GAN dose-dependently decreased ethanol intake. THIP dose-dependently decreased ethanol intake in both paradigms, altering both the consummatory and appetitive processes of operant self-administration as well as shifting the drinking patterns in both procedures. These results add to literature suggesting time-dependent effects of neurosteroids to promote the onset, and to subsequently decrease, ethanol drinking behavior, and they support a role for extrasynaptic GABAA receptor activation in ethanol reinforcement. PMID:22613838

  14. Blood and liver acetaldehyde concentration in rats following acetaldehyde inhalation and intravenous and intragastric ethanol administration

    SciTech Connect

    Watanabe, A.; Hobara, N.; Nagashima, H.

    1986-10-01

    Ethanol is metabolized to acetaldehyde, a highly reactive product of ethanol oxidation. Ethanol might be blended with gasoline and used as a fuel in the future; biohazard of acetaldehyde inhalation must be discussed. Recent improvements in our ability to measure acetaldehyde levels in blood and various tissues have made the assessment of acetaldehyde's role in alcoholic organ intoxication possible. Blood and liver acetaldehyde concentrations in rats were reported as being linearly correlated following intragastric ethanol administration. Acetaldehyde was administered by inhalation to study its toxicity. However, liver concentrations following the inhalation was not investigated. The present communication describes the relationship between blood and liver acetaldehyde concentrations in rats following acetaldehyde inhalation and different routes of ethanol administration.

  15. Effects of Withania somnifera on oral ethanol self-administration in rats.

    PubMed

    Peana, Alessandra T; Muggironi, Giulia; Spina, Liliana; Rosas, Michela; Kasture, Sanjay B; Cotti, Elisabetta; Acquas, Elio

    2014-10-01

    Recent evidence has shown that Withania somnifera Dunal (Ashwagandha or Indian ginseng), a herbal remedy used in traditional medicine, impairs morphine-elicited place conditioning. Here, we investigated the effect of W. somnifera roots extract (WSE) on motivation for drinking ethanol using operant self-administration paradigms. Wistar rats were trained to self-administer ethanol (10%) by nose-poking. The effects of WSE (25-75 mg/kg) were evaluated on acquisition and maintenance, on ethanol breakpoint under a progressive-ratio schedule of reinforcement and on the deprivation effect and reinstatement of seeking behaviours. Moreover, on the basis of the recent suggestion of an involvement of GABAB receptors in WSE central effects, we studied the interaction between WSE and GABAB ligands. The effect of WSE on saccharin (0.05%) oral self-administration was also tested. The results show that WSE reduced the acquisition, maintenance and breakpoint of ethanol self-administration. WSE also reduced the deprivation effect, reinstatement of ethanol-seeking behaviours and saccharin reinforcement. Furthermore, the GABAB receptor antagonist, phaclofen, counteracted the ability of WSE to impair the maintenance of ethanol self-administration. These findings show that WSE, by an action that may involve GABAB receptors, impairs motivation for drinking ethanol and suggest that further investigations should be performed to determine whether W. somnifera may represent a new approach for the management of alcohol abuse. PMID:25115596

  16. Effects of Withania somnifera on oral ethanol self-administration in rats.

    PubMed

    Peana, Alessandra T; Muggironi, Giulia; Spina, Liliana; Rosas, Michela; Kasture, Sanjay B; Cotti, Elisabetta; Acquas, Elio

    2014-10-01

    Recent evidence has shown that Withania somnifera Dunal (Ashwagandha or Indian ginseng), a herbal remedy used in traditional medicine, impairs morphine-elicited place conditioning. Here, we investigated the effect of W. somnifera roots extract (WSE) on motivation for drinking ethanol using operant self-administration paradigms. Wistar rats were trained to self-administer ethanol (10%) by nose-poking. The effects of WSE (25-75 mg/kg) were evaluated on acquisition and maintenance, on ethanol breakpoint under a progressive-ratio schedule of reinforcement and on the deprivation effect and reinstatement of seeking behaviours. Moreover, on the basis of the recent suggestion of an involvement of GABAB receptors in WSE central effects, we studied the interaction between WSE and GABAB ligands. The effect of WSE on saccharin (0.05%) oral self-administration was also tested. The results show that WSE reduced the acquisition, maintenance and breakpoint of ethanol self-administration. WSE also reduced the deprivation effect, reinstatement of ethanol-seeking behaviours and saccharin reinforcement. Furthermore, the GABAB receptor antagonist, phaclofen, counteracted the ability of WSE to impair the maintenance of ethanol self-administration. These findings show that WSE, by an action that may involve GABAB receptors, impairs motivation for drinking ethanol and suggest that further investigations should be performed to determine whether W. somnifera may represent a new approach for the management of alcohol abuse.

  17. Synaptic action of ethanol on cerebellar auditory granule cells reveals acute tolerance

    SciTech Connect

    Huang, C.M.; Liu, G.; Huang, R.H. )

    1991-03-11

    The cerebellum is very sensitive to acute intoxication by ethanol. The authors have recorded electrophysiological responses of granule cells to auditory stimulation from the posterior cerebellar vermis of cats before and after a relatively low dose of ethanol. Auditory responses of granule cells were severely inhibited by ethanol at a transient, peak ethanol concentration of 15-18 mM in the cerebrospinal fluid (CSF). Thereafter, the clearance of ethanol from CSF followed an exponential time course, with 50% of the CSF ethanol being cleared with every passing hour. Auditory responses of granule cells returned to control levels within 60-90 minutes, despite the presence of a DSF ethanol concentration at 8-10mM, indicating acute tolerance. Moreover, a second, identical dose of ethanol, delivered two hours after the first dose produced an attenuated inhibition in the auditory response of cerebellar granule cells. The inhibition took a longer time to be evident but a shorter time to recover than that followed by the first dose of ethanol.

  18. Perillyl alcohol protects against ethanol induced acute liver injury in Wistar rats by inhibiting oxidative stress, NFκ-B activation and proinflammatory cytokine production.

    PubMed

    Khan, Abdul Quaiyoom; Nafees, Sana; Sultana, Sarwat

    2011-01-11

    Oxidative stress and inflammation are two major etiological factors that are suggested to play key roles in the development of ethanol induced liver injury. Release of proinflammatory cytokine like tumor necrosis factor alpha (TNF-α) and activation of nuclear factor kappa-B (NFκ-B) may strongly intensify inflammation and cell damage. Additionally, reactive oxygen species (ROS) also exerts significant effect in this whole cell signaling machinery. The present study was designed to investigate the protective effects of perillyl alcohol (POH) on ethanol-induced acute liver injury in Wistar rats and its probable mechanism. We have successfully demonstrated that pre-treatment with POH, besides exerting antioxidant activity might be able to modulate TNF-α release and NFκ-B activation. Rats were divided into five groups and treated with ethanol or POH via an intragastric tube for one week. Control group was treated with vehicle, and ethanol treated group was given ethanol (5 g/kg body wt). Animal of treatment groups were pretreated with POH (50 & 100 mg/kg body wt) and have been given ethanol. Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase and hepatic malondialdehyde were increased significantly by ethanol treatment. Ethanol administration decreased hepatic reduced glutathione content and various antioxidant enzymes activity. TNF-α production and NFκ-B activation was also found to be increased after ethanol administration. POH pre-treatment significantly ameliorates ethanol induced acute liver injury possibly by inhibition of lipid peroxidation, replenishment of endogenous enzymatic and non-enzymatic defense system, downregulation of TNF-α as well as NFκ-B.

  19. [Anatomo-histological and histochemical study of acute lesions of the gastroduodenal mucosa, produced by ethanol, before and after truncal vagotomy plus pyloroplasty in rats].

    PubMed

    Bartolomucci, A C; da Silva, A L; Barbosa, A J; Nogueira, A M

    1990-01-01

    The anatomo-pathologic alterations determined by ethanol in the gastroduodenal mucosa of rats are studied, as well as its action about truncal vagotomy plus pyloroplasty (VT + P). We use albino rats submitted to the administration of ethanol, 33% --via orogastric catheter- and to truncal vagotomy plus pyloroplasty, as well the association of the 2 variants. The utilization of ethanol, according to the up to date methodology, can be confirmed by a simple experimental production method of acute ulcer in rats. The VT + P determined acute ulcers in the 24 hour observation group, besides acute inflammatory lesions and with the decrease of mucins, diffusively, in the gastroduodenal mucosa. The performance of VT + P, 2 hours after the administration of ethanol, period in which the lesions are entirely settled, determined and aggravation of the gastric lesions through the increase of the media ulcerous gastric area and its histological aspects. On the other hand, the performance of VT + P, followed by the administration of ethanol 2 hours after, also determined an aggravation of gastric lesions, according to the same former parameters. When it was the time to perform the VT + P, 10 days before the administration of ethanol, or the inverse, a small reduction at the ulcerous gastric area had accrued but it did not amount to much. There was not a characterization of preventive effects or curative of this surgical procedure considering the gastric lesions produced by ethanol, but there was characterization of aggravating effect. All the possible hypothesis to the aggravation of these lesions are also discussed with the utilization of VT + P, as well its clinical use on the human being.

  20. Ethanol self-administration in Maudsley reactive and Maudsley nonreactive inbred rats.

    PubMed

    Adams, Nelson; Mitchell, Pamela S; Campbell, Santiba D; Samson, Herman H

    2002-04-01

    This study was performed to investigate ethanol self-administration in inbred Maudsley rats, which were selected for differences in stress susceptibility and which often differ in their home cage ethanol consumption. Adult, male, Maudsley reactive (MR/Har) and Maudsley nonreactive (MNRA/Har) rats were tested in a standard protocol for the sucrose-substitution procedure for the initiation of self-administration of ethanol in an operant setting. Before and after initiation for self-administration in the operant setting, rats were tested for home cage consumption of 10% (vol./vol.) ethanol in a two-bottle test for 14 consecutive days. During the sucrose-substitution procedure, MNRA/Har rats consumed more sucrose and ethanol than did MR/Har rats. In addition, MNRA/Har rats self-administered a greater amount of ethanol during a concentration manipulation with the use of a fixed ratio (FR) 4 response requirement. However, both strains self-administered low amounts of 10% ethanol (MNRA/Har, 0.15 g/kg/day; MR/Har, 0.08 g/kg/day) after concentration manipulation compared with those observed in outbred rats and alcohol-preferring rats tested under identical conditions in other studies. Both MR/Har and MNRA/Har rats markedly increased their ethanol intake in the home cage after the initiation protocol, but there was no difference between MR/Har and MNRA/Har on that measure. The failure of MR/Har rats to self-administer ethanol was inconsistent with their home cage drinking in other studies, and this is distinctly different from the self-administration pattern of high-alcohol-drinking rat lines tested in this paradigm.

  1. Effects of acute ethanol exposure on hepatic metallothionein, zinc and glutathione in male and female rats

    SciTech Connect

    Harris, J.; Harrell, B. )

    1991-03-15

    The purpose of this study was to determine the simultaneous responses of hepatic metallothionein (MT), zinc (Zn) and glutathione (GSH) in male and female rats to an acute ethanol dose. In male rats, hepatic MT has been shown to be induced by an acute ethanol dose. The Sprague-Dawley rats were fed the Lieber-DeCarli control diet for a five day period and then divided into 6 groups: baseline females and males, ethanol-treated females and males, pair-fed females and males. At t=0, baseline rats were killed, ethanol-treated rats were given ethanol by intragastric tube, and pair-fed rats were given ethanol by intragastric tube, and pair-fed rats were given an isocaloric sucrose solution by intragastric tube. At t=24 h, the ethanol-treated and pair-fed rats were killed. Livers were assayed for MT. Zn and GSH. Concentrations of blood ethanol (BEC) were significantly greater for male than female rats. A two way ANOVA with the independent variables being time and sex was performed to analyze differences for hepatic MT, Zn and GSH. For rats dosed with ethanol and killed 24 h later compared with rats at baseline, hepatic MT was significantly greater and hepatic Zn and GSH were not significantly different. Hepatic MT, Zn and GSH were not significantly different by sex. A significant correlation existed between hepatic Zn/g and MT/g. In conclusion, 24 h after an acute dose of ethanol, female as well as male rats responded with the induction of hepatic MT; and enough cysteine was available for the induction of hepatic MT and the maintenance of hepatic GSH levels. The measurement of Zn bound to hepatic MT rather than total hepatic Zn would be desirable to discern if changes in Zn distribution occur.

  2. Acute extracellular ethanol load does not produce hyponatremia by internal osmoregulation

    SciTech Connect

    Jackson, J.E.; Tzamaloukas, A.H.; Long, D.A.

    1986-03-05

    Hyponatremia is frequently present in subjects intoxicated with ethanol. To study whether an acute increase in extracellular osmolality by addition of ethanol creates any clinically appreciable osmotic shift of intracellular water extracellularly, they infused over 20 sec 11 mmol/kg of ethanol intravenously into 5 anesthetized dogs (2 with intact renal function, 3 anuric) and measured plasma sodium and ethanol concentrations and osmolality at frequent intervals for 100 min after the end of the infusion. For a range of ethanol concentration between 4 and 120 mmol/l, changes in osmolality were equal to ethanol concentration in plasma water (y = -0.49 + 1.06 x mosm/kg per mmol/l, r = 0.981, p < 0.01). Plasma sodium concentration remained unchanged from baseline throughout the experiments, even at 1 min post-infusion, when osmolality was 78 +/- 25 mosm/kg above the baseline. An acute increase in extracellular osmolality created by rapid intravenous infusion of a large dose of ethanol does not create any osmotic shift of intracellular water extracellularly, that can be detected by dilution of extracellular sodium. The mechanism of hyponatremia in ethanol intoxication is not internal osmoregulation, but abnormalities in external balance of body water and/or solute.

  3. Operant self-administration models for testing the neuropharmacological basis of ethanol consumption in rats.

    PubMed

    June, Harry L; Gilpin, Nicholas W

    2010-04-01

    Operant self-administration procedures are used to assess the neural basis of ethanol-seeking behavior under a wide range of experimental conditions. In general, rats do not spontaneously self-administer ethanol in pharmacologically meaningful amounts. This unit provides a step-by-step guide for training rats to self-administer quantities of ethanol that produce moderate to high blood-alcohol content. Different protocols are used for rats that are genetically heterogeneous versus rats that are selectively bred for high alcohol preference. Also, these protocols have different sets of advantages and disadvantages in terms of the ability to control for caloric intake and taste of solutions in operant testing. Basic self-administration protocols can also be altered to focus on different aspects of the motivational properties of ethanol (for example, those related to dependence). This unit provides multiple protocols that lead to alcohol intake in rats, which can be pharmacologically probed relative to a variety of control conditions.

  4. Acute Oral Ethanol Exposure Triggers Asthma In Cockroach Allergen–Sensitized Mice

    PubMed Central

    Bouchard, Jacqueline C.; Kim, Jiyoun; Beal, Dominic R.; Vaickus, Louis J.; Craciun, Florin L.; Remick, Daniel G.

    2013-01-01

    Asthma may be triggered by multiple mediators, including allergen-IgE cross-linking and non-IgE mechanisms. Several clinical studies have shown acute ethanol consumption exacerbates asthma, yet no animal model exists to study this process. We developed a model of ethanol-triggered asthma in allergen-sensitized mice to evaluate the mechanisms of ethanol inducing asthma-like responses. Outbred mice were exposed to cockroach allergens on Days 0 and 14; and on Day 21, mice received ethanol by oral gavage. Tracer studies confirmed alcohol aspiration did not occur. Within 30 minutes, alcohol induced degranulation of over 74% of mast cells, and multiple parameters of asthma-like pulmonary inflammation were triggered. Ethanol-gavaged mice had a fivefold increased production of eotaxin-2 (534 pg/mL) and a sevenfold increase in bronchoalveolar eosinophils (70,080 cells). Ethanol induced a 10-fold increase in IL-13, from 84 pg/mL in sensitized mice to 845 pg/mL in ethanol-gavaged sensitized mice. In cockroach allergen–sensitized mice, ethanol triggered asthma-like changes in respiratory physiology and a significant fivefold increase in airway mucin production. Importantly, none of these asthmatic exacerbations were observed in normal mice gavaged with ethanol. Cromolyn sodium effectively stabilized mast cells, yet increased mucin production and bronchoalveolar eosinophil recruitment. Together, these data show a single oral alcohol exposure will trigger asthma-like pulmonary inflammation in allergen-sensitized mice, providing a novel asthma model. PMID:22796441

  5. Seven-day ethanol administration influence on the rat brain histaminergic neurons.

    PubMed

    Zimatkin, Sergey M; Phedina, Ekaterina M

    2015-09-01

    The purpose of the study is to clarify the effect of 7 days of ethanol administration upon brain histaminergic neurons in rats. Male Wistar rats were injected intraperitoneally (i.p.) with 20% ethanol/saline (0.85% NaCl) daily, over 7 days, whereas control rats were given saline. The animals were decapitated 24 h after the 7th injection and samples of hypothalamus were prepared for light and electron microscopy, accompanied by morphometry to examine the histaminergic neurons. It was found that ethanol administration gradually decreased the duration of alcohol-induced sleep and decreased the total amount of histaminergic neurons and the amount of histologically normal neurons, but increased the amount of hypochromic neurons and shadow cells. The histaminergic neuron bodies and nuclei decreased in size. The ultrastructural changes in histaminergic neurons demonstrated activation of their nuclear apparatus, both destruction or hypertrophy and hyperplasia of organelles, especially lysosomes. The histochemical examination revealed the activation of lactate dehydrogenase and acid phosphatase, and inhibition of NADH-, NADPhH, and succinate dehydrogenases. Following 7 days of ethanol administration, histaminergic neurons exhibit the structural signs of hyperactivity, which can be related to neuronal adaptation to the actions of ethanol, and increased behavioral tolerance to ethanol.

  6. 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. PMID:27376896

  7. 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.

  8. Evaluation of acute skin irritation and phototoxicity by aqueous and ethanol fractions of Angelica keiskei

    PubMed Central

    LEE, SANG-HAN

    2013-01-01

    In this study, to assess whether aqueous and ethanol fractions of Angelica keiskei induce acute skin irritation and phototoxicity, acute skin irritancy and phototoxicity tests were performed. The skin of rabbits or guinea pigs was treated with these fractions (100 mg/dose) and whether the animals sustained significant skin damage was determined. The data demonstrated that the aqueous and ethanol fractions of Angelica keiskei did not induce acute toxicity in the skin of the animals, as assessed by anatomical and pathological observations. The results from the present study suggest that these aqueous and ethanol fractions of Angelica keiskei have promising potential uses as cosmetic ingredients that do not induce significant levels of skin irritation or phototoxicity. PMID:23251240

  9. Physiological and behavioral effects of acute ethanol hangover in juvenile, adolescent, and adult rats.

    PubMed

    Brasser, Susan M; Spear, Norman E

    2002-04-01

    This study examined differential responding of juvenile, adolescent, and adult rats after intoxication from an acute alcohol challenge. Experiment I generated blood ethanol curves for subjects 25, 35, or 110 days postnatal, after doses of 2.0 or 4.0 g/kg, assessing elimination rates and time of drug clearance. Experiment 2 compared ethanol's initial hypothermic and delayed hyperthermic effect across age by 48-hr temperature measurement with telemetry. At clearance or 24 hr after alcohol exposure, Experiment 3 tested subjects for changes in acoustic startle reactivity and ultrasonic vocalization (USV). Younger rats showed an absent or reduced tendency for residual hyperthermia, and adults showed alterations in USV observed as aftereffects of intoxication, despite greater initial blood alcohol levels and ethanol hypothermia in the former. The lesser ethanol hangover effects in weanlings and adolescents may be due in part to faster ethanol elimination at these ages compared with adults.

  10. Interaction between vitamin E and glutathione in rat brain: Effect of chronic ethanol administration.

    PubMed

    Marcus, S R; Chandrakala, M V; Nadiger, H A

    1998-12-01

    The protection against ethanol-induced lipid peroxidation is rendered by antioxidants such as vitamin E and glutathione (GSH) interacting with each other and also functioning independently. A study of the levels of GSH and activities of glutathione peroxidase (GP), glutathione reductase (GR) and glutathione transferase (GST) in the cerebral cortex (CC), cerebellum (CB) and brain stem (BS) of vitamin E-supplemented and -deficient rats subjected to ethanol administration for 30 days was carried out. Chronic ethanol administration to vitamin E-supplemented rats elevated GP, GR and GST activities in the three regions and GSH levels in the CB. Chronic ethanol administration to vitamin E-deficient rats elevated GR activity in the three regions and GP activity in the CC and CB, decreased GST activity in the CC and CB, but did not alter GSH levels compared with normal rats subjected to chronic ethanol administration. The results indicate that vitamin E helps to maintain GSH levels to combat increased peroxidation while its absence has a deleterious effect.

  11. Acute and Cytotoxicity Studies of Aqueous and Ethanolic Leaf Extracts of Chromolaena odorata.

    PubMed

    Asomugha, R N; Ezejiofor, A N; Okafor, P N; Ijeh, I I

    2015-01-01

    Chromolaena odorata, a commonly used traditional remedy for different ailments, believed to be quite safe in terms of toxicity was evaluated for acute toxicity and cytotoxic potentials. Acute toxicity was done on albino Wistar rats using the Lorke method while brine shrimps were used to test for cytotoxicity. The results showed that the estimated LD50 for the aqueous and ethanolic extracts was 2154 and > 5000 mg kg(-1) body weight, respectively. Cytotoxicity to brine shrimps showed LC50 values of 324 and 392 ppm for aqueous and ethanolic extracts, respectively. These results indicate the relative non toxic nature of Chromolaena odorata extracts.

  12. The influence of mecamylamine on ethanol and sucrose self-administration.

    PubMed

    Ford, Matthew M; Fretwell, Andrea M; Nickel, Jeffrey D; Mark, Gregory P; Strong, Moriah N; Yoneyama, Naomi; Finn, Deborah A

    2009-09-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to be critically involved in ethanol-related behaviors as well as in neurochemical responses to ethanol. However, discernment of nAChR contribution to ethanol reinforcement and consumption remains incomplete. The current studies examined the influence of the nAChR antagonist mecamylamine (MEC) on operant ethanol self-administration using a procedure that independently assessed appetitive and consumptive processes, and compared these findings to effects of MEC on sucrose self-administration. Male C57BL/6J (B6) mice were trained to respond for 30-min access to a retractable drinking tube containing either 10% v/v ethanol (10E) or 5% w/v sucrose (5S). Once trained, mice were habituated to saline injection and then treated with a series of MEC doses (0-8 mg/kg; i.p.) in a within-subject design. In a separate cohort, MEC was evaluated for its influence on locomotor activity. MEC dose-dependently reduced 10E and 5S self-administration. The suppression in ethanol intake was attributable to a reduction in bout frequency, whereas the attenuation in sucrose intake was due to a decrease in bout size. Doses of MEC (6-8 mg/kg) that altered drinking patterns were also found to impair locomotor activity. Although MEC non-selectively reduced 10E and 5S intakes in mice, there was some specificity in alterations of the underlying drinking pattern for each reinforcer. Assessment of drinking topography within an operant self-administration procedure may provide useful insights regarding the role of nAChR function in the regulation of ethanol consumption. PMID:19501109

  13. Acute behavioural comparisons of toluene and ethanol in human subjects.

    PubMed Central

    Echeverria, D; Fine, L; Langolf, G; Schork, T; Sampaio, C

    1991-01-01

    A comparison of toluene and ethanol (EtOH) induced changes in central nervous system (CNS) function and symptoms were evaluated in two studies, and when possible the effects of toluene were expressed in EtOH equivalent units. The toluene concentrations were 0, 75, and 150 ppm, bracketing the American Conference of Governmental Industrial Hygienists threshold limit value (ACGIH TLV) of 100 ppm. The socially relevant EtOH doses were 0.00, 0.33, and 0.66 g EtOH/kg body weight, equivalent to two and four 3.5% 12 ounce beers. Forty two paid college students were used in each study. In the first study, subjects were exposed to toluene and an odour masking agent menthol (0.078 ppm) for seven hours over three days. In the second study EtOH or a placebo was administered at 1530 across three days also in the presence of menthol. Verbal and visual short term memory (Sternberg, digit span, Benton, pattern memory), perception (pattern recognition), psychomotor skill (simple reaction time, continuous performance, symbol-digit, hand-eye coordination, finger tapping, and critical tracking), manual dexterity (one hole), mood (profile on mood scales (POMS), fatigue (fatigue checklist), and verbal ability were evaluated at 0800, 1200, and 1600. Voluntary symptoms and observations of sleep were collected daily. A 3 x 3 latin square design evaluated solvent effects simultaneously controlling for learning and dose sequence. An analysis of variance and test for trend were performed on am-pm differences reflecting an eight hour workday and on pm scores for each solvent, in which subjects were their own control Intersubject variation in absorbance was monitored in breath. A 5 to 10% decrement was considered meaningful if consistent with a linear trend at p less than 0.05. At 150 ppm toluene, losses in performance were 6.0% for digit span, 12.1% for pattern recognition (latency), 5% for pattern memory (number correct), 6.5% for one hole, and 3% for critical tracking. The number of headaches

  14. 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

  15. Metabolic and structural consequences of ethanol and chloroquin administration during gestation on the developing fetus

    SciTech Connect

    Sharma, A.; Rawat, A.K.

    1987-05-01

    In the present study the effects of ethanol and chloroquin administration during gestation have been investigated on the developing rat fetus. Ethanol was given in liquid Sustacal diet as 30% of calories and controls were fed isocaloric sucrose-diet. Chloroquin was given intragastrically corresponding controls received saline. Chloroquin resulted in prenatal growth retardation leading to maximum decrease of 46% in body weight of the fetus. It also resulted in 30% higher incidence of hepatomegaly; 15% higher incidence of liquification of visceral organs; 34% decrease in the ossification of sternum; 9% higher defects of cleft palate, wrist drop, clubbed foot and brain liquification compared to the corresponding controls. Ethanol resulted in pre and post-natal growth retardation, cleft palate, still births and lowered brain weights. Fetuses from the ethanol-fed group also showed inhibited protein synthesis, RNA and DNA synthesis in the brain compared to the controls.

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

    PubMed

    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

  17. 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

  18. Catalase-independent early-gene expression in rat brain following acute ethanol exposure.

    PubMed

    Canales, Juan J

    2004-07-30

    Early-gene expression evoked by acute ethanol treatment was studied in rat brain by quantitative immunocytochemistry, with reference to ethanol metabolism by the enzyme catalase. Colocalization with mu-opioid receptor (MOR) sites was also examined. Ethanol challenges [1, 2.5, and 4 g/kg intraperitoneally (i.p.)] evoked dose-dependent increases in c-Fos expression in several brain regions, but overlap with MOR-rich sites was only partial. Strong inhibition of brain catalase activity (ca. 60%) with 3-amino-1,2,4-triazole (AT, 1 g/kg i.p.) did not alter ethanol-induced c-Fos nor Krox-24 expression in any of the brain regions analyzed. This evidence demonstrates that catalase-mediated metabolism is not a requisite for c-Fos nor Krox-24 induction in rat brain following acute ethanol treatment, and suggests that ethanol is by itself capable of eliciting strong neuronal and circuit-level adaptations in the nervous system.

  19. Systemic administration of D-penicillamine prevents the locomotor activation after intra-VTA ethanol administration in rats.

    PubMed

    Martí-Prats, Lucía; Sánchez-Catalán, María José; Hipólito, Lucía; Orrico, Alejandro; Zornoza, Teodoro; Polache, Ana; Granero, Luis

    2010-10-11

    Although recently published studies seem to confirm the important role displayed by acetaldehyde (ACH), the main metabolite of ethanol, in the behavioral effects of ethanol, the origin of ACH is still a matter of debate. While some authors confer more importance to the central (brain metabolism) origin of ACH, others indicate that the hepatic origin could be more relevant. In this study we have addressed this topic using an experimental approach that combines local microinjections of ethanol into the ventral tegmental area (VTA) (which guarantees the brain origin of the ACH) to induce motor activation in rats together with systemic administration (i.p.) of several doses (0, 12.5, 25 and 50 mg/kg) of D-penicillamine (DP), a sequestering agent of ACH with contrasted efficiency to abolish the behavioral effects of the drug. Our results clearly show that DP prevented in a dose-dependent manner the motor activation induced by intra-VTA ethanol, being the 50 mg/kg dose the most efficient. DP per se did not affect the basal activity of the rats. In order to determine the specificity of the DP action, we also studied the effects of DP 50 mg/kg on the DAMGO-induced motor activation after the intra-VTA administration of this mu-opioid receptors agonist. DP did not significantly modify the motor activation induced by DAMGO thus confirming the specificity of the DP effects. Our results clearly suggest that the brain-derived ACH is necessary to manifest the activating effects resulting from ethanol administration. PMID:20691754

  20. Optogenetic stimulation of VTA dopamine neurons reveals that tonic but not phasic patterns of dopamine transmission reduce ethanol self-administration.

    PubMed

    Bass, Caroline E; Grinevich, Valentina P; Gioia, Dominic; Day-Brown, Jonathan D; Bonin, Keith D; Stuber, Garret D; Weiner, Jeff L; Budygin, Evgeny A

    2013-01-01

    There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA) dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors. Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known. In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive. Here, we sought to address these gaps in our knowledge using a newly developed viral-mediated gene delivery strategy to selectively express Channelrhodopsin-2 (ChR2) on dopamine cells in the VTA of wild-type rats. We then used this approach to precisely control VTA dopamine transmission during voluntary ethanol drinking sessions. The results confirmed that ChR2 was selectively expressed on VTA dopamine cells and delivery of blue light pulses to the VTA induced dopamine release in accumbal terminal fields with very high temporal and spatial precision. Brief high frequency VTA stimulation induced phasic patterns of dopamine release in the nucleus accumbens. Lower frequency stimulation, applied for longer periods mimicked tonic increases in accumbal dopamine. Notably, using this optogenetic approach in rats engaged in an intermittent ethanol drinking procedure, we found that tonic, but not phasic, stimulation of VTA dopamine cells selectively attenuated ethanol drinking behaviors. Collectively, these data demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors.

  1. Assessment of Expression of Genes Coding GABAA Receptors during Chronic and Acute Intoxication of Laboratory Rats with Ethanol.

    PubMed

    Osechkina, N S; Ivanov, M B; Nazarov, G V; Batotsyrenova, E G; Lapina, N V; Babkin, A V; Berdinskikh, I S; Melekhova, A S; Voitsekhovich, K O; Lisitskii, D S; Kashina, T V

    2016-02-01

    Expression of genes encoding the individual subunits of ionotropic GABAA receptor was assessed after acute and chronic intoxication of rats with ethanol. The chronic 1-month-long exposure to ethanol signifi cantly decreased (by 38%) expression of Gabrb1 gene in the hippocampus. Acute exposure to ethanol elevated expression of genes Gabrb1 (by 1.7 times), Gabra1 (by 3.8 times), and Gabra4 (by 6.5 times), although it diminished expression of Gabra2 gene by 1.4 times. In preliminarily alcoholized rats, acute intoxication with ethanol enhanced expression of genes Gabrb1 and Gabra5 by 1.7 and 8.7 times, respectively. There was neither acute nor chronic effect of ethanol on expression of gene Gabra3. PMID:26902358

  2. Distribution of methamphetamine and its metabolite amphetamine in acute and subacute ethanol-methamphetamine combination abuse model rats.

    PubMed

    Liang, Man; Liu, Yan; Zheng, Na; Ananda, Sunnassee; Liu, Liang

    2012-01-01

    The aim of this study is to investigate the distribution of methamphetamine (MA) and its metabolite amphetamine (AP) in rat models of acute and subacute MA-ethanol combination abuse. Rats were fed with 20% ethanol for 4 weeks (chronic active-drinking group), and MA was injected intraperitoneally into chronically drinking and normal rats over 5 and 14 days, respectively. Then the rats from the acute and subacute combination abuse groups were euthanized, and ethanol, MA, and AP concentrations in samples were quantified. Except for the similar ethanol concentrations among acute and subacute groups, the MA and AP levels between groups were quite different. The concentrations of MA and AP in rats' liver, lung, kidney, and brain were much higher than other tissues, regardless of combination with ethanol. Also, MA and AP levels in subacute rats groups were higher than those in acute groups, and the levels of MA and the formation of AP in rats subjected to the combination abuse with ethanol were higher than in MA-only intoxicated rats. We conclude that ethanol has no bearing on the MA and AP distribution in body fluids and tissues, yet it can increase MA levels and markedly accelerate the formation of AP in combination-abuse rats. Comparing the acute and subacute combination-abuse rats' samples, it can be deduced that various accumulated amounts of MA and AP were unaffected by ethanol, even after multi-dose injection, regardless of acute or subacute use.

  3. Acute effects of ethanol in the control of protein synthesis in isolated rat liver cells

    SciTech Connect

    Girbes, T.; Susin, A.; Ayuso, M.S.; Parrilla, R.

    1983-10-01

    The acute effect of ethanol on hepatic protein synthesis is a rather controversial issue. In view of the conflicting reports on this subject, the effect of ethanol on protein labeling from L-(/sup 3/H)valine in isolated liver cells was studied under a variety of experimental conditions. When tracer doses of the isotope were utilized, ethanol consistently decreased the rate of protein labeling, regardless of the metabolic conditions of the cells. This inhibition was not prevented by doses of 4-methylpyrazole large enough to abolish all the characteristic metabolic effects of ethanol, and it was not related to perturbations on the rates of L-valine transport and/or proteolysis. When ethanol was tested in the presence of saturating doses of L-(/sup 3/H)valine no effect on protein labeling was observed. These observations suggest that the ethanol effect in decreasing protein labeling from tracer doses of the radioactive precursor does not reflect variations in the rate of protein synthesis but reflects changes in the specific activity of the precursor. These changes probably are secondary to variations in the dimensions of the amino acid pool utilized for protein synthesis. Even though it showed a lack of effect when tested alone, in the presence of saturating doses of the radioactive precursor ethanol inhibited the stimulatory effects on protein synthesis mediated by glucose and several gluconeogenic substrates. This effect of ethanol was not prevented by inhibitors of alcohol dehydrogenase, indicating that a shift of the NAD system to a more reduced state is not the mediator of its action. It is suggested that ethanol probably acted by changing the steady-state levels of some common effector(s) generated from the metabolism of all these fuels or else by preventing the inactivation of a translational repressor.

  4. Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models.

    PubMed

    Anderson, Rachel I; Becker, Howard C; Adams, Benjamin L; Jesudason, Cynthia D; Rorick-Kehn, Linda M

    2014-01-01

    To examine the role of orexin-1 and orexin-2 receptor activity on ethanol self-administration, compounds that differentially target orexin (OX) receptor subtypes were assessed in various self-administration paradigms using high-drinking rodent models. Effects of the OX1 antagonist SB334867, the OX2 antagonist LSN2424100, and the mixed OX1/2 antagonist almorexant (ACT-078573) on home cage ethanol consumption were tested in ethanol-preferring (P) rats using a 2-bottle choice procedure. In separate experiments, effects of SB334867, LSN2424100, and almorexant on operant ethanol self-administration were assessed in P rats maintained on a progressive ratio operant schedule of reinforcement. In a third series of experiments, SB334867, LSN2424100, and almorexant were administered to ethanol-preferring C57BL/6J mice to examine effects of OX receptor blockade on ethanol intake in a binge-like drinking (drinking-in-the-dark) model. In P rats with chronic home cage free-choice ethanol access, SB334867 and almorexant significantly reduced ethanol intake, but almorexant also reduced water intake, suggesting non-specific effects on consummatory behavior. In the progressive ratio operant experiments, LSN2424100 and almorexant reduced breakpoints and ethanol consumption in P rats, whereas the almorexant inactive enantiomer and SB334867 did not significantly affect the motivation to consume ethanol. As expected, vehicle-injected mice exhibited binge-like drinking patterns in the drinking-in-the-dark model. All three OX antagonists reduced both ethanol intake and resulting blood ethanol concentrations relative to vehicle-injected controls, but SB334867 and LSN2424100 also reduced sucrose consumption in a different cohort of mice, suggesting non-specific effects. Collectively, these results contribute to a growing body of evidence indicating that OX1 and OX2 receptor activity influences ethanol self-administration, although the effects may not be selective for ethanol consumption

  5. Pyranocycloartobiloxanthone A, a novel gastroprotective compound from Artocarpus obtusus Jarret, against ethanol-induced acute gastric ulcer in vivo.

    PubMed

    Sidahmed, Heyam M A; Hashim, Najihah Mohd; Amir, Junaidah; Abdulla, Mahmood Ameen; Hadi, A Hamid A; Abdelwahab, Siddig Ibrahim; Taha, Manal Mohamed Elhassan; Hassandarvish, Pouya; Teh, Xinsheng; Loke, Mun Fai; Vadivelu, Jamuna; Rahmani, Mawardi; Mohan, Syam

    2013-07-15

    Pyranocycloartobiloxanthone A (PA), a xanthone derived from the Artocarpus obtusus Jarret, belongs to the Moraceae family which is native to the tropical forest of Malaysia. In this study, the efficacy of PA as a gastroprotective compound was examined against ethanol-induced ulcer model in rats. The rats were pretreated with PA and subsequently exposed to acute gastric lesions induced by absolute ethanol. The ulcer index, gastric juice acidity, mucus content, histological analysis, glutathione (GSH) levels, malondialdehyde level (MDA), nitric oxide (NO) and non-protein sulfhydryl group (NP-SH) contents were evaluated in vivo. The activities of PA as anti-Helicobacter pylori, cyclooxygenase-2 (COX-2) inhibitor and free radical scavenger were also investigated in vitro. The results showed that the oral administration of PA protects gastric mucosa from ethanol-induced gastric lesions. PA pretreatment significantly (p<0.05) restored the depleted GSH, NP-SH and NO levels in the gastric homogenate. Moreover, PA significantly (p<0.05) reduced the elevated MDA level due to ethanol administration. The gastroprotective effect of PA was associated with an over expression of HSP70 and suppression of Bax proteins in the ulcerated tissue. In addition, PA exhibited a potent FRAP value and significant COX-2 inhibition. It also showed a significant minimum inhibitory concentration (MIC) against H. pylori bacterium. The efficacy of PA was accomplished safely without the presence of any toxicological parameters. The results of the present study indicate that the gastroprotective effect of PA might contribute to the antioxidant and anti-inflammatory properties as well as the anti-apoptotic mechanism and antibacterial action against Helicobacter pylori.

  6. Acute and chronic effects of ethanol on learning-related synaptic plasticity.

    PubMed

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

    2014-02-01

    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.

  7. Altered prefrontal connectivity after acute heroin administration during cognitive control.

    PubMed

    Schmidt, André; Borgwardt, Stefan; Gerber, Hana; Schmid, Otto; Wiesbeck, Gerhard A; Riecher-Rössler, Anita; Bendfeldt, Kerstin; Smieskova, Renata; Lang, Undine E; Rubia, Katya; Walter, Marc

    2014-09-01

    Neuroimaging studies have reported reduced activity in a broad network of brain regions during response inhibition in heroin-dependent patients. However, how heroin in an acute dose modulates the neural correlates of response inhibition and the underlying brain connectivity has not yet been investigated. In this double-blind placebo-controlled study, we used functional magnetic resonance imaging to examine whether acute heroin administration changed whole brain activity during response inhibition in 26 heroin-dependent patients. We then applied dynamic causal modelling to investigate the effect of an acute dose of heroin on the functional interactions between the dorsal anterior cingulate cortex (dACC) and the bilateral inferior frontal gyri (IFG). Heroin acutely reduced dACC activity, as well as the inhibition-induced modulation of connectivity from the dACC to the right IFG compared with placebo. Furthermore, dACC activity was positively related to false alarm rates after placebo but not heroin administration. These results suggest that acute heroin administration impairs cognitive control in dependent patients by reducing the activity in the dACC activity and the functional connectivity from the dACC to the right IFG.

  8. Gastroprotective effect of 2-mercaptoethane sulfonate against acute gastric mucosal damage induced by ethanol.

    PubMed

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2016-05-01

    Gastric mucosal damage induced by ethanol is a serious medical problem. Recent evidences suggest that reactive oxygen species and inflammatory mediators play a key role in the destruction of gastric mucosa. The present study was aimed to evaluate the potential beneficial effect of MESNA (2-mercaptoethane sulfonate) against ethanol-induced gastric mucosal damage in mice. The animals were orally pretreated with vehicle or MESNA and then treated with acidified ethanol to induce gastric mucosal damage. One hour after ethanol ingestion mice were euthanized and stomach samples were collected for biochemical analysis. Macroscopic and histopathological evaluation of gastric mucosa showed that pretreatment with MESNA attenuated gastric lesions induced by ethanol. Administration of MESNA significantly increased glutathione content and superoxide dismutase and catalase activity in the gastric tissues. In addition, MESNA markedly reduced ethanol-induced lipid peroxidation, myeloperoxidase activity, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1 levels. These findings suggest that the thiol-containing compound MESNA is able to decrease alcohol-induced oxidative stress and inflammation in the gastric tissue. It seems that MESNA may have a protective effect against ethanol-induced gastric mucosal damage. PMID:26967742

  9. Dependence on dose of the acute effects of ethanol on liver metabolism in vivo.

    PubMed Central

    Guynn, R W; Pieklik, J R

    1975-01-01

    The dose dependence of the acute effects of ethanol upon liver intermediary metabolism in vivo has been demonstrated in rats. Ethanol was given i.p. in doses of 0.69, 1.7, and 3.0 g/kg in equal volumes (20 ml/kg). The liver was freeze-clamped 120 min after injection, and multiple metabolites were measured in the perchloric acid extract of the tissue. Each group showed a significantly different pattern of metabolites, redox states, and phosphorylation potentials although the rate of ethanol disappearance, at least between the two highest dose groups, was not significantly different. The mitochondrial free [NAD+]/[NADH] ratios and the cytoplasmic free [NADP+]/[NADPH] ratio were paradoxically most reduced with the lowest dose of ethanol and became progressively more oxidized with increasing dose. Once established, the differences in these ratios between the groups tended to persist with time, relatively independent of the concentration of ethanol. In a somewhat different pattern, the phosphorylation potential ([ATP]/[ADP][P1]) remained at the control level in the low-dose group but was significantly elevated in the two higher-dose groups. The results, therefore, show distinct and complicated dose-dependent patterns of intermediary metabolism that cannot be explained completely by any one hypothesis but that imply significant dose-dependent effects of ethanol upon intermediary metabolism not directly related to NADH production. PMID:422

  10. Lack of effect of ethanol on cocaine prime-induced reinstatement of extinguished cocaine self-administration in rhesus monkeys.

    PubMed

    Czoty, Paul W

    2016-10-01

    Cocaine and alcohol are commonly co-abused for reasons that are incompletely understood. Laboratory animal studies have suggested that, although the reinforcing effects of low cocaine doses are increased following chronic ethanol (EtOH) consumption, acute EtOH administration does not consistently alter cocaine self-administration. The present study examined whether EtOH influences another abuse-related effect of cocaine: reinstatement of extinguished responding. Rhesus monkeys that had previously consumed EtOH for 8 weeks (2.0 g/kg over 1 h, 5 days/week) self-administered up to 10 injections per day of 0.1 mg/kg cocaine under a fixed-interval 300-s schedule. After responding had been extinguished by substituting saline for cocaine, a pre-session infusion of saline or EtOH (0.5 or 1.0 g/kg, intravenously over 10 min) was followed by a 'priming' injection of saline or cocaine (intravenously). Responding was increased significantly by priming injections of cocaine, but not saline. EtOH infusions neither reinstated behavior when administered before a saline prime nor altered the priming effect of cocaine. The inability of EtOH to alter the response-reinstating ability of cocaine provides further evidence for a lack of acute behavioral interactions between cocaine and EtOH. PMID:27509315

  11. Serotonin-3 receptors in the posterior ventral tegmental area regulate ethanol self-administration of alcohol-preferring (P) rats.

    PubMed

    Rodd, Zachary A; Bell, Richard L; Oster, Scott M; Toalston, Jamie E; Pommer, Tylene J; McBride, William J; Murphy, James M

    2010-05-01

    Several studies indicated the involvement of serotonin-3 ([5-hydroxy tryptamine] 5-HT(3)) receptors in regulating alcohol-drinking behavior. The objective of this study was to determine the involvement of 5-HT(3) receptors within the ventral tegmental area (VTA) in regulating ethanol self-administration by alcohol-preferring (P) rats. Standard two-lever operant chambers (Coulbourn Instruments, Allentown, PA) were used to examine the effects of seven consecutive bilateral microinfusions of ICS 205-930 (ICS), a 5-HT(3) receptor antagonist, directly into the posterior VTA on the acquisition and maintenance of 15% (vol/vol) ethanol self-administration. P rats readily acquired ethanol self-administration by the fourth session. The three highest doses (0.125, 0.25, and 1.25 microg) of ICS prevented acquisition of ethanol self-administration. During the acquisition postinjection period, all rats treated with ICS demonstrated higher responding on the ethanol lever, with the highest dose producing the greatest effect. In contrast, during the maintenance phase, the three highest doses (0.75, 1.0, and 1.25 microg) of ICS significantly increased responding on the ethanol lever; after the 7-day dosing regimen, responding on the ethanol lever returned to control levels. Microinfusion of ICS into the posterior VTA did not alter the low responding on the water lever and did not alter saccharin (0.0125% wt/v) self-administration. Microinfusion of ICS into the anterior VTA did not alter ethanol self-administration. Overall, the results of this study suggest that 5-HT(3) receptors in the posterior VTA of the P rat may be involved in regulating ethanol self-administration. In addition, chronic operant ethanol self-administration and/or repeated treatments with a 5-HT(3) receptor antagonist may alter neuronal circuitry within the posterior VTA.

  12. Serotonin-3 Receptors in the Posterior Ventral Tegmental Area Regulate Ethanol Self-Administration of Alcohol-Preferring (P) Rats

    PubMed Central

    Rodd, Zachary A.; Bell, Richard L.; Oster, Scott M.; Toalston, Jamie E.; Pommer, Tylene J.; McBride, William J.; Murphy, James M.

    2015-01-01

    Several studies indicated the involvement of serotonin-3 (5-HT3) receptors in regulating alcohol-drinking behavior. The objective of this study was to determine the involvement of 5-HT3 receptors within the ventral tegmental area (VTA) in regulating ethanol self-administration by alcohol-preferring (P) rats. Standard two-lever operant chambers were used to examine the effects of 7 consecutive bilateral micro-infusions of ICS205-930 (ICS), a 5-HT3 receptor antagonist, directly into the posterior VTA on the acquisition and maintenance of 15% (v/v) ethanol self-administration. P rats readily acquired ethanol self-administration by the 4th session. The three highest doses (0.125, 0.25 and 1.25 ug) of ICS prevented acquisition of ethanol self-administration. During the acquisition post-injection period, all rats treated with ICS demonstrated higher responding on the ethanol lever, with the highest dose producing the greatest effect. In contrast, during the maintenance phase, the 3 highest doses (0.75, 1.0 and 1.25 ug) of ICS significantly increased responding on the ethanol lever; following the 7-day dosing regimen, responding on the ethanol lever returned to control levels. Micro-infusion of ICS into the posterior VTA did not alter the low responding on the water lever, and did not alter saccharin (0.0125% w/v) self-administration.. Micro-infusion of ICS into the anterior VTA did not alter ethanol self-administration. Overall, the results of this study suggest that 5-HT3 receptors in the posterior VTA of the P rat may be involved in regulating ethanol self-administration. In addition, chronic operant ethanol self-administration, and/or repeated treatments with a 5-HT3 receptor antagonist may alter neuronal circuitry within the posterior VTA. PMID:20682192

  13. Thyroxine administration prevents matrilineal intergenerational consequences of in utero ethanol exposure in rats.

    PubMed

    Tunc-Ozcan, Elif; Harper, Kathryn M; Graf, Evan N; Redei, Eva E

    2016-06-01

    The neurodevelopmental fetal alcohol spectrum disorder (FASD) is characterized by cognitive and behavioral deficits in the offspring. Conferring the deficits to the next generation would increase overall FASD disease burden and prevention of this transmission could be highly significant. Prior studies showed the reversal of these behavioral deficits by low dose thyroxine (T4) supplementation to the ethanol-consuming mothers. Here we aim to identify whether prenatal ethanol (PE) exposure impairs hippocampus-dependent learning and memory in the second-generation (F2) progeny, and whether T4 administration to the ethanol-consuming dam can prevent it. Sprague-Dawley (S) dams received control diets (ad libitum and nutritional control) or ethanol containing liquid diet with and without simultaneous T4 (0.3mg/L diet) administration. Their offspring (SS F1) were mated with naive Brown Norway (B) males and females generating the SB F2 and BS F2 progeny. Hippocampus-dependent contextual fear memory and hippocampal expression of the thyroid hormone-regulated type 3 deiodinase, (Dio3) and neurogranin (Nrgn) were assessed. SS F1 PE-exposed females and their SB F2 progeny exhibited fear memory deficits. T4 administration to the mothers of F1 females reversed these deficits. Although SS F1 PE-exposed males also experienced fear memory deficit, this was neither transmitted to their BS F2 offspring nor reversed by prenatal T4 treatment. Hippocampal Dio3 and Nrgn expression showed similar pattern of changes. Grandmaternal ethanol consumption during pregnancy affects fear memory of the matrilineal second-generation progeny. Low dose T4 supplementation prevents this process likely via altering allele-specific and total expression of Dio3 in the hippocampus. PMID:27090562

  14. Thyroxine administration prevents matrilineal intergenerational consequences of in utero ethanol exposure in rats.

    PubMed

    Tunc-Ozcan, Elif; Harper, Kathryn M; Graf, Evan N; Redei, Eva E

    2016-06-01

    The neurodevelopmental fetal alcohol spectrum disorder (FASD) is characterized by cognitive and behavioral deficits in the offspring. Conferring the deficits to the next generation would increase overall FASD disease burden and prevention of this transmission could be highly significant. Prior studies showed the reversal of these behavioral deficits by low dose thyroxine (T4) supplementation to the ethanol-consuming mothers. Here we aim to identify whether prenatal ethanol (PE) exposure impairs hippocampus-dependent learning and memory in the second-generation (F2) progeny, and whether T4 administration to the ethanol-consuming dam can prevent it. Sprague-Dawley (S) dams received control diets (ad libitum and nutritional control) or ethanol containing liquid diet with and without simultaneous T4 (0.3mg/L diet) administration. Their offspring (SS F1) were mated with naive Brown Norway (B) males and females generating the SB F2 and BS F2 progeny. Hippocampus-dependent contextual fear memory and hippocampal expression of the thyroid hormone-regulated type 3 deiodinase, (Dio3) and neurogranin (Nrgn) were assessed. SS F1 PE-exposed females and their SB F2 progeny exhibited fear memory deficits. T4 administration to the mothers of F1 females reversed these deficits. Although SS F1 PE-exposed males also experienced fear memory deficit, this was neither transmitted to their BS F2 offspring nor reversed by prenatal T4 treatment. Hippocampal Dio3 and Nrgn expression showed similar pattern of changes. Grandmaternal ethanol consumption during pregnancy affects fear memory of the matrilineal second-generation progeny. Low dose T4 supplementation prevents this process likely via altering allele-specific and total expression of Dio3 in the hippocampus.

  15. Herbal SGR Formula Prevents Acute Ethanol-Induced Liver Steatosis via Inhibition of Lipogenesis and Enhancement Fatty Acid Oxidation in Mice.

    PubMed

    Qiu, Ping; Li, Xiang; Kong, De-Song; Li, Huan-Zhou; Niu, Cong-Cong; Pan, Su-Hua

    2015-01-01

    Our previous study indicated that herbal SGR formula partially attenuates ethanol-induced fatty liver, but the underlying mechanisms remain unclear. In the present study, mice were pretreated with SGR (100 and 200 mg/kg/d bw) for 30 d before being exposed to ethanol (4.8 g/kg bw). The biochemical indices and histopathological changes were examined to evaluate the protective effects and to explore potential mechanisms by investigating the adiponectin, tumor necrosis factor-α (TNF-α), peroxisome proliferators-activated receptor-α (PPAR-α), sterol regulatory element binding protein-1c (SREBP-1c), adenosine monophosphate-activated protein kinase (AMPK), and so forth. Results showed that SGR pretreatment markedly inhibited acute ethanol-induced liver steatosis, significantly reduced serum and hepatic triglyceride (TG) level, and improved classic histopathological changes. SGR suppressed the protein expression of hepatic SREBP-1c and TNF-α and increased adiponectin, PPAR-α, and AMPK phosphorylation in the liver. Meanwhile, acute toxicity tests showed that no death or toxic side effects within 14 days were observed upon oral administration of the extracts at a dose of 16 g/kg body wt. These results demonstrate that SGR could protect against acute alcohol-induced liver steatosis without any toxic side effects. Therefore, our studies provide novel molecular insights into the hepatoprotective effect of SGR formula, which may be exploited as a therapeutic agent for ethanol-induced hepatosteatosis. PMID:26101535

  16. Herbal SGR Formula Prevents Acute Ethanol-Induced Liver Steatosis via Inhibition of Lipogenesis and Enhancement Fatty Acid Oxidation in Mice

    PubMed Central

    Qiu, Ping; Li, Xiang; Kong, De-song; Li, Huan-zhou; Niu, Cong-cong; Pan, Su-hua

    2015-01-01

    Our previous study indicated that herbal SGR formula partially attenuates ethanol-induced fatty liver, but the underlying mechanisms remain unclear. In the present study, mice were pretreated with SGR (100 and 200 mg/kg/d bw) for 30 d before being exposed to ethanol (4.8 g/kg bw). The biochemical indices and histopathological changes were examined to evaluate the protective effects and to explore potential mechanisms by investigating the adiponectin, tumor necrosis factor-α (TNF-α), peroxisome proliferators-activated receptor-α (PPAR-α), sterol regulatory element binding protein-1c (SREBP-1c), adenosine monophosphate-activated protein kinase (AMPK), and so forth. Results showed that SGR pretreatment markedly inhibited acute ethanol-induced liver steatosis, significantly reduced serum and hepatic triglyceride (TG) level, and improved classic histopathological changes. SGR suppressed the protein expression of hepatic SREBP-1c and TNF-α and increased adiponectin, PPAR-α, and AMPK phosphorylation in the liver. Meanwhile, acute toxicity tests showed that no death or toxic side effects within 14 days were observed upon oral administration of the extracts at a dose of 16 g/kg body wt. These results demonstrate that SGR could protect against acute alcohol-induced liver steatosis without any toxic side effects. Therefore, our studies provide novel molecular insights into the hepatoprotective effect of SGR formula, which may be exploited as a therapeutic agent for ethanol-induced hepatosteatosis. PMID:26101535

  17. Acute and chronic ethanol exposure differentially regulate CB1 receptor function at glutamatergic synapses in the rat basolateral amygdala.

    PubMed

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

    2016-09-01

    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.

  18. 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

  19. 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 Central

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

    2014-01-01

    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

  20. Oral administration of ethanol with aspirin increases the concentration of salicylic acid in plasma and organs, especially the brain, in mice.

    PubMed

    Kato, Hideaki; Yoshimoto, Kanji; Kobayashi, Masaki; Sakabe, Masaaki; Funaki, Hironao; Ikegaya, Hiroshi

    2010-06-10

    Aspirin (acetylsalicylic acid) has been widely used as an over-the-counter drug to relieve pain throughout the world. In suicide attempts, aspirin is one of the most common drugs taken in large quantities. The concentration of salicylic acid shows a low-level distribution in the mouse brain, a site that may be critical regarding the expression of symptoms (e.g. hyperpnea, coma, convulsion and tremor) during acute aspirin toxicity. Therefore, it was suggested that sensitivity to salicylic acid concerning acute toxicity was higher in the brain than in other organs. Moreover, it is thought that it is common for aspirin and ethanol to be ingested at the same time. Therefore, the present study was designed to investigate the influence of ethanol on the distribution of salicylic acid, which is a primary metabolite of aspirin, and its related metabolite, salicyluric acid. The oral co-administration of aspirin (0.5g/kg) and ethanol (2.5g/kg; 10ml/kg of 25% (w/v)) enhanced the concentrations of salicylic acid in the plasma and organs, especially in the brain, compared with the aspirin alone-treated group. On the other hand, ethanol did not influence the concentrations of salicyluric acid in the plasma and kidney compared with the aspirin alone-treated group. These results suggest that ethanol enhances aspirin absorption from the gastrointestinal tract but has no influence on its metabolism. Thus, it is dangerous to ingest the alcohol and aspirin at the same time, as this may exacerbate the acute toxicity of aspirin.

  1. Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice

    SciTech Connect

    Yin Huquan; Kim, Mingoo; Kim, Ju-Han; Kong, Gu; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-IL; Lee, Mi-Ock; Lee, Byung-Hoon

    2007-09-15

    Ethanol induces cumulative liver damage including steatosis, steatohepatitis and cirrhosis. The aim of this study is to investigate the global intrahepatic gene expression profile in the mouse liver treated with ethanol. A single oral dose of 0.5 or 5 g/kg ethanol was administered to male ICR mice, and liver samples were obtained after 6, 24 and 72 h. Histopathological evaluation showed typical fatty livers in the high-dose group at 24 h. Microarray analysis identified 28 genes as being ethanol responsive (two-way ANOVA; p < 0.05), after adjustment by the Benjamini-Hochberg multiple testing correction; these genes displayed {>=} 2-fold induction or repression. The expression of genes that are known to be involved in fatty acid synthesis was examined. The transcript for lipogenic transcription factor, sterol regulatory element (SRE)-binding factor 1 (Srebf1), was upregulated by acute ethanol exposure. Of the genes known to contain SRE or SRE-like sequences and to be regulated by SRE-binding protein 1 (SREBP1), those encoding malic enzyme (Mod1), ATP-citrate lyase (Acly), fatty acid synthase (Fasn) and stearyl-CoA desaturase (Scd1) were induced by ethanol. Quantitative real-time PCR confirmed the changes in the expression levels of the selected genes. The change in the Srebf1 mRNA level correlates well with that of the SREBP1 protein expression as well as its binding to the promoters of the target genes. The present study identifies differentially expressed genes that can be applied to the biomarkers for alcohol-binge-induced fatty liver. These results support the hypothesis by which ethanol-induced steatosis in mice is mediated by the fatty acid synthetic pathway regulated by SREBP1.

  2. Moderate ingestion of ethanol induces development of tolerance to the acute positive chronotropic effect of ethanol in the rat heart

    SciTech Connect

    Gallardo-Carpentier, A.; Carpentier, R.G.

    1986-03-01

    The influence of moderate ingestion of ethanol (E) on the acute cardiac effects of E, carbachol (CBL), and isoproterenol (ISOP) was studied in rat litter-mates pair-fed a liquid diet for 24 weeks. The rats on E (E-R) received 14% of total caloric intake as E. The normal rats (N-%) received the same diet except for isocaloric substitution of carbohydrates for E. Sinoatrial (SA) preparations were superfused with Tyrode (36/sup 0/C) and intracellular microelectrodes were used to monitor (1) SA automatically, and (2) atrial action potentials (AAP). E 40-80 mg% increased SA rate in N-R, but in E-R this action was evident only with E 240 mg%. E ingestion did not modify the effects of CBL or ISOP on SA rate. E 240 mg% shortened the AAP in N-R and E-R. E ingestion did not modify the effects of CBL or ISOP on AAP. In summary: (a) Small doses of E enhance SA automaticity in vitro. (b) Moderate ingestion of E induces development of tolerance to the positive chronotropic effect of E without changing (1) the acute effects of CBL or ISOP on SA rate and AAP, or (2) the shortening effect of ETOH on AP.

  3. Role of cannabinoidergic mechanisms in ethanol self-administration and ethanol seeking in rat adult offspring following perinatal exposure to {delta}{sup 9}-tetrahydrocannabinol

    SciTech Connect

    Economidou, Daina; Mattioli, Laura; Ubaldi, Massimo; Lourdusamy, Anbarasu; Soverchia, Laura; Hardiman, Gary; Campolongo, Patrizia; Cuomo, Vincenzo; Ciccocioppo, Roberto

    2007-08-15

    The present study evaluated the consequences of perinatal {delta}{sup 9}-tetrahydrocannabinol ({delta}{sup 9}-THC) treatment (5 mg/kg/day by gavage), either alone or combined with ethanol (3% v/v as the only fluid available), on ethanol self-administration and alcohol-seeking behavior in rat adult offspring. Furthermore, the effect of the selective cannabinoid CB{sub 1} receptor antagonist, SR-141716A, on ethanol self-administration and on reinstatement of ethanol-seeking behavior induced either by stress or conditioned drug-paired cues was evaluated in adult offspring of rats exposed to the same perinatal treatment. Lastly, microarray experiments were conducted to evaluate if perinatal treatment with {delta}{sup 9}-tetrahydrocannabinol, ethanol or their combination causes long-term changes in brain gene expression profile in rats. The results of microarray data analysis showed that 139, 112 and 170 genes were differentially expressed in the EtOH, {delta}{sup 9}-THC, or EtOH + {delta}{sup 9}-THC group, respectively. No differences in alcohol self-administration and alcohol seeking were observed between rat groups. Intraperitoneal (IP) administration of SR-141716A (0.3-3.0 mg/kg) significantly reduced lever pressing for ethanol and blocked conditioned reinstatement of alcohol seeking. At the same doses SR-141716A failed to block foot-shock stress-induced reinstatement of alcohol seeking. The results reveal that perinatal exposure to {delta}{sup 9}-THC ethanol or their combination results in evident changes in gene expression patterns. However, these treatments do not significantly affect vulnerability to ethanol abuse in adult offspring. On the other hand, the results obtained with SR-141716A emphasize that endocannabinoid mechanisms play a major role in ethanol self-administration, as well as in the reinstatement of ethanol-seeking behavior induced by conditioned cues, supporting the idea that cannabinoid CB{sub 1} receptor antagonists may represent interesting

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

    SciTech Connect

    Naik, Bhiken; 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.

  5. 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

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

    PubMed

    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

    2016-01-06

    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.

  7. Deletion of agouti-related protein blunts ethanol self-administration and binge-like drinking in mice.

    PubMed

    Navarro, M; Cubero, I; Ko, L; Thiele, T E

    2009-06-01

    The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). Recent pharmacological and genetic evidence suggests that melanocortin receptor (MCR) signaling modulates neurobiological responses to ethanol and ethanol intake. Agouti-related protein (AgRP) is synthesized by neurons in the arcuate nucleus of the hypothalamus and is a natural antagonist of MCRs. Because central administration of the functionally active AgRP fragment AgRP-(83-132) increases ethanol intake by C57BL/6 J mice, we determined if mutant mice lacking normal production of AgRP (AgRP(-/-)) and maintained on a C57BL/6 J genetic background would show reduced self-administration of ethanol relative to littermate wild-type (AgRP(+/+)) mice. AgRP(-/-) mice showed reduced 8% (v/v) ethanol-reinforced lever-pressing behavior relative to AgRP(+/+) mice in daily 2-h sessions, but normal sucrose-, saccharin- and water-reinforced lever-pressing. Similarly, AgRP(-/-) mice showed reduced consumption of 8% ethanol in a two-bottle limited access test (2 h/day), although this effect was largely sex-dependent. Using drinking-in-the-dark (DID) procedures, AgRP(-/-) mice showed blunted binge-like drinking of 20% (v/v) ethanol which was associated with lower blood ethanol levels (85 mg/dl) relative to AgRP(+/+) mice (133 mg/dl) after 4 h of intake. AgRP(-/-) mice showed normal ethanol metabolism and did not show altered sensitivity to the sedative effects of ethanol. These observations with genetically altered mice are consistent with previous pharmacological data and suggest that endogenous AgRP signaling modulates the reinforcing properties of ethanol and binge-like ethanol drinking.

  8. The effects of acute ethanol exposure and ageing on rat brain glutathione metabolism.

    PubMed

    Sommavilla, Michela; Sánchez-Villarejo, M Victoria; Almansa, Inmaculada; Sánchez-Vallejo, Violeta; Barcia, Jorge M; Romero, Francisco Javier; Miranda, María

    2012-09-01

    Binge alcohol consumption in adolescents is increasing, and it has been proposed that immature brain deals poorly with oxidative stress. The aim of our work was to study the effect of an acute dose of ethanol on glutathione (GSH) metabolism in frontal cortex, hippocampus and striatum of juvenile and adult rats. We have observed no change in levels of glutathione produced by acute alcohol in the three brain areas studied of juvenile and adult rats. Only in the frontal cortex the ratio of GSH/GSSG was increased in the ethanol-treated adult rats. GSH levels in the hippocampus and striatum were significantly higher in adult animals compared to young ones. Higher glutathione peroxidase (GPx) activity in adult rats was observed in frontal cortex and in striatum. Our data show an increased GSH concentration and GPx activity in different cerebral regions of the adult rat, compared to the young ones, suggesting that age-related variations of total antioxidant defences in brain may predispose young brain structures to ethanol-induced, oxidative stress-mediated tissue damage.

  9. Endogenously elevated n-3 polyunsaturated fatty acids alleviate acute ethanol-induced liver steatosis.

    PubMed

    Huang, Wei; Wang, Bin; Li, Xiangyong; Kang, Jing X

    2015-01-01

    Effective means for the prevention of alcohol-induced liver disease, a global health problem, have yet to be developed. We evaluated whether the high endogenous levels of omega-3 polyunsaturated acids (n-3 PUFA) in fat-1 transgenic mice could protect them against acute ethanol-induced liver steatosis. We induced alcoholic liver steatosis in 9-week-old male heterozygous fat-1 mice and their wild-type (WT) male littermates through three oral gavages of 60% ethanol at 4.7 g/kg body weight. Hepatic lipid accumulation was significantly increased in both alcohol treatment groups, but by much less in the fat-1 group compared with the WT group. Fat-1 mice exhibited significantly lower levels of total hepatic/plasma TG and plasma alanine aminotransferase activity. Accordingly, hepatic expression of lipogenesis-related genes (e.g., SREBP-1c, FAS, and SCD-1) and plasma levels of inflammatory cytokines (e.g., IL-6, TNF-α, and MCP-1) were reduced in the fat-1 mice. Furthermore, decreased hepatic expression of cytochrome P450 2E1 (CYP2E1) and increased hepatic levels of PPAR-α and HO-1 were observed in the fat-1 mice, compared to the WT mice. These findings show that elevated tissue n-3 PUFA protect against acute ethanol-induced liver steatosis in fat-1 mice, possibly through the down-regulation of hepatic lipogenesis, inflammatory response, and oxidative stress.

  10. Interactions of ethanol on the acute toxicity of cocaine in the rat

    SciTech Connect

    Trouve, R. ); Latour, C ); Nahas, G.G. Columbia Univ., New York, NY )

    1992-02-26

    Administration of 65 mg/kg in the awake rate, restrained and instrumented, is associated with cardiovascular toxicity, convulsions and lethality within 9 feet 44 inches {plus minus} 4 feet 56 inches. Such an outcome is prevented if selected Ca{sup 2+} antagonists are administered intraarterially 5 minutes following cocaine. Four additional groups of Sprague Dawley rats were studied. The first was administered I.P. ethanol 1.5-2.0 gr. Such doses were well tolerated only producing hypertension of 50 minutes duration and all animals survived without apparent ill effects. Second and third groups were first administered the same doses of ethanol and 15 minutes later 65 mg/kg of cocaine. Survival time was 5 feet 49 inches with 1.5 mg/kg ethanol and 5 feet 57 inches {plus minus} 1 foot 26 inches with 2 mg/kg, significantly less than after cocaine administration alone. In a fourth group, animals were treated intraarterially with nicardipine or flunarizine, 2 minutes after cocaine. Survival time was not different from saline control. Ethanol enhances significantly cocaine lethal toxicity in the rate and prevents the protective effects of antidotes to this alkaloid.

  11. The effects of acute ethanol exposure on inhibitors of hepatic regenerative activity in the rat.

    PubMed

    Zhang, M N; Gong, Y; Minuk, G Y

    2000-04-01

    The purpose of this study was to identify the mechanism(s) whereby acute ethanol exposure inhibits hepatic regenerative activity in the rat. Adult, male, Sprague-Dawley rats (200-250 g) were randomized to receive either ethanol (1 g/kg i.p. q 4 h) or an equal volume of saline (controls) for 24 h beginning 1 h prior to a 70% partial hepatectomy (PHx). At 0, 3, 6, 12 and 24 h post-PHx, rats were sacrificed (N = 4-6/group), and the expression of the following genes associated with inhibition of hepatocyte proliferation were documented; p53, p21, transforming growth factor-beta1 (TGF-beta1) and gamma aminobutyric acid transport protein (GABA-TP). Inhibition of hepatic regenerative activity was confirmed by 3H-thymidine incorporation into hepatic DNA at 24 h post-PHx. The results of the study revealed that in ethanol-treated rats, DNA synthesis was inhibited by 37% when compared to saline-treated controls (p < 0.01). Regarding suppressor gene expression, both p21 and TGF-beta1 mRNA expression in ethanol-treated rats were similar to those obtained in saline-treated controls. Although p53 mRNA expression differed in the two groups, in the ethanol-treated group, p53 mRNA expression was decreased rather than increased (relative to controls) at 24 h post-PHx, a finding not in keeping with inhibition of DNA synthesis. GABA-TP mRNA was strongly expressed prior to PHx in both ethanol- and saline-treated rats. Following PHx, GABA-TP mRNA expression decreased in both groups but remained low in the saline-treated group while returning to pre-PHx values in ethanol-treated rats. In summary, the results of this study indicate that the inhibitory effects of ethanol on hepatic regeneration are not associated with significant or the appropriate changes in mRNA expression of the p53, p21 or TGF-beta1 suppressor genes. On the other hand, transcriptional changes in GABA-TP gene expression post-PHx are in keeping with an inhibitory effect of GABA on hepatic regeneration.

  12. The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

    PubMed Central

    Kumar, Sandeep; Porcu, Patrizia; Werner, David F.; Matthews, Douglas B.; Diaz-Granados, Jaime L.; Helfand, Rebecca S.

    2010-01-01

    The past decade has brought many advances in our understanding of GABAA receptor-mediated ethanol action in the central nervous system. We now know that specific GABAA receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABAA receptors promoting increases in GABA sensitivity. Ethanol’s effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABAA receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism. PMID:19455309

  13. Adenosinergic modulation of the imidazoline I₁-receptor-dependent hypotensive effect of ethanol in acute renal failure.

    PubMed

    Harraz, Osama F; El-Gowelli, Hanan M; Mohy El-Din, Mahmoud M; Ghazal, Abdel-Rheem M; El-Mas, Mahmoud M

    2012-08-01

    We reported that inhibition of central sympathetic pools of imidazoline I(1) receptors abolishes the hypotensive effect of ethanol in rats with glycerol-induced acute renal failure (ARF). This study investigated whether adenosine receptors modulate the ethanol-I(1)-receptor interaction. The effect of selective blockade of adenosine A(1), A(2A), or A(2B) receptors on hemodynamic responses to ethanol in the absence and presence of the I(1)-receptor agonist moxonidine was determined in ARF rats. Ethanol (1g/kg i.v.) decreased and increased blood pressure (BP) and heart rate (HR), respectively. Pretreatment with moxonidine abolished the hypotensive but not the tachycardic effect of ethanol. The hypotensive effect of ethanol remained unaltered after selective blockade of A(1), A(2A), or A(2B) receptors with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-(3-chlorostyryl) caffeine (CSC) and alloxazine, respectively. Neither was ethanol hypotension affected after inhibition of adenosine uptake by dipyridamole (DPY). Alternatively, the ability of moxonidine to abolish ethanol hypotension was still evident in presence of alloxazine whereas it disappeared or weakened in rats pretreated with CSC and DPCPX, respectively. These findings implicate adenosine A(2A) receptors in the moxonidine-evoked inhibition of the hypotensive action of ethanol. A modulatory role for adenosine A(1) site in the ethanol-I(1)-receptor interaction is also possible through as yet unidentified mechanism. PMID:22613216

  14. The effect of acute ethanol consumption on the human retinal circulation: a study in diabetic and non-diabetic subjects.

    PubMed

    Dhasmana, D; Herbert, L; Patel, V; Chen, H C; Jones, M; Kohner, E M

    1994-01-01

    The effects of acute ethanol consumption on retinal haemodynamics and retinal vascular autoregulation to oxygen in the human retinal circulation were studied in 10 diabetic (mean age +/- SD: 38.2 +/- 11.1) and 16 non-diabetic (mean age +/- SD: 32.4 +/- 8.8) subjects. Subjects drank 0.5 g of ethanol, as vodka, per kg of body weight, diluted in sugar-free orange juice. Retinal blood flow was determined using laser Doppler velocimetry and computerised image analysis. The effect of ethanol on oxygen reactivity, as a measure of autoregulation, was also determined after 60% oxygen inhalation. All subjects demonstrated a significant fall in mean arterial blood pressure (control group 3.3%, p = 0.04, diabetic subjects 5.7%, p = 0.05), after ethanol intake. Ethanol caused no significant change in retinal blood flow. Oxygen reactivity was found to be 38.3% (22.4-47.7, median and interquartile range) in the non-diabetic subjects at baseline, and 30.7% (10.8-42.1) after ethanol ingestion. In diabetic subjects, the oxygen reactivity was 33.2% (19.8-46.8) at baseline and 24.5% (21.1-32.1) after ethanol. In this study ethanol did not significantly affect retinal blood flow or impair autoregulation. These results suggest that the retinal circulation may be able to autoregulate despite the presence of ethanol, in contrast to other vascular beds where ethanol changes flow. PMID:7819729

  15. Acute caffeine administration affects zebrafish response to a robotic stimulus.

    PubMed

    Ladu, Fabrizio; Mwaffo, Violet; Li, Jasmine; Macrì, Simone; Porfiri, Maurizio

    2015-08-01

    Zebrafish has been recently proposed as a valid animal model to investigate the fundamental mechanisms regulating emotional behavior and evaluate the modulatory effects exerted by psychoactive compounds. In this study, we propose a novel methodological framework based on robotics and information theory to investigate the behavioral response of zebrafish exposed to acute caffeine treatment. In a binary preference test, we studied the response of caffeine-treated zebrafish to a replica of a shoal of conspecifics moving in the tank. A purely data-driven information theoretic approach was used to infer the influence of the replica on zebrafish behavior as a function of caffeine concentration. Our results demonstrate that acute caffeine administration modulates both the average speed and the interaction with the replica. Specifically, zebrafish exposed to elevated doses of caffeine show reduced locomotion and increased sensitivity to the motion of the replica. The methodology developed in this study may complement traditional experimental paradigms developed in the field of behavioral pharmacology.

  16. An ultrastructural analysis of the effects of ethanol self-administration on the hypothalamic paraventricular nucleus in rhesus macaques

    PubMed Central

    Jimenez, Vanessa A.; Helms, Christa M.; Cornea, Anda; Meshul, Charles K.; Grant, Kathleen A.

    2015-01-01

    A bidirectional relationship between stress and ethanol exists whereby stressful events are comorbid with problematic ethanol use and prolonged ethanol exposure results in adaptations of the physiological stress response. Endocrine response to stress is initiated in the hypothalamic paraventricular nucleus (PVN) with the synthesis and release of corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP). Alterations in CRH and AVP following long-term ethanol exposure in rodents is well demonstrated, however little is known about the response to ethanol in primates or the mechanisms of adaptation. We hypothesized that long-term ethanol self-administration in nonhuman primates would lead to ultrastructural changes in the PVN underlying adaptation to chronic ethanol. Double-label immunogold electron microscopy (EM) was used to measure presynaptic gamma-aminobutyric acid (GABA) and glutamate density within synaptic terminals contacting CRH- and AVP-immunoreactive dendrites. Additionally, pituitary-adrenal hormones (ACTH, cortisol, DHEA-s and aldosterone) under two conditions (low and mild stress) were compared before and after self-administration. All hormones were elevated in response to the mild stressor independent of ethanol consumption. The presynaptic glutamate density in recurrent (i.e., intra-hypothalamic) CRH terminals was highly related to ethanol intake, and may be a permissive factor in increased drinking due to stress. Conversely, glutamate density within recurrent AVP terminals showed a trend-level increase following ethanol, but was not related to average daily consumption. Glutamate density in non-recurrent AVP terminals was related to aldosterone under the low stress condition while GABAergic density in this terminal population was related to water consumption. The results reveal distinct populations of presynaptic terminals whose glutamatergic or GABAergic density were uniquely related to water and ethanol consumption and circulating

  17. Effects of binge ethanol administration on the behavioral outcome of rats after lateral fluid percussion brain injury.

    PubMed

    Prasad, R M; Doubinskaia, I; Singh, D K; Campbell, G; Mace, D; Fletcher, A; Dendle, P; Yurek, D M; Scheff, S W; Kraemer, P J

    2001-10-01

    This study examined the effects of 4 weeks of binge ethanol administration (BEAn) on the behavioral outcome in rats after lateral fluid percussion (FP) brain injury. Rats were intragastrically given 7.5 mL/kg of either 40% ethanol in 5% glucose solution (3 g ethanol/kg; binge ethanol group), or 5% glucose solution (vehicle group), twice on Thursday and Friday of 3 consecutive weeks. Then rats from both groups were subjected to either lateral FP brain injury of moderate severity (1.8 atm) or to sham operation. Postinjury behavioral measurements revealed that brain injury caused significant spatial learning disability in both groups. There were no significant differences in mean search latencies in the sham animals between the vehicle and binge ethanol groups. On the other hand, the mean search latency of the binge ethanol group was significantly higher than that of the vehicle group in trial blocks 2 and 4. There were no significant differences in the target visits (expressed as mean zone difference [MZD]) during the probe trial between the injured animals of binge ethanol and vehicle groups. However, there was only a minor trend towards worsened MZD score in the binge-injured animals. Histologic analysis of injured animals from both injured ethanol and vehicle groups revealed similar extents of ipsilateral cortical and observable hippocampal damage. These results suggest that 4 weeks of binge ethanol treatment followed by ethanol intoxication at the time of injury worsens some aspects of the spatial learning ability of rats. This worsening is probably caused by subtle, undetectable morphologic damage by binge ethanol administration.

  18. Nurses' medication administration practices at two Singaporean acute care hospitals.

    PubMed

    Choo, Janet; Johnston, Linda; Manias, Elizabeth

    2013-03-01

    This study examined registered nurses' overall compliance with accepted medication administration procedures, and explored the distractions they faced during medication administration at two acute care hospitals in Singapore. A total of 140 registered nurses, 70 from each hospital, participated in the study. At both hospitals, nurses were distracted by personnel, such as physicians, radiographers, patients not under their care, and telephone calls, during medication rounds. Deviations from accepted medication procedures were observed. At one hospital, the use of a vest during medication administration alone was not effective in avoiding distractions during medication administration. Environmental factors and distractions can impact on the safe administration of medications, because they not only impair nurses' level of concentration, but also add to their work pressure. Attention should be placed on eliminating distractions through the use of appropriate strategies. Strategies that could be considered include the conduct of education sessions with health professionals and patients about the importance of not interrupting nurses while they are administering medications, and changes in work design.

  19. In vitro anti oxidant activity and acute oral toxicity of Terminalia paniculata bark ethanolic extract on Sprague Dawley rats

    PubMed Central

    Mopuri, Ramgopal; Meriga, Balaji

    2014-01-01

    Objective To ensure the safety and evaluate the anti oxidant activity of Terminalia paniculata (T. paniculata) ethanolic extract in Sprague Dawley rats. Methods The solvent extracts (hexane, ethyl acetate and ethanol) of T. paniculata were subjected to phytochemical analysis and their DPPH radical scavenging activity was assayed. The oral acute toxicity was evaluated using ethanolic extract of T. paniculata. Results Ethyl acetate and ethanolic extracts showed more phytochemicals, whereas highest DPPH scavenging activity was found in ethanolic extract. In an acute toxicity study, T. paniculata ethanolic extract was orally administered (1 000 mg/kg body weight) to rats and observed for 72 h for any toxic symptoms and the dose was continued up to 14 d. On the 15th day rats were sacrificed and blood samples were collected from control and test animals and analyzed for some biochemical parameters. We did not observe any behavioral changes in test groups in comparison with their controls. Also, there were no significant alterations in biochemical, hematological (hemoglobin content and blood cells count) and liver function parameters such as serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, alkaline phosphatase, total proteins, albumin and bilirubin levels between T. paniculata ethanolic extract treated and normal control groups. Conclusions Together our results demonstrated that T. paniculata ethanolic possessed potent antioxidant activity and it was safer and non toxic to rats even at higher doses and therefore could be well considered for further investigation for its medicinal and therapeutic efficacy. PMID:25182554

  20. Effects of ethanol hangover on the operant self-administration of cocaine in rats.

    PubMed

    Briscoe, R J; Gauvin, D V

    1999-01-01

    To assess the interaction of experimentally induced ethanol hangover and cocaine self-administration, rats maintained to self-administer cocaine (0.5 mg/kg/inj) were given either saline or 2 or 4 g/kg ethanol (10% w/v, IP) 15 h prior to cocaine access (dose range tested 0.03-1.0 mg/kg/inj). Cocaine was shown to be dose-dependently self-administered in a significant inverted U-shaped function. EtOH hangover had a significant effect on the dose-dependent effects of cocaine, resulting in a general flattening of the inverted U-shaped function with increasing intensity of hangover. A significant dose-dependent reduction in the number of reinforcer deliveries occurred at the peak of the cocaine dose-response function (0.06 mg/kg/inj) following the 2 and 4 g/kg EtOH pretreatment doses when compared to saline pretreatment. These data suggest that hangover may alter the ability for moderate doses of cocaine to "prime" and maintain stable self-administration behavior.

  1. Factors that modify the metabolism of ethanol in rat liver and adaptive changes produced by its chronic administration

    PubMed Central

    Videla, L.; Israel, Y.

    1970-01-01

    1. 2,4-Dinitrophenol (0.1mm) increases by 100–160% the rate of ethanol metabolism by rat liver slices incubated in a medium saturated with a gas mixture containing O2+CO2+N2 (18:5:77). Similar effects are produced by relatively low concentrations of arsenate (10mm). At higher concentrations (37.5 and 50mm) arsenate inhibits the rate of ethanol metabolism. 2. When liver slices are incubated under an atmosphere containing O2+CO2 (95:5) the metabolism of ethanol increases by about 100% over that obtained with O2+CO2+N2 (18:5:77). However, under these conditions the activating effect of dinitrophenol is no longer observed. 3. Chronic administration of ethanol to rats for 3–4 weeks, in doses from 3 to 8g/kg per day, increases by 70–90% the ability of the liver to metabolize ethanol. In the liver slices of these rats, although an O2+CO2+N2 (18:5:77) mixture was used, dinitrophenol does not further increase the metabolism of ethanol. If the chronic administration of ethanol is discontinued for two weeks, the rate of ethanol metabolism is lowered to control values and the activating effect of dinitrophenol is recovered. 4. No change in alcohol dehydrogenase activity was found in the liver of the rats in which the metabolism of ethanol had been increased as a result of the chronic ethanol treatment; a 40% increase in the activity of succinate dehydrogenase was observed. PMID:5484675

  2. Acute effects of ethanol on sex hormones in non-alcoholic men and women.

    PubMed

    Ellingboe, J

    1987-01-01

    Chronic alcohol consumption has long been known to interfere with reproductive function and sexual behavior, but specific effects of acute alcohol ingestion on sex hormones have been studied only recently. An attempt is made in this review to summarize and explain conflicting results from studies of the acute effects of alcohol on the hypothalamic-pituitary-gonadal axis, with healthy non-alcoholic men and women as subjects. In men, moderate to high doses of ethanol have been reported to suppress plasma testosterone. Although some clinical studies have not supported this observation, considerable evidence documents direct alcohol inhibition of testosterone biosynthesis in the testis. After alcohol ingestion, plasma LH remains unchanged or increases, probably because of reduced androgen negative feedback. In analogous studies with women during the late follicular phase of the menstrual cycle, alcohol does not decrease plasma estradiol or alter LH levels. Furthermore, it has been reported that plasma levels of estradiol, progesterone and testosterone increase during alcohol treatment in the midluteal phase, while gonadotropins tend to decrease. Alcohol has no effect on LH secretion in post-menopausal women. Because reports on the acute effects of alcohol in men have not been consistent, it remains to be determined if acute alcohol effects in men and women are really different. In men, provocative tests of gonadotropin response to LHRH stimulation were normal during periods of intoxication and hangover, indicating that ethanol has no significant direct effect on LH secretion at the pituitary level. It seems more likely that alcohol changes plasma levels of sex steroids by altering hepatic, gonadal, and possibly adrenal metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Acute and chronic tramadol administration impair spatial memory in rat

    PubMed Central

    Hosseini-Sharifabad, Ali; Rabbani, Mohammad; Sharifzadeh, Mohammad; Bagheri, Narges

    2016-01-01

    Tramadol hydrochloride, a synthetic opioid, acts via a multiple mechanism of action. Tramadol can potentially change the behavioral phenomena. The present study evaluates the effect of tramadol after single or multiple dose/s on the spatial memory of rat using object recognition task (ORT). Tramadol, 20 mg/kg, was injected intraperitoneally (i.p) as a single dose or once a day for 21 successive days considered as acute or chronic treatment respectively. After treatment, animals underwent two trials in the ORT. In the first trial (T1), animals encountered with two identical objects for exploration in a five-minute period. After 1 h, in the T2 trial, the animals were exposed to a familiar and a nonfamiliar object. The exploration times and frequency of the exploration for any objects were recorded. The results showed that tramadol decreased the exploration times for the nonfamiliar object in the T2 trial when administered either as a single dose (P<0.001) or as the multiple dose (P<0.05) compared to the respective control groups. Both acute and chronic tramadol administration eliminated the different frequency of exploration between the familiar and nonfamiliar objects. Our findings revealed that tramadol impaired memory when administered acutely or chronically. Single dose administration of tramadol showed more destructive effect than multiple doses of tramadol on the memory. The observed data can be explained by the inhibitory effects of tramadol on the wide range of neurotransmitters and receptors including muscarinic, N-methyl D-aspartate, AMPA as well as some second messenger like cAMP and cGMP or its stimulatory effect on the opioid, gama amino butyric acid, dopamine or serotonin in the brain. PMID:27051432

  4. Acute and chronic tramadol administration impair spatial memory in rat.

    PubMed

    Hosseini-Sharifabad, Ali; Rabbani, Mohammad; Sharifzadeh, Mohammad; Bagheri, Narges

    2016-01-01

    Tramadol hydrochloride, a synthetic opioid, acts via a multiple mechanism of action. Tramadol can potentially change the behavioral phenomena. The present study evaluates the effect of tramadol after single or multiple dose/s on the spatial memory of rat using object recognition task (ORT). Tramadol, 20 mg/kg, was injected intraperitoneally (i.p) as a single dose or once a day for 21 successive days considered as acute or chronic treatment respectively. After treatment, animals underwent two trials in the ORT. In the first trial (T1), animals encountered with two identical objects for exploration in a five-minute period. After 1 h, in the T2 trial, the animals were exposed to a familiar and a nonfamiliar object. The exploration times and frequency of the exploration for any objects were recorded. The results showed that tramadol decreased the exploration times for the nonfamiliar object in the T2 trial when administered either as a single dose (P<0.001) or as the multiple dose (P<0.05) compared to the respective control groups. Both acute and chronic tramadol administration eliminated the different frequency of exploration between the familiar and nonfamiliar objects. Our findings revealed that tramadol impaired memory when administered acutely or chronically. Single dose administration of tramadol showed more destructive effect than multiple doses of tramadol on the memory. The observed data can be explained by the inhibitory effects of tramadol on the wide range of neurotransmitters and receptors including muscarinic, N-methyl D-aspartate, AMPA as well as some second messenger like cAMP and cGMP or its stimulatory effect on the opioid, gama amino butyric acid, dopamine or serotonin in the brain. PMID:27051432

  5. The effects of acute ethanol on growth in rat liver: steady state c-myc transcripts.

    PubMed

    Lumpkin, C K; Taylor, J M; Tarpley, M D; Hayden, J B; Badger, T M; McClung, J K

    1992-01-01

    In order to elucidate the effects of acute ethanol on compensatory liver growth (regeneration), the steady state c-myc mRNA levels were studied following two-thirds partial hepatectomy. After surgery, control rat livers exhibited two peaks of c-myc transcripts, at 0.5-2 h and at 8-10 h. Sham surgery did not induce c-myc mRNA expression. Ethanol (3 g/kg), administered by gavage at 1 hour prehepatectomy, had no effect on the initial peak of c-myc mRNA; however, the second peak was eliminated. Control gavage of isocaloric glucose prior to partial hepatectomy had no effects on either of the subsequent c-myc mRNA peaks. Blood alcohol levels were found to be elevated throughout the prereplicative phase. These results suggest that ethanol may disrupt proto-oncogene expression near the restriction point at the G1/S boundary of the cell cycle in hepatocytes.

  6. 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.

  7. Immunoproteomic identification of biotransformed self-proteins from the livers of female Balb/c mice following chronic ethanol administration.

    PubMed

    Kaur, Inderjeet; Katyal, Anju

    2012-06-01

    Chronic alcohol consumption culminates in alcoholic hepatitis which is characterized by ballooning degeneration of hepatocytes and perivenous inflammation. The aldehydes produced by ethanol oxidation and lipid peroxidation form adducts with the hepatic proteins rendering them immunogenic and initiating an autoimmune response. The present study was designed to identify these immunoreactive hepatic proteins in ethanol-treated Balb/c mice. Liver cytosolic, mitochondrial, and microsomal proteins from the ethanol-treated and control female Balb/c mice were size fractionated on SDS-PAGE and immunoblotted with the sera from the individual animal. The immunoreactive proteins were identified using antimouse IgG antibody and characterized by MALDI-TOF. It is the first report demonstrating that 15 hepatic proteins show immunoreactivity following alcohol administration. The identified autoreactive proteins ranged in function from metabolism to cytoskeletal support. Remarkably, three key enzymes of ethanol metabolism, namely alcohol dehydrogenase, aldehyde dehydrogenase I and III as well as important antioxidant enzyme glutathione S-transferase were found to be autoreactive upon ethanol treatment. We conclude that ethanol treatment induces biotransformation of host proteins from almost every compartment of the cell, especially the enzymes involved in the detoxification of ethanolic insult being the major target for biotransformation. Hence, we propose that these proteins can be the potential candidates for the biomarker studies.

  8. Acute mild footshock alters ethanol drinking and plasma corticosterone levels in C57BL/6J male mice, but not DBA/2J or A/J male mice

    PubMed Central

    Matthews, Douglas B.; Morrow, A. Leslie; Todd, O’Buckley; Flanigan, Timothy J.; Berry, Raymond B.; Cook, Melloni N.; Mittleman, Guy; Goldowitz, Dan; Tokunaga, Sayaka; Silvers, Janelle M.

    2008-01-01

    Stress is an often-reported cause for alcohol consumption in humans. Acute intermittent footshock is a frequently used paradigm to produce stress in laboratory animals including mice. The effect produced by intermittent footshock stress on ethanol self-administration has been inconsistent: both increases and decreases in ethanol consumption have been reported. The current set of studies further investigates, in three commonly studied mouse strains, the effect of footshock stress on ethanol self-administration. Furthermore, the effect of footshock on plasma corticosterone levels was determined to investigate potential biochemical correlates. Adult male C57BL/6J, DBA/2J, and A/J mice were allowed to self-administer 10% (wt/vol) ethanol for 12 days in a standard 23-h two-bottle paradigm before receiving either 15 min of mild inescapable footshock or no footshock. Shock intensity was equal to the mean intensity at which each strain vocalized as previously determined. Following footshock, animals had the opportunity to self-administer ethanol for an additional 23 h. Separate animals were subjected to either footshock or no shock prior to collection of plasma for corticosterone. Mild footshock stress altered ethanol self-administration and increased plasma corticosterone levels in C57BL/6J mice. Footshock stress did not alter ethanol self-administration or plasma corticosterone levels in DBA/2J or A/J mice. These data demonstrate that mild footshock stress is a suboptimal method of modeling the stress-induced increases in ethanol consumption often reported by humans. PMID:18599253

  9. Ethanol and Phencyclidine Interact with Respect to Nucleus Accumbens Dopamine Release: Differential Effects of Administration Order and Pretreatment Protocol

    PubMed Central

    Pickering, Chris; Chau, Pei Pei; Söderpalm, Bo; Ericson, Mia

    2010-01-01

    Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP) injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP's effect was potentiated by ethanol (180% increase vs 150%). To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pretreated for 5 days with 2.58 mg/kg PCP according to previously used ‘PFC hypofunction protocols’. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this low PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1) or Glut3 (SLC2A3), monocarboxylate transporter MCT2 (SLC16A7), glutamate transporters GLT-1 (SLC1A2) or GLAST (SLC1A3), the immediate early gene Arc (Arg3.1) or GABAergic neuron markers GAT-1 (SLC6A1) and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration. PMID:20589092

  10. The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys

    PubMed Central

    Burnett, Elizabeth J.; Grant, Kathleen A.; Davenport, April T.; Hemby, Scott E.; Friedman, David P.

    2014-01-01

    BACKGROUND Chronic alcohol consumption reduces brain serotonin and alters the synaptic mechanisms involved in memory formation. Hippocampal 5-HT1A receptors modulate these mechanisms, but the neuroadaptive response of 5HT1A receptors to chronic alcohol self-administration is not well understood. METHODS Hippocampal tissue from monkeys that voluntarily self-administered ethanol for 12 months (n=9) and accompanying controls (n=8) were prepared for in vitro receptor autoradiography and laser capture microdissection. The 5-HT1A receptor antagonist, [3H]MPPF, and the agonist, [3H]8-OH-DPAT, were used to measure total and G-protein coupled 5-HT1A receptors respectively. The expression of the genes encoding the 5-HT1A receptor and its trafficking protein Yif1B was measured in microdissected dentate gyrus (DG) granule cells and CA1 pyramidal neurons. RESULTS An increase in G-protein coupled, but not total, receptors was observed in the posterior pyramidal cell layer of CA1 in ethanol drinkers compared to controls. Chronic ethanol self-administration was also associated with an up-regulation of total and G-protein coupled 5-HT1A receptors in the posterior DG polymorphic layer. Changes in receptor binding were not associated with concomitant changes in 5-HT1A receptor mRNA expression. Chronic ethanol self-administration was associated with a significant increase in Yif1B gene expression in posterior CA1 pyramidal neurons. CONCLUSIONS Chronic, ethanol self-administration up-regulates hippocampal 5-HT1A receptor density in a region-specific manner that does not appear to be due to alterations at the level of transcription but instead may be due to increased receptor trafficking. Further exploration of the mechanisms mediating chronic ethanol-induced 5-HT1A receptor up-regulation and how hippocampal neurotransmission is altered is warranted. PMID:24467872

  11. 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. PMID:27314669

  12. Protective effects of ethanolic extract of Nigella sativa seed in paracetamol induced acute hepatotoxicity in vivo.

    PubMed

    Kushwah, D S; Salman, M T; Singh, P; Verma, V K; Ahmad, A

    2014-04-01

    Paracetamol overdose causes serious liver necrosis. Hepatoprotective activity of ethanolic extract of Nigella sativa in Paracetamol induced acute hepatotoxicity was investigated in rats. Fasted male Wistar rats were orally treated with Nigella sativa extract in graded doses for 5 days followed by Nigella sativa extract and paracetamol 3 g kg(-1) on 6 and 7th day. Circulatory liver markers and reduced glutathione (GSH) levels were estimated and histopathological study of liver performed. Paracetamol caused a significant increase in serum alkaline phosphatase, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and total Bilirubin and a significant decrease in GSH compared to control. Nigella sativa pretreatment significantly prevented the increase in liver enzymes and total bilirubin and decrease in GSH level as compared to paracetamol group. Liver histopathology showed marked reduction in sinusoidal dilatation, midzonal necrosis, portal triaditis and occasional apoptosis in Nigella sativa extract treated groups as compared to group receiving only paracetamol. Nigella sativa extract possesses hepatoprotective action against paracetamol induced acute hepatoxicity. Further research is needed to advocate its prophylactic use for drug induced hepatotoxicity.

  13. The discriminative stimulus properties of acute ethanol withdrawal (hangover) in rats.

    PubMed

    Gauvin, D V; Youngblood, B D; Holloway, F A

    1992-04-01

    Twenty male Sprague-Dawley rats were trained to discriminate pentylenetetrazole (PTZ, 15 mg/kg, intraperitoneally) from saline (SAL) under a drug discrimination procedure. Test sessions were conducted with 10 randomly selected subjects. Tests with various doses of PTZ resulted in a dose-dependent increase in the percentage of total session responses emitted on the PTZ-appropriate lever without a significant change in response rates across a wide range of test PTZ doses. Rats did not generalize the PTZ stimulus to ethanol (ETOH) up to ETOH test doses that completely suppressed responding. High acute ETOH doses (2, 3, and 4 g/kg) administered at various time points prior to discrimination test sessions engendered responding on the PTZ-appropriate level in a quantitative fashion, that was dose- and time-dependent. This acute ETOH delayed effect from these high doses replicates our previously published study using a Drug 1-Drug 2 discrimination task with Chlordiazepoxide and PTZ. More importantly, we suggest that the present behavioral assay may be a sensitive animal analogue of human "hangover" phenomena.

  14. Combined effects of acute, very-low-dose ethanol and delta(9)-tetrahydrocannabinol in healthy human volunteers

    PubMed Central

    Ballard, Michael E.; de Wit, Harriet

    2011-01-01

    Rationale Previous studies examining the combined effects of ethanol and cannabis, or its primary psychoactive ingredient, Δ9-tetrahydrocannabinol (THC), have provided mixed results. Data from an in vitro study suggests that combined, sub-threshold doses of these drugs may interact to produce synergistic effects. Very low doses of the two drugs in combination have not been tested in humans. Materials and Methods This study assessed whether combinations of acute, very-low doses of ethanol and THC produce synergistic effects on subjective, cognitive, and physiological measures. Healthy volunteers (n=11) received capsules containing placebo or THC (2.5mg), and beverages containing placebo or ethanol (0.1 and 0.2g/kg) alone, and in combination, across separate sessions, in a within-subjects, randomized, double-blind design. During each session, participants completed measures of working memory, psychomotor ability, and simple reaction time, and provided subjective mood and drug effect ratings. Cardiovascular measures were obtained at regular intervals. Results As intended, when administered alone, these very-low doses of ethanol and THC had only moderate effects on isolated measures. The combined effects of these drugs were not synergistic, and in some cases appeared to be less-than-additive. Conclusions Our data provide no evidence for synergistic effects of acute combinations of very-low-dose ethanol and THC on subjective or physiologic response, or on cognitive performance. PMID:21110996

  15. Changes in electrocortical arousal following acute trimethylbenzene administration in rats.

    PubMed

    Tomas, T; Lutz, P; Wiaderna, D

    2000-01-01

    The purpose of this investigation was to compare the neurotoxic potential of trimethylbenzene (TMB) isomers (the solvents) with that of benzene derivatives with a smaller number of methyl groups (toluene). The experiments were performed on WAG/Rij rats with EEG recording electrodes implanted in the fronto-parietal cortex. The solvents, toluene or TMB isomers: 1,3,5-TMB (mesitylene), 1,2,3-TMB (hemimellitene) or 1,2,4-TMB (pseudocumene), were diluted with olive oil and administered intragastrically via gavage at an acute dose of 0.002, 0.008, or 0.032 mol/kg. The electrocortical activity was recorded for 20 min before, and for 60 min after the solvent administration. The electrocorticograms were analysed with respect to the number and duration of the high-voltage spindles (HVS), a form of activity sensitive to the arousal level. In case of each solvent the observed effect--inhibition of the HVS activity--was dose-related. However, the effect produced by TMB isomers was in each case less pronounced than that of toluene. Among TMBs, pseudocumene displayed the least significant effect, and the efficacy of two other TMB isomers was similar. PMID:10846847

  16. Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol.

    PubMed

    Suryanarayanan, A; Carter, J M; Landin, J D; Morrow, A L; Werner, D F; Spigelman, I

    2016-08-01

    Mounting evidence indicates that ethanol (EtOH) exposure activates neuroimmune signaling. Alterations in pro-inflammatory cytokines after acute and chronic EtOH exposure have been heavily investigated. In contrast, little is known about the regulation of neurotransmission and/or modulation by anti-inflammatory cytokines in the brain after an acute EtOH exposure. Recent evidence suggests that interleukin-10 (IL-10), an anti-inflammatory cytokine, is upregulated during withdrawal from chronic EtOH exposure. In the present study, we show that IL-10 is increased early (1 h) after a single intoxicating dose of EtOH (5 g/kg, intragastric) in Sprague Dawley rats. We also show that IL-10 rapidly regulates GABAergic transmission in dentate gyrus neurons. In brain slice recordings, IL-10 application dose-dependently decreases miniature inhibitory postsynaptic current (mIPSC) area and frequency, and decreases the magnitude of the picrotoxin sensitive tonic current (Itonic), indicating both pre- and postsynaptic mechanisms. A PI3K inhibitor LY294002 (but not the negative control LY303511) ablated the inhibitory effects of IL-10 on mIPSC area and Itonic, but not on mIPSC frequency, indicating the involvement of PI3K in postsynaptic effects of IL-10 on GABAergic transmission. Lastly, we also identify a novel neurobehavioral regulation of EtOH sensitivity by IL-10, whereby IL-10 attenuates acute EtOH-induced hypnosis. These results suggest that EtOH causes an early release of IL-10 in the brain, which may contribute to neuronal hyperexcitability as well as disturbed sleep seen after binge exposure to EtOH. These results also identify IL-10 signaling as a potential therapeutic target in alcohol-use disorders and other CNS disorders where GABAergic transmission is altered. PMID:27016017

  17. Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol

    PubMed Central

    Suryanarayanan, A.; Carter, J.M.; Landin, J.D.; Morrow, A.L.; Werner, D.F.; Spigelman, I.

    2016-01-01

    Mounting evidence indicates that ethanol (EtOH) exposure activates neuroimmune signaling. Alterations in pro-inflammatory cytokines after acute and chronic EtOH exposure have been heavily investigated. In contrast, little is known about the regulation of neurotransmission and/or modulation by anti-inflammatory cytokines in the brain after an acute EtOH exposure. Recent evidence suggests that interleukin-10 (IL-10), an anti-inflammatory cytokine, is upregulated during withdrawal from chronic EtOH exposure. In the present study, we show that IL-10 is increased early (1 h) after a single intoxicating dose of EtOH (5 g/kg, intragastric) in Sprague Dawley rats. We also show that IL-10 rapidly regulates GABAergic transmission in dentate gyrus neurons. In brain slice recordings, IL-10 application dose-dependently decreases miniature inhibitory postsynaptic current (mIPSC) area and frequency, and decreases the magnitude of the picrotoxin sensitive tonic current (Itonic), indicating both pre- and postsynaptic mechanisms. A PI3K inhibitor LY294002 (but not the negative control LY303511) ablated the inhibitory effects of IL-10 on mIPSC area and Itonic, but not on mIPSC frequency, indicating the involvement of PI3K in postsynaptic effects of IL-10 on GABAergic transmission. Lastly, we also identify a novel neurobehavioral regulation of EtOH sensitivity by IL-10, whereby IL-10 attenuates acute EtOH-induced hypnosis. These results suggest that EtOH causes an early release of IL-10 in the brain, which may contribute to neuronal hyperexcitability as well as disturbed sleep seen after binge exposure to EtOH. These results also identify IL-10 signaling as a potential therapeutic target in alcohol-use disorders and other CNS disorders where GABAergic transmission is altered. PMID:27016017

  18. Acute effects of ethanol on pattern reversal and flash-evoked potentials in rats and the relationship to body temperature.

    PubMed

    Boyes, W K; Hetzler, B E; Dyer, R S

    1993-01-01

    The effects of acute ethanol treatment on flash and pattern reversal visual evoked potentials (FEPs and PREPs, respectively) were examined in three experiments using Long-Evans rats. The relationships of evoked potential parameters with blood ethanol concentration and body temperature were examined. In Experiment 1, rats were treated i.p. with vehicle or 0.5, 1.0 or 2.0 g ethanol/kg body weight, and tested 30 min later. The 2.0 g/kg group had prolonged latencies of PREP peaks, no changes in PREP peak-to-peak amplitudes, and lower body temperatures than saline-treated controls. The peak latency shifts were significantly correlated with both blood ethanol concentration and body temperature, and were of a magnitude to be expected from similar changes in body temperature alone. Experiment 2 measured both PREPs and paired-flash FEPs in rats 30 min after injection of either 0, 0.5 or 2.0 g/kg ethanol. PREP changes were found following treatment with the high dose which were similar to those of Experiment 1. Some FEP peak latencies were prolonged and peak-to-peak amplitudes were reduced by both doses of ethanol, despite the fact that body temperatures were reduced at only the high dose. At 2.0 g/kg ethanol, the FEP changes in latency, but not amplitude, were in accordance with what would be expected from body temperature changes alone. The third study attempted to investigate the role of reduced body temperature in producing the visual evoked potential changes by testing at room temperatures of 22 or 30 degrees C. Contrary to expectations, the rats receiving 2 g/kg ethanol were approx. 1 degree C cooler than controls at both room temperatures. Evoked potential latencies were greater in ethanol-treated rats than controls at both room temperatures. There were no significant effects of ethanol on FEP amplitudes. Overall, the effects of low doses of ethanol were independent of temperature changes, but the effects of higher doses of ethanol (2.0 g/kg) could not be

  19. Protective effect of panax notoginseng saponins on acute ethanol-induced liver injury is associated with ameliorating hepatic lipid accumulation and reducing ethanol-mediated oxidative stress.

    PubMed

    Ding, Ren-Bo; Tian, Ke; Cao, Yi-Wei; Bao, Jiao-Lin; Wang, Meng; He, Chengwei; Hu, Yuanjia; Su, Huanxing; Wan, Jian-Bo

    2015-03-11

    The aim of present study was to evaluate the effects of Panax notoginseng saponins (PNS) against acute ethanol-induced liver injury and further to elucidate its probable mechanisms. Mice were treated with PNS (100 or 300 mg/kg) once daily for seven consecutive days priors to ethanol gavage (4.7 g/kg) every 12 h for a total of three doses. Acute alcohol gavage dramatically significantly increased serum activities of alanine aminotransferase (ALT) (23.4 ± 5.0 IU/L vs 11.7 ± 4.1 IU/L) and aspartate aminotransferase (AST) (52.6 ± 14.9 IU/L vs 31.1 ± 12.9 IU/L), and hepatic triglyceride level (4.04 ± 0.64 mg/g vs 1.92 ± 0.34 mg/g), these elevations were significantly diminished by pretreatment with PNS at dose of 100 mg/kg or 300 mg/kg. Alcohol exposure markedly induced the lipolysis of white adipose tissue (WAT), up-regulated protein expression of the phosphorylated hormone-sensitive lipase (p-HSL, p < 0.01), and total HSL (p < 0.01), and enhanced fatty acid uptake capacity in liver as indicated by increasing hepatic CD36 expression (p < 0.01), these effects were attenuated by PNS treatment. Additionally, PNS suppressed the elevation of reactive oxygen species (ROS) production and malondialdehyde (MDA) content, reduced TNF-α and IL-6 levels, restored glutathione (GSH) level, enhanced the superoxide dismutase (SOD) activity in liver, and abrogated cytochrome P450 2E1 (CYP2E1) induction. These data demonstrated that pretreatment with PNS protected against acute ethanol-induced liver injury, possibly through ameliorating hepatic lipid accumulation and reducing CYP2E1-mediated oxidative stress. Our findings also suggested that PNS may be potential to be developed as an effective agent for acute ethanol-induced liver injury. PMID:25665731

  20. Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates

    SciTech Connect

    Larosche, Isabelle; Choumar, Amal; Fromenty, Bernard; Letteron, Philippe; Abbey-Toby, Adje; Van Remmen, Holly; Epstein, Charles J.; Richardson, Arlan; Feldmann, Gerard; Pessayre, Dominique; Mansouri, Abdellah

    2009-02-01

    Alcohol consumption increases reactive oxygen species formation and lipid peroxidation, whose products can damage mitochondrial DNA (mtDNA) and alter mitochondrial function. A possible role of manganese superoxide dismutase (MnSOD) on these effects has not been investigated. To test whether MnSOD overexpression modulates alcohol-induced mitochondrial alterations, we added ethanol to the drinking water of transgenic MnSOD-overexpressing (TgMnSOD) mice and their wild type (WT) littermates for 7 weeks. In TgMnSOD mice, alcohol administration further increased the activity of MnSOD, but decreased cytosolic glutathione as well as cytosolic glutathione peroxidase activity and peroxisomal catalase activity. Whereas ethanol increased cytochrome P-450 2E1 and mitochondrial ROS generation in both WT and TgMnSOD mice, hepatic iron, lipid peroxidation products and respiratory complex I protein carbonyls were only increased in ethanol-treated TgMnSOD mice but not in WT mice. In ethanol-fed TgMnSOD mice, but not ethanol-fed WT mice, mtDNA was depleted, and mtDNA lesions blocked the progress of polymerases. The iron chelator, DFO prevented hepatic iron accumulation, lipid peroxidation, protein carbonyl formation and mtDNA depletion in alcohol-treated TgMnSOD mice. Alcohol markedly decreased the activities of complexes I, IV and V of the respiratory chain in TgMnSOD, with absent or lesser effects in WT mice. There was no inflammation, apoptosis or necrosis, and steatosis was similar in ethanol-treated WT and TgMnSOD mice. In conclusion, prolonged alcohol administration selectively triggers iron accumulation, lipid peroxidation, respiratory complex I protein carbonylation, mtDNA lesions blocking the progress of polymerases, mtDNA depletion and respiratory complex dysfunction in TgMnSOD mice but not in WT mice.

  1. Prenatal exposure to ethanol during late gestation facilitates operant self-administration of the drug in 5-day-old rats.

    PubMed

    Miranda-Morales, Roberto Sebastián; Nizhnikov, Michael E; Spear, Norman E

    2014-02-01

    Prenatal ethanol exposure modifies postnatal affinity to the drug, increasing the probability of ethanol use and abuse. The present study tested developing rats (5-day-old) in a novel operant technique to assess the degree of ethanol self-administration as a result of prenatal exposure to low ethanol doses during late gestation. On a single occasion during each of gestational days 17-20, pregnant rats were intragastrically administered ethanol 1 g/kg, or water (vehicle). On postnatal day 5, pups were tested on a novel operant conditioning procedure in which they learned to touch a sensor to obtain 0.1% saccharin, 3% ethanol, or 5% ethanol. Immediately after a 15-min training session, a 6-min extinction session was given in which operant behavior had no consequence. Pups were positioned on a smooth surface and had access to a touch-sensitive sensor. Physical contact with the sensor activated an infusion pump, which served to deliver an intraoral solution as reinforcement (Paired group). A Yoked control animal evaluated at the same time received the reinforcer when its corresponding Paired pup touched the sensor. Operant behavior to gain access to 3% ethanol was facilitated by prenatal exposure to ethanol during late gestation. In contrast, operant learning reflecting ethanol reinforcement did not occur in control animals prenatally exposed to water only. Similarly, saccharin reinforcement was not affected by prenatal ethanol exposure. These results suggest that in 5-day-old rats, prenatal exposure to a low ethanol dose facilitates operant learning reinforced by intraoral administration of a low-concentration ethanol solution. This emphasizes the importance of intrauterine experiences with ethanol in later susceptibility to drug reinforcement. The present operant conditioning technique represents an alternative tool to assess self-administration and seeking behavior during early stages of development.

  2. Sex-related differences in effect of ethanol administration and folic acid supplementation on pancreatic amylase in rats.

    PubMed

    García-Benítez, Olga; Delgado-Villa, Maria Jesús; Murillo, Maria Luisa; Carreras, Olimpia

    2004-01-01

    The present study was designed to determine whether folic acid supplement is sufficient to reverse the negative effects of ethanol consumption on amylase activity during gestation, lactation, and growth. Moreover, this study investigated the sex-related differences in amylase content in the pancreatic tissue, serum, and urine. The animals were randomized into three groups: Control group (CG) received water and a basic rat diet during pregnancy, lactation, and growth; Ethanol-rats (EG) were fed an ethanol diet during pregnancy, the suckling period, and growth until death; and Ethanol + folic acid group (E + FG) were handled the same way as those of EG, except they received a folic acid supplement from reproduction until the end of experimental period. Our results showed that ethanol consumption decreased the pancreatic amylase level in offspring rats at 2 months postpartum. Folic acid supplementation did not alter pancreatic amylase activities. In offspring males, ethanol administration decreased serum amylase activity at 2 months postpartum. Folic acid supplementation in males resulted in higher serum amylase levels than those corresponding to the ethanol-fed group. In females, no significant differences between groups in serum amylase levels were found. Ethanol consumption decreased urinary amylase excretion (at 30 days and 2 months postpartum), but the folic acid-supplemented group showed a more pronounced decrease in urine amylase activity than in the ethanol-fed group. At 30 days postpartum, no sex difference in urinary amylase was identified. However, in general, males showed higher values for urine amylase than females at 2 months postpartum. A folic acid-supplemented diet exerts an advantageous effect on amylase in serum in offspring males at 2 months postpartum of mothers fed ethanol during gestation and lactation periods, because amylase renal absorption is increased. In offspring females, amylase renal absorption is also increased, but we did not observed

  3. Lack of aldehyde dehydrogenase ameliorates oxidative stress induced by single-dose ethanol administration in mouse liver.

    PubMed

    Matsumoto, Akiko; Ichiba, Masayoshi; Horita, Mikako; Yamashita, Zenko; Takahashi, Tatsuya; Isse, Toyohi; Oyama, Tsunehiro; Kawamoto, Toshihiro; Tomokuni, Katsumaro

    2007-02-01

    Polymorphism of aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2, is far more common in East Asian countries. Acetaldehyde, an intermediate metabolite of ethanol, is metabolized very slowly in people who have ALDH2*2, as the mutated ALDH2 lacks acetaldehyde metabolizing activity. On the other hand, it is well established that metabolism of ethanol causes oxidative stress in liver tissue. To examine the consequences of this polymorphism on ethanol-induced oxidative stress in liver tissue, we conducted a study using Aldh2 knockout mice. Aldh2+/+ and Aldh2-/- mice were orally administered ethanol at a dose of 5g/kg body weight. Levels of malondialdehyde, an indicator of oxidative stress, and glutathione, a key antioxidant, in liver tissue were analyzed 0-24h after administration. Levels of malondialdehyde were significantly lower in Aldh2-/- mice than in Aldh2+/+ mice at 12h after injection, while levels of glutathione were higher in Aldh2-/- mice than in Aldh2+/+ mice at 6 and 12h after injection. Our results suggest that a lack of ALDH ameliorates ethanol-induced oxidative stress in liver tissue. PMID:17452299

  4. Hyperhydrating effect of acute administration of angiotensin II in rats.

    PubMed

    Fregly, M J; Wilson, K M; Rowland, N E; Cade, J R

    1992-01-01

    Water intake, urine output, and fluid exchange (water intake less urine output) were measured in rats at hourly intervals for 7 hours and at 24 hours following acute administration of angiotensin II (AII, 200 micrograms/kg SC). AII induced the expected abrupt increase in water intake and a more gradual increase in urine output. The change in fluid exchange (fluid exchange of the AII-treated group less fluid exchange of controls) became positive within the first hour after treatment with AII, decreased linearly with time, and reached 0 at approximately 10 to 12 hours after treatment with AII. When AII was administered intracerebroventricularly (50 ng), similar results were observed. In this case, the change in fluid exchange (delta F) reached 0 in about 6 hours. Imposition of a water load (1% of body weight, IP) on the group receiving AII SC failed to affect the time required for delta F to reach 0 if the water load was disregarded. However, inclusion of the load as a part of intake extended the time the rats remained in positive fluid balance beyond that of the nonloaded, AII-treated control group. In the case of the larger water load (3% of body weight, IP), delta F returned to that of controls in about 4 to 5 hours if the water load was disregarded. However, inclusion of the load as part of intake extended the period of hyperhydration well beyond that of both the nonloaded, AII-treated group and the AII-treated group given the 1% load.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. The effects of ethanol administration on brush border membrane glycolipids in rat intestine.

    PubMed

    Grewal, Ravneet K; Mahmood, Akhtar

    2010-09-01

    Ethanol ingestion is well known to induce morphological and biochemical changes in intestine and is responsible for intestinal dysfunctions. Luminal surface of enterocytes is rich in glycolipids, but the effects of ethanol ingestion on membrane glycolipids are not well characterized. In the present study, rats were given 1 mL of 30% ethanol daily for 15, 25, 35, and 56 days. Ethanol feeding for 15 days did not affect glycolipid pattern in microvillus membranes, but the levels of cerebrosides (glucosylceramide, lactosylceramide, globotriasyloceramide) were enhanced in rats fed with ethanol for 35 or 56 days compared with controls. In contrast, the content of fucolipids and gangliosides was reduced in rats on ethanol ingestion for 35 or 56 days. The observed changes in membrane glycolipids were substantiated using biotinylated lectins Jacalin (affinity for N-acetylgalactosamine) and Aleuria aurantia (affinity for α-l-fucose). The incorporation of [(14)C]-mannose and [(14)C]-glucosamine revealed an increase (P<.01) in glucosamination and reduction (P<.01) in mannosylation of glycolipids from ethanol-fed rats for 45 days compared with controls. These findings were further characterized by autoradiography of the glycolipids separated on thin layer chromatograms. These findings indicate that ethanol ingestion modulates the glycolipids composition of brush borders, resulting in generalized aberration of intestinal glycosylation in chronic alcoholism in rats. PMID:20708369

  6. Hepatoprotective Effects of Traditional Chinese Medicine on Liver Fibrosis from Ethanol Administration following Partial Hepatectomy.

    PubMed

    Wu, Jia-Ping; Ho, Tsung-Jung; Tsai, Chin-Chuan; Yeh, Yu-Lan; Lin, Chien-Chung; Lin, Kuan-Ho; Hsieh, Dennis Jine-Yuan; Chen, Li-Mien; Pan, Lung-Fa; Huang, Chih-Yang

    2015-12-31

    The aim of this study was to establish the effective hepatoprotective properties of traditional Chinese medicines (TCMs) in fibrotic rat liver regeneration after partial hepatectomy (PHx). Fibrosis was induced in rats by ethanol (EtOH, 5 ml/kg) administration for 6, 24, 72, and 168 h. The rats were then fed four TCMs (1 g/kg/day, Codonopsis pilosula (CP), Salvia miltorrhiza Bunge (SMB), Bupleurum kasi (BK), and Elephantopus scaber L (ESL)) to Spraque-Dawley rats for 6, 24, 72 and 168 h, respectively. Surgical 70% cirrhotic fibrosis PHx was then conducted at 6, 24, 72, and 168 h. The effects on liver regeneration were examined to estimate and measure hepatocyte growth factor (HGF), focal adhesion kinase (FAK), Cyclin D1, Cyclin E, and retinoblastoma protein (pRb) protein expression using Western blotting analysis. Cyclin D1, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2 and TIMP-3 mRNA by Reverse transcription polymerase chain reaction (RT-PCR) were analyzed in cirrhotic fibrosis rats. Transforming growth factor-β1 (TGF-β1), Cyclin D1, Cyclin E, pRb and E2F mRNA expression levels were determined in fibrotic rats following PHx using RT-PCR. We found elevated glutamyl oxaloacetic transaminase (GOT), glutamyl pyrubic transaminase (GPT), alkaline phosphatase (ALP), gammaglutamyl transpeptidase (γ-GT), glutathione (GSH), nonprotein sulfhydryl (NPSH) and total bilirubin in serum after 6 h EtOH administration. These levels were progressively decreased over 168 h. Total protein and albumin were reduced in serum after 6 h administration and then progressively increased. In contrast, tissues disorder histology and morphology were determined in liver sections. After rats were fed TCMs we found that SMB extraction not only induced HGF, FAK, Cyclin D1, and pRb protein expression and Cyclin D1 mRNA increases, but also reduced MMP-2 and MMP-9 after 24 and 72 h post injury. In the cell cycle S phase the Cyclin E protein

  7. Effect of acute and chronic ethanol pre-treatment on the disposition of phencyclidine (PCP) in the rat.

    PubMed

    Vadlamani, N L; Pontani, R B; Misra, A L

    1982-05-01

    Disposition of [H] Phencyclidine in brain, plasma and adipose tissue of rats acutely and chronically-treated with ethanol was studied using a method possessing high sensitivity and specificity for PCP. In rats acutely-treated with ethanol (5 g/kg PO dose) and PCP (10 mg/kg IP dose), dispositional factors did not play a role in the intensifies pharmacological and behavioral effects of PCP. However in rats chronically-treated with 2.5 g/kg PO dose of ethanol twice a day for 19 days, the disposition of PCP (5 mg/kg IP dose) was significantly altered and the values of PCP in brain, plasma and adipose tissue were significantly higher than those in the control group. Although inhibition of PCP metabolism and a comparatively slower rate of its elimination appear to account for the potentiation of drug effects in animals chronically-treated with ethanol, interaction of drugs at the level of the central nervous system cannot be ruled out. PMID:7089042

  8. Evaluation of the antidepressant-like effects of acute and sub-acute administration of crocin and crocetin in mice

    PubMed Central

    Amin, Bahareh; Nakhsaz, Alireza; Hosseinzadeh, Hossein

    2015-01-01

    Objective: The present study was designed to investigate the putative antidepressant effects of crocin and crocetin, two major active ingredients of Crocus sativus L. (saffron) using mice in two different regimens of acute and sub-acute administration. Material and Methods: In acute treatment, antidepressant-like activities of crocin and crocetin (10, 20 and 40 mg/kg, i.p.) were evaluated using forced swim test (FST). In sub-acute study (21 times with 24-h intervals), antidepressant-like effects of oral administration of drugs were examined using FST and tail suspension test (TST). Locomotor activity and motor coordination were studied using open field and rotarod tests, respectively. Results: Acute treatment with crocin (40 mg/kg) and crocetin (20 and 40 mg/kg) produced antidepressant-like effect in FST without affecting the baseline locomotion in mice. Sub-acute oral administration of crocin significantly decreased immobility time only at the highest dose (100 mg/kg). Crocetin (12.5, 25 and 50 mg/kg) was able to decrease immobility time in FST and TST. Locomotor activity and coordination of mice were not affected by crocin or crocetin. Conclusion: Since higher doses of crocin was required to show antidepressant effects, more efficacy of crocetin may be concluded. This observation provides further support for metabolism of crocin to crocetin following oral administration. PMID:26468466

  9. Acute ethanol exposure induces behavioural differences in two zebrafish (Danio rerio) strains: a time course analysis.

    PubMed

    Pannia, Emanuela; Tran, Steven; Rampersad, Mindy; Gerlai, Robert

    2014-02-01

    The zebrafish has been proposed as a model organism to study genetic effects influencing behaviour and also as a tool with which the mechanisms of the action of alcohol (ethanol or EtOH) in the vertebrate brain may be investigated. In the current study we exposed zebrafish from two genetically distinct strains (WIK and TU) to a computer animated image of a natural predator of this species, the Indian leaf fish. We measured the subjects' behavioural responses in the presence of different acute doses of alcohol (0.00, 0.25, 0.50, and 1.00% vol/vol) using an observation based event-recording method. We found fish of both strains to exhibit an atypical predator inspection response during the presentation of the animated predator image coupled with a classical fear response, increased jumping frequency. We found numerous alcohol induced behavioural changes and more importantly also revealed alcohol induced strain dependent changes as well, including different dose-response trajectories for WIK vs. TU in predator inspection response, general swimming activity, location of swimming (top vs. bottom half of the tank) and freezing. The results suggest that zebrafish of the TU strain may be more tolerant at least to lower doses of alcohol as compared to WIK. The characterization of strain differences in zebrafish will aid the identification of possible molecular mechanisms involved in alcohol's actions in the vertebrate brain. PMID:24239692

  10. Phytochemical and acute toxicity of ethanolic extract of Enantia chlorantha (oliv) stem bark in albino rats

    PubMed Central

    Abatan, Mathew O.

    2013-01-01

    It is presumed that drugs sourced from herbs have lesser side effects than allopathic drugs. Enantia chlorantha is widely used in herbal medicine for the treatment of several ailments such as jaundice, malaria, fever, infective hepatitis, etc. However its toxicity profiles are not well documented. The effects of ethanolic extract of E. chlorantha stem bark on body weight changes, biochemical and haematological parameters as well as histology of vital organs (heart, kidneys and liver) were assessed. Also, the phytochemical constituent of the plant was analysed. Albino rats of both sexes were randomly divided into five groups (A–E) of five rats each and the ethanolic extract of E. chlorantha stem bark extract was administered by oral gavage in a single dose. Group A rats were administered 500 mg/kg of the extract, group B; 1000 mg/kg, group C; 2000 mg/kg, group D; 3000 mg/kg and group E rats received distilled water (10 ml/kg) and served as control. The extract caused significant (p<0.05) decreases in the levels of packed cell volume, haemoglobin concentration and red blood cell counts in a dose dependent manner. Further, significant alterations were not observed in the serum biochemical parameters analysed (AST, ALP, ALT, blood urea nitrogen, total protein, albumin, globulin and bilirubin). In addition, the extract at 1000, 2000 and 3000 mg/kg caused congestion in the heart and kidney of experimental rats. These results suggest that oral administration of E. chlorantha may produce severe toxic effects at relatively high doses, thus caution should be exercised in its use. PMID:24678252

  11. Short-term and long-term ethanol administration inhibits the placental uptake and transport of valine in rats

    SciTech Connect

    Patwardhan, R.V.; Schenker, S.; Henderson, G.I.; Abou-Mourad, N.N.; Hoyumpa, A.M. Jr.

    1981-08-01

    Ethanol ingestion during pregnancy causes a pattern of fetal/neonatal dysfunction called the FAS. The effects of short- and long-term ethanol ingestion on the placental uptake and maternal-fetal transfer of valine were studied in rats. The in vivo placental uptake and fetal uptake were estimated after injection of 0.04 micromol of /sub 14/C-valine intravenously on day 20 of gestation in Sprague-Dawley rats. Short-term ethanol ingestion (4 gm/kg) caused a significant reduction in the placental uptake of /sub 14/C-valine by 33%, 60%, and 30%, and 31% at 2.5, 5, 10, and 15 min after valine administration, respectively (p less than 0.01), and a similar significant reduction occurred in the fetal uptake of /sub 14/C-valine (p less than 0.01). Long-term ethanol ingestion prior to and throughout gestation resulted in a 47% reduction in placental valine uptake (p less than 0.01) and a 46% reduction in fetal valine uptake (p less than 0.01). Long-term ethanol feeding from day 4 to day 20 of gestation caused a 32% reduction in placental valine uptake (p less than 0.01) and a 26% reduction in fetal valine uptake (p less than 0.01). We conclude that both short- and long-term ingestion of ethanol inhibit the placental uptake and maternal-fetal transfer of an essential amino acid--valine. An alteration of placental function may contribute to the pathogenesis of the FAS.

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

    SciTech Connect

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

  13. Influences of acute ethanol exposure on locomotor activities of zebrafish larvae under different illumination.

    PubMed

    Guo, Ning; Lin, Jia; Peng, Xiaolan; Chen, Haojun; Zhang, Yinglan; Liu, Xiuyun; Li, Qiang

    2015-11-01

    Larval zebrafish present unique opportunities to study the behavioral responses of a model organism to environmental challenges during early developmental stages. The purpose of the current study was to investigate the locomotor activities of AB strain zebrafish larvae at 5 and 7 days post-fertilization (dpf) in response to light changes under the influence of ethanol, and to explore potential neurological mechanisms that are involved in ethanol intoxication. AB strain zebrafish larvae at both 5 and 7 dpf were treated with ethanol at 0% (control), 0.1%, 0.25%, 0.5%, 1%, and 2% (v/v%). The locomotor activities of the larvae during alternating light-dark challenges, as well as the locomotor responses immediately following the light transitions, were investigated. The levels of various neurotransmitters were also measured in selected ethanol-treated groups. The larvae at 5 and 7 dpf demonstrated similar patterns of locomotor responses to ethanol treatment. Ethanol treatment at 1% increased the swimming distances of the zebrafish larvae in the dark periods, but had no effect on the swimming distances in the light periods. In contrast, ethanol treatment at 2% increased the swimming distances in the light periods, but did not potentiate the swimming activity in the dark periods, compared to controls. Differences in the levels of neurotransmitters that are involved in norepinephrine, dopamine, and serotonin pathways were also observed in groups with different ethanol treatments. These results indicated the behavioral studies concerning the ethanol effects on locomotor activities of zebrafish larvae could be carried out as early as 5 dpf. The 1% and 2% ethanol-treated zebrafish larvae modeled ethanol effects at different intoxication states, and the differences in neurotransmitter levels suggested the involvement of various neurotransmitter pathways in different ethanol intoxication states. PMID:26384924

  14. Influences of acute ethanol exposure on locomotor activities of zebrafish larvae under different illumination.

    PubMed

    Guo, Ning; Lin, Jia; Peng, Xiaolan; Chen, Haojun; Zhang, Yinglan; Liu, Xiuyun; Li, Qiang

    2015-11-01

    Larval zebrafish present unique opportunities to study the behavioral responses of a model organism to environmental challenges during early developmental stages. The purpose of the current study was to investigate the locomotor activities of AB strain zebrafish larvae at 5 and 7 days post-fertilization (dpf) in response to light changes under the influence of ethanol, and to explore potential neurological mechanisms that are involved in ethanol intoxication. AB strain zebrafish larvae at both 5 and 7 dpf were treated with ethanol at 0% (control), 0.1%, 0.25%, 0.5%, 1%, and 2% (v/v%). The locomotor activities of the larvae during alternating light-dark challenges, as well as the locomotor responses immediately following the light transitions, were investigated. The levels of various neurotransmitters were also measured in selected ethanol-treated groups. The larvae at 5 and 7 dpf demonstrated similar patterns of locomotor responses to ethanol treatment. Ethanol treatment at 1% increased the swimming distances of the zebrafish larvae in the dark periods, but had no effect on the swimming distances in the light periods. In contrast, ethanol treatment at 2% increased the swimming distances in the light periods, but did not potentiate the swimming activity in the dark periods, compared to controls. Differences in the levels of neurotransmitters that are involved in norepinephrine, dopamine, and serotonin pathways were also observed in groups with different ethanol treatments. These results indicated the behavioral studies concerning the ethanol effects on locomotor activities of zebrafish larvae could be carried out as early as 5 dpf. The 1% and 2% ethanol-treated zebrafish larvae modeled ethanol effects at different intoxication states, and the differences in neurotransmitter levels suggested the involvement of various neurotransmitter pathways in different ethanol intoxication states.

  15. 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.

  16. Analysis of hepatic gene expression during fatty liver change due to chronic ethanol administration in mice

    SciTech Connect

    Yin, H.-Q.; Je, Young-Tae; Kim, Mingoo; Kim, Ju-Han; Kong, Gu; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-IL; Lee, Mi-Ock; Lee, Byung-Hoon

    2009-03-15

    Chronic consumption of ethanol can cause cumulative liver damage that can ultimately lead to cirrhosis. To explore the mechanisms of alcoholic steatosis, we investigated the global intrahepatic gene expression profiles of livers from mice administered alcohol. Ethanol was administered by feeding the standard Lieber-DeCarli diet, of which 36% (high dose) and 3.6% (low dose) of the total calories were supplied from ethanol for 1, 2, or 4 weeks. Histopathological evaluation of the liver samples revealed fatty changes and punctate necrosis in the high-dose group and ballooning degeneration in the low-dose group. In total, 292 genes were identified as ethanol responsive, and several of these differed significantly in expression compared to those of control mice (two-way ANOVA; p < 0.05). Specifically, the expression levels of genes involved in hepatic lipid transport and metabolism were examined. An overall net increase in gene expression was observed for genes involved in (i) glucose transport and glycolysis, (ii) fatty acid influx and de novo synthesis, (iii) fatty acid esterification to triglycerides, and (iv) cholesterol transport, de novo cholesterol synthesis, and bile acid synthesis. Collectively, these data provide useful information concerning the global gene expression changes that occur due to alcohol intake and provide important insights into the comprehensive mechanisms of chronic alcoholic steatosis.

  17. Anti-inflammatory activity of four solvent fractions of ethanol extract of Mentha spicata L. investigated on acute and chronic inflammation induced rats.

    PubMed

    Arumugam, P; Priya, N Gayatri; Subathra, M; Ramesh, A

    2008-07-01

    Anti-inflammatory effects of four solvent fractions of ethanol extract of Mentha spicata were evaluated in acute and chronic inflammation induced in Wistar albino rats. Lipid peroxidation (LPO) and some antioxidants produced during chronic inflammation were quantitated. Hexane (320mg/kg of body weight in 25% DMSO), chloroform (320mg/kg body weight in 25% DMSO), ethyl acetate (160mg/kg body weight in 25% DMSO), aqueous (320mg/kg of body weight in ddH(2)O) fractions, two negative control groups (25% DMSO and ddH(2)O) and two anti-inflammatory drugs (Diclofenac: 25mg/kg of body weight; Indomethacin: 10mg/kg of body weight both in ddH(2)O) were administered by oral intubations to the eight groups of rats consisting six animals, each. In acute study, 1% carrageenan was injected subcutaneously in the sub-plantar region of the right hind paw after 1h of administration of test doses. The increased paw edema was measured at 0.5, 1, 2, 4, 8, 16 and 24h intervals. In the chronic study, the oral administration was carried out for seven consecutive days. On eighth day, four sterile cotton pellets (50mg each) were implanted subcutaneously in the dorsal region of the rats. On the sixteenth day, the rats were sacrificed and the cotton pellets with granulomatous tissue were dissected out and weighed (fresh and dry). Both in chronic and acute inflammation, ethyl acetate (EAF) and aqueous fraction (AF) were effective. EAF is comparable with the positive standards in chronic inflammation. The results indicate that EAF's anti-inflammatory activity is largely due to its ability to modulate in vivo antioxidants.

  18. 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. PMID:22577377

  19. 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.

  20. 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

  1. A SUBSET OF VENTRAL TEGMENTAL AREA DOPAMINE NEURONS RESPONDS TO ACUTE ETHANOL

    PubMed Central

    MREJERU, A.; MARTIÍ-PRATS, L.; AVEGNO, E. M.; HARRISON, N. L.; SULZER, D.

    2015-01-01

    The mechanisms by which alcohol drinking promotes addiction in humans and self-administration in rodents remain obscure, but it is well known that alcohol can enhance dopamine (DA) neurotransmission from neurons of the ventral tegmental area (VTA) and increase DA levels within the nucleus accumbens and prefrontal cortex. We recorded from identified DA neuronal cell bodies within ventral midbrain slices prepared from a transgenic mouse line (TH-GFP) using long-term stable extracellular recordings in a variety of locations and carefully mapped the responses to applied ethanol (EtOH). We identified a subset of DA neurons in the medial VTA located within the rostral linear and interfascicular nuclei that fired spontaneously and exhibited a concentration-dependent increase of firing frequency in response to EtOH, with some neurons responsive to as little as 20 mM EtOH. Many of these medial VTA DA neurons were also insensitive to the D2 receptor agonist quinpirole. In contrast, DA neurons in the lateral VTA (located within the parabrachial pigmented and paranigral nuclei) were either unresponsive or responded only to 100 mM EtOH. Typically, these lateral VTA DA cells had very slow firing rates, and all exhibited inhibition by quinpirole via D2 “autoreceptors”. VTA non-DA cells did not show any significant response to low levels of EtOH. These findings are consistent with evidence for heterogeneity among midbrain DA neurons and provide an anatomical and pharmacological distinction between DA neuron sub-populations that will facilitate future mechanistic studies on the actions of EtOH in the VTA. PMID:25660505

  2. Effects of ethanol concentration and fixed-ratio requirement on ethanol self-administration by P rats in a continuous access situation.

    PubMed

    Files, F J; Andrews, C M; Lewis, R S; Samson, H H

    1993-02-01

    Rats, from the alcohol preferring (P) line, were placed in operant chambers in which food pellets, water, and 10% ethanol (v/v) were available continuously for 23 hr/day. During Experiment 1, the effects of changing ethanol concentration and response requirement for ethanol were examined. Ten percent and 20% ethanol (v/v) were available on two fixed ratio (FR) schedules, FR 1 and FR 4, for 2 weeks each. During Experiment 2, the effects of increasing the response requirement for ethanol were investigated. Starting with FR 4, the FR requirement for ethanol doubled during 2-week intervals until FR 32 was in effect. For the final phase of these studies, water was placed in the dipper for 1 week followed by a return to 10% ethanol in the dipper. The results from Experiment 1 indicated that when the FR requirement was decreased from FR 4 to FR 1, ethanol-reinforced responding decreased but total daily intake increased. Lowering the FR requirement did not affect the number of ethanol bouts per day but bout size increased. Ethanol concentration had no effect on bout size but the number of bouts per day decreased when the concentration was increased to 20%. Since bout size was unchanged by increasing the ethanol concentration, intake per bout increased at 20% ethanol. The results from Experiment 2 indicated that increasing the response requirement for ethanol decreases ethanol intake. When water was placed in the dipper, responding decreased to the lowest levels observed in the experiment. When ethanol was returned to the dipper, responding returned to baseline levels.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. [On the importance of a comprehensive study for diagnostics of death from acute ethanol poisoning and coronary heart disease].

    PubMed

    Porodenko, V A; Korkhmazov, V T

    2011-01-01

    Over 30 000 cases of acute poisoning with ethyl alcohol and its surrogates are recorded annually in this country. Differential diagnostics between fatal poisoning and death from coronary heart disease encounters serious difficulties. The authors report a comprehensive forensic chemical, morphometric, and pathomorphological study of the activity of ethanol-oxidizing enzyme systems in the internal organs. The results of histochemical examination provide a basis for the extension of diagnostic potential of the available methods and the enhancement of the objective value of expert reports. PMID:21866846

  4. Locomotor sensitization to ethanol impairs NMDA receptor-dependent synaptic plasticity in the nucleus accumbens and increases ethanol self-administration

    PubMed Central

    Abrahao, K.P.; Ariwodola, O.J.; Butler, T.R.; Rau, A.R.; Skelly, M.J.; Carter, E.; Alexander, N.P.; McCool, B.A.; Souza-Formigoni, M.L.O.; Weiner, J.L.

    2013-01-01

    Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percentage of alcohol users become addicted. Notably, the specific neural substrates responsible for individual differences in vulnerability to alcohol addiction are not known. In these studies, we used rodent models to study behavioral and synaptic correlates related to individual differences in the development of ethanol locomotor sensitization, a form of drug-dependent behavioral plasticity associated with addiction vulnerability. Male Swiss mice were treated daily with saline or 1.8 g/kg ethanol for 21 days. Locomotor activity tests were performed once a week for 15 min immediately after saline or ethanol injections. After at least eleven days of withdrawal, cohorts of saline and ethanol-treated mice were used to characterize the relationships between locomotor sensitization, ethanol drinking, and glutamatergic synaptic transmission in the nucleus accumbens. Ethanol-treated mice that expressed locomotor behavioral sensitization to ethanol drank significantly more ethanol than saline-treated subjects and ethanol-treated animals resilient to this form of behavioral plasticity. Moreover, ethanolsensitized mice also had reduced accumbal NMDA receptor function and expression, as well as deficits in NMDA receptor-dependent long term depression in the nucleus accumbens core after a protracted withdrawal. These findings suggest that disruption of accumbal core NMDA receptor-dependent plasticity may represent a synaptic correlate associated with ethanol-induced locomotor sensitization and increased propensity to consume ethanol. PMID:23486954

  5. Behavioral effects of acute and long-term administration of catnip (Nepeta cataria) in mice.

    PubMed

    Massoco, C O; Silva, M R; Gorniak, S L; Spinosa, M S; Bernardi, M M

    1995-12-01

    Catnip or catmint (Nepeta cataria) is a plant used extensively to treat human diseases and in toys for pets. We investigated the effects of acute and long-term administration of the plant on some behaviors of mice. The plant was fed as 10% of the normal diet for 2 h/d for 1 or 7 d. Acute and long-term dosing increased both rearing and locomotion frequencies observed in an open field. Acute exposure to catnip increased stereotyped behavior and susceptibility to seizures, did not interfere with haloperidol-induced catalepsy, and decreased sleeping time after sodium pentobarbital administration. Long-term exposure induced tolerance to stereotypic behavior, catalepsy and sleeping time, and increased the susceptibility to seizures induced by picrotoxin and strychnine. An amphetamine-like effect of catnip was suggested to explain the acute effects, while dispositional and functional adaptative changes were considered involved with the long-term effects.

  6. Self administration of cocaine in monkeys receiving LAAM acutely or chronically.

    PubMed

    Gerak, Lisa R; Galici, Ruggero; France, Charles P

    2008-01-28

    Polydrug abuse remains a common problem among opioid abusers as well as patients in opioid maintenance programs. Although cocaine abuse has been reported in patients receiving methadone, the incidence of cocaine use in patients receiving l-alpha-acetylmethadol (LAAM) has not been well established. The goal of this study was to determine whether acute or chronic administration of LAAM modified the reinforcing effects of cocaine using a self-administration procedure in rhesus monkeys. Four monkeys responded under a fixed ratio (FR) 30 schedule to receive i.v. infusions of cocaine (0.0032-0.32 mg/kg/infusion) in the absence of other treatment, after acute LAAM administration (0.1-1.0 mg/kg, s.c.), and during daily administration of 1.0 mg/kg of LAAM. Cocaine maintained self-administration responding that exceeded responding maintained by saline; acutely administered LAAM had small and variable effects on self administration of cocaine. Daily LAAM administration increased the number of infusions received of at least one dose of cocaine. These studies indicated that LAAM administration did not attenuate the reinforcing effects of cocaine, suggesting that LAAM would not likely alter cocaine abuse in patients undergoing treatment for opioid abuse. PMID:17764707

  7. Roux-en-Y gastric bypass increases intravenous ethanol self-administration in dietary obese rats.

    PubMed

    Polston, James E; Pritchett, Carolyn E; Tomasko, Jonathan M; Rogers, Ann M; Leggio, Lorenzo; Thanos, Panayotis K; Volkow, Nora D; Hajnal, Andras

    2013-01-01

    Roux-en-Y gastric bypass surgery (RYGB) is an effective treatment for severe obesity. Clinical studies however have reported susceptibility to increased alcohol use after RYGB, and preclinical studies have shown increased alcohol intake in obese rats after RYGB. This could reflect a direct enhancement of alcohol's rewarding effects in the brain or an indirect effect due to increased alcohol absorption after RGYB. To rule out the contribution that changes in alcohol absorption have on its rewarding effects, here we assessed the effects of RYGB on intravenously (IV) administered ethanol (1%). For this purpose, high fat (60% kcal from fat) diet-induced obese male Sprague Dawley rats were tested ~2 months after RYGB or sham surgery (SHAM) using both fixed and progressive ratio schedules of reinforcement to evaluate if RGYB modified the reinforcing effects of IV ethanol. Compared to SHAM, RYGB rats made significantly more active spout responses to earn IV ethanol during the fixed ratio schedule, and achieved higher breakpoints during the progressive ratio schedule. Although additional studies are needed, our results provide preliminary evidence that RYGB increases the rewarding effects of alcohol independent of its effects on alcohol absorption.

  8. Self-Administration of Ethanol, Cocaine, or Nicotine Does Not Decrease the Soma Size of Ventral Tegmental Area Dopamine Neurons

    PubMed Central

    Mazei-Robison, Michelle S.; Appasani, Raghu; Edwards, Scott; Wee, Sunmee; Taylor, Seth R.; Picciotto, Marina R.; Koob, George F.; Nestler, Eric J.

    2014-01-01

    Our previous observations show that chronic opiate administration, including self-administration, decrease the soma size of dopamine (DA) neurons in the ventral tegmental area (VTA) of rodents and humans, a morphological change correlated with increased firing rate and reward tolerance. Given that a general hallmark of drugs of abuse is to increase activity of the mesolimbic DA circuit, we sought to determine whether additional drug classes produced a similar morphological change. Sections containing VTA were obtained from rats that self-administered cocaine or ethanol and from mice that consumed nicotine. In contrast to opiates, we found no change in VTA DA soma size induced by any of these other drugs. These data suggest that VTA morphological changes are induced in a drug-specific manner and reinforce recent findings that some changes in mesolimbic signaling and neuroplasticity are drug-class dependent. PMID:24755634

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

    SciTech Connect

    Wallis, C.; Rezazadeh, S.M.; Forster, M.J.; Lal, H. )

    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. 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.

  10. The effects of acute exposure to ethanol on neurotensin and guanine nucleotide-stimulation of phospholipase C activity in intact NIE-115 neuroblastoma cells

    SciTech Connect

    Smith, T.L. )

    1990-01-01

    Both ethanol and neurotensin produce sedation and hypothermia. When administered in combination the behavioral effects of these two substances are potentiated. In order to better understand the biochemical nature of this interaction, the direct effects of ethanol on neurotensin receptors and an associated signal transduction process were determined in NIE-115 neuroblastoma cells. Ethanol in physiologically relevant concentrations significantly reduced neurotensin stimulated ({sup 3}H)inositol phosphate production while having no effect on the specific binding of ({sup 3}H)neurotensin. In addition, ethanol up to 200 mM had no effect on GTPYS mediated ({sup 3}H)inositol phosphate production. The results indicate that acute exposure ethanol partially disrupts the normal coupling of activated neurotensin receptors to the guanine nucleotide binding protein associated with phospholipase C.

  11. Low-Dose Prazosin Alone and in Combination with Propranolol or Naltrexone: Effects on Ethanol- and Sucrose-Seeking and Self-Administration in the P Rat

    PubMed Central

    Verplaetse, Terril L.; Czachowski, Cristine L.

    2015-01-01

    Rationale Evidence suggests that the noradrenergic system mediates ethanol-reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. Methods This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer-seeking and self-administration. Male alcohol-preferring (P) rats (n=20/experiment) were trained to complete a response requirement (RR) resulting in access to 1% sucrose (n=10) or 10% ethanol (n=10) for 20min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, 1.0 mg/kg; intraperitoneally (IP)) or prazosin in combination with propranolol (5 mg/kg (IP); Exp1) or in combination with naltrexone (0.03 mg/kg (subcutaneously (SC); Exp2). Results For Exp1, prazosin alone effectively decreased sucrose-seeking more than ethanol-seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol-seeking more than sucrose-seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp2, prazosin alone and naltrexone alone were effective in decreasing ethanol-seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol-seeking and consumption and sucrose intake, but not sucrose-seeking. Conclusions Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone, but also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers. PMID:25743758

  12. 2D spatiotemporal visualization system of expired gaseous ethanol after oral administration for real-time illustrated analysis of alcohol metabolism.

    PubMed

    Wang, Xin; Ando, Eri; Takahashi, Daishi; Arakawa, Takahiro; Kudo, Hiroyuki; Saito, Hirokazu; Mitsubayashi, Kohji

    2010-08-15

    A novel 2-dimensional spatiotemporal visualization system of expired gaseous ethanol after oral administration for real-time illustrated analysis of alcohol metabolism has been developed, which employed a low level light CCD camera to detect chemiluminescence (CL) generated by catalytic reactions of standard gaseous ethanol and expired gaseous ethanol after oral administration. First, the optimization of the substrates for visualization and the concentration of luminol solution for CL were investigated. The cotton mesh and 5.0 mmol L(-1) luminol solution were selected for further investigations and this system is useful for 0.1-20.0 mmol L(-1) of H(2)O(2) solution. Then, the effect of pH condition of Tris-HCl buffer solution was also evaluated with CL intensity and under the Tris-HCl buffer solution pH 10.1, a wide calibration range of standard gaseous ethanol (30-400 ppm) was obtained. Finally, expired air of 5 healthy volunteers after oral administration was measured at 15, 30, 45, 60, 75, 90, 105 and 120 min after oral administration, and this system showed a good sensitivity on expired gaseous ethanol for alcohol metabolism. The peaks of expired gaseous ethanol concentration appeared within 30 min after oral administration. During the 30 min after oral administration, the time variation profile based on mean values showed the absorption and distribution function, and the values onward showed the elimination function. The absorption and distribution of expired gaseous ethanol in 5 healthy volunteers following first-order absorption process were faster than the elimination process, which proves efficacious of this system for described alcohol metabolism in healthy volunteers. This system is expected to be used as a non-invasive method to detect VOCs as well as several other drugs in expired air for clinical purpose.

  13. Acute administration of l-tyrosine alters energetic metabolism of hippocampus and striatum of infant rats.

    PubMed

    Ramos, Andrea C; Ferreira, Gabriela K; Carvalho-Silva, Milena; Furlanetto, Camila B; Gonçalves, Cinara L; Ferreira, Gustavo C; Schuck, Patrícia F; Streck, Emilio L

    2013-08-01

    Tyrosinemia type II is an inborn error of metabolism caused by mutations in the gene that encodes tyrosine aminotransferase, which leads to increased blood tyrosine levels. Considering that tyrosine levels are highly elevated in fluids of patients with tyrosinemia type II, and that previous studies demonstrated significant alterations in brain energy metabolism of young rats caused by l-tyrosine, the present study aimed to evaluate the effect of acute administration of l-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase, and mitochondrial respiratory chain complexes I, II, II-III, and IV in posterior cortex, hippocampus, and striatum of infant rats. Wistar rats (10 days old) were killed 1h after a single intraperitoneal injection of tyrosine (500 mg/kg) or saline. The activities of energy metabolism enzymes were evaluated in brain of rats. Our results demonstrated that acute administration of l-tyrosine inhibited the activity of citrate synthase activity in striatum and increased the activities of malate dehydrogenase and succinate dehydrogenase in hippocampus. On the other hand, these enzymes were not affected in posterior cortex. The activities of complex I and complex II were inhibited by acute administration of l-tyrosine in striatum. On the other hand, the acute administration of l-tyrosine increased the activity of activity of complex II-III in hippocampus. Complex IV was not affected by acute administration of l-tyrosine in infant rats. Our results indicate an alteration in the energy metabolism in hippocampus and striatum of infant rats after acute administration of l-tyrosine. If the same effects occur in the brain of the patients, it is possible that energy metabolism impairment may be contribute to possible damage in memory and cognitive processes in patients with tyrosinemia type II. PMID:23602810

  14. Acute administration of l-tyrosine alters energetic metabolism of hippocampus and striatum of infant rats.

    PubMed

    Ramos, Andrea C; Ferreira, Gabriela K; Carvalho-Silva, Milena; Furlanetto, Camila B; Gonçalves, Cinara L; Ferreira, Gustavo C; Schuck, Patrícia F; Streck, Emilio L

    2013-08-01

    Tyrosinemia type II is an inborn error of metabolism caused by mutations in the gene that encodes tyrosine aminotransferase, which leads to increased blood tyrosine levels. Considering that tyrosine levels are highly elevated in fluids of patients with tyrosinemia type II, and that previous studies demonstrated significant alterations in brain energy metabolism of young rats caused by l-tyrosine, the present study aimed to evaluate the effect of acute administration of l-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase, and mitochondrial respiratory chain complexes I, II, II-III, and IV in posterior cortex, hippocampus, and striatum of infant rats. Wistar rats (10 days old) were killed 1h after a single intraperitoneal injection of tyrosine (500 mg/kg) or saline. The activities of energy metabolism enzymes were evaluated in brain of rats. Our results demonstrated that acute administration of l-tyrosine inhibited the activity of citrate synthase activity in striatum and increased the activities of malate dehydrogenase and succinate dehydrogenase in hippocampus. On the other hand, these enzymes were not affected in posterior cortex. The activities of complex I and complex II were inhibited by acute administration of l-tyrosine in striatum. On the other hand, the acute administration of l-tyrosine increased the activity of activity of complex II-III in hippocampus. Complex IV was not affected by acute administration of l-tyrosine in infant rats. Our results indicate an alteration in the energy metabolism in hippocampus and striatum of infant rats after acute administration of l-tyrosine. If the same effects occur in the brain of the patients, it is possible that energy metabolism impairment may be contribute to possible damage in memory and cognitive processes in patients with tyrosinemia type II.

  15. Adolescent and adult rats differ in the amnesic effects of acute ethanol in two hippocampus-dependent tasks: Trace and contextual fear conditioning.

    PubMed

    Hunt, Pamela S; Barnet, Robert C

    2016-02-01

    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. Experiment 2a and b 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.

  16. Gynura procumbens Reverses Acute and Chronic Ethanol-Induced Liver Steatosis through MAPK/SREBP-1c-Dependent and -Independent Pathways.

    PubMed

    Li, Xiao-Jun; Mu, Yun-Mei; Li, Ting-Ting; Yang, Yan-Ling; Zhang, Mei-Tuo; Li, Yu-Sang; Zhang, Wei Kevin; Tang, He-Bin; Shang, Hong-Cai

    2015-09-30

    The present study aimed to evaluate the hepatoprotective effect and mechanism of action of Gynura procumbens on acute and chronic ethanol-induced liver injuries. Ethanol extract from G. procumbens stems (EEGS) attenuated acute ethanol-induced serum alanine aminotransferase levels and hepatic lipid accumulation. Therefore, EEGS was successively extracted by petroleum, ethyl acetate, and n-butyl alcohol. The results showed that the n-butyl alcohol extract was the active fraction of EEGS, and hence it was further fractionated on a polyamide glass column. The 60% ethanol-eluted fraction that contained 13.6% chlorogenic acid was the most active fraction, and its effect was further evaluated using a chronic model. Both the n-butyl alcohol extract and the 60% ethanol-eluted fraction inhibited chronic ethanol-induced hepatic lipid accumulation by modulating lipid metabolism-related regulators through MAPK/SREBP-1c-dependent and -independent signaling pathways and ameliorated liver steatosis. Our findings suggest that EEGS and one of its active ingredients, chlorogenic acid, may be developed as potential effective agents for ethanol-induced liver injury.

  17. Very Early Administration of Progesterone for Acute Traumatic Brain Injury

    PubMed Central

    Wright, David W.; Yeatts, Sharon D.; Silbergleit, Robert; Palesch, Yuko Y.; Hertzberg, Vicki S.; Frankel, Michael; Goldstein, Felicia C.; Caveney, Angela F.; Howlett-Smith, Harriet; Bengelink, Erin M.; Manley, Geoffrey T.; Merck, Lisa H.; Janis, L. Scott; Barsan, William G.

    2015-01-01

    BACKGROUND Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P = 0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS This clinical trial did not show a

  18. [The protective effect of pantothenic acid derivatives and changes in the system of acetyl CoA metabolism in acute ethanol poisoning].

    PubMed

    Moiseenok, A G; Dorofeev, B F; Omel'ianchik, S N

    1988-01-01

    Calcium pantothenate (CaP), calcium 4'-phosphopantothenate (CaPP), pantethine, panthenol, sulfopantetheine and CoA decrease acute toxicity of acetaldehyde in mice. All studied compounds diminish duration of the narcotic action of ethanol--ET (3.5 g/kg intraperitoneally) in mice and rats. In the latter this effect is realized at the expense of "long sleeping" and "middle sleeping" animals. CaP (150 mg/kg subcutaneously) and CaPP (100 mg/kg subcutaneously) prevent hypothermia and a decrease of oxygen consumption in rats induced by ET administration. Combined administration of ET, CaP and CaPP leads to a characteristic increase of acid-soluble CoA fractions in the rat liver and a relative decrease of acetyl CoA synthetase and N-acetyltransferase reactions. The antitoxic effect of preparations of pantothenic acid is not mediated by CoA-dependent reactions of detoxication, but most probably is due to intensification of ET oxidation and perhaps to its elimination from the organism. PMID:2905277

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

    PubMed

    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.

  20. 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

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

    PubMed

    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

  2. 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. PMID:26628398

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

    PubMed Central

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

    2015-01-01

    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. PMID:26628398

  4. 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.

  5. Tolerance to Ethanol or Nicotine Results in Increased Ethanol Self-Administration and Long-Term Depression in the Dorsolateral Striatum.

    PubMed

    Abburi, Chandrika; Wolfman, Shannon L; Metz, Ryan A E; Kamber, Rinya; McGehee, Daniel S; McDaid, John

    2016-01-01

    Ethanol (EtOH) and nicotine are the most widely coabused drugs. Tolerance to EtOH intoxication, including motor impairment, results in greater EtOH consumption and may result in a greater likelihood of addiction. Previous studies suggest that cross-tolerance between EtOH and nicotine may contribute to the abuse potential of these drugs. Here we demonstrate that repeated intermittent administration of either EtOH or nicotine in adult male Sprague Dawley rats results in tolerance to EtOH-induced motor impairment and increased EtOH self-administration. These findings suggest that nicotine and EtOH cross-tolerance results in decreased aversive and enhanced rewarding effects of EtOH. Endocannabinoid signaling in the dorsolateral striatum (DLS) has been implicated in both EtOH tolerance and reward, so we investigated whether nicotine or EtOH pretreatment might modulate endocannabinoid signaling in this region. Using similar EtOH and nicotine pretreatment methods resulted in increased paired-pulse ratios of evoked EPSCs in enkephalin-positive medium spiny neurons in DLS slices. Thus, EtOH and nicotine pretreatment may modulate glutamatergic synapses in the DLS presynaptically. Bath application of the CB1 receptor agonist Win 55,2-212 increased the paired-pulse ratio of evoked EPSCs in control slices, while Win 55,2-212 had no effect on paired-pulse ratio in slices from either EtOH- or nicotine-pretreated rats. Consistent with these effects, nicotine pretreatment occluded LTD induction by high-frequency stimulation of the corticostriatal inputs to the dorsolateral striatum. These results suggest that nicotine and EtOH pretreatment modulates striatal synapses to induce tolerance to the motor-impairing effects of EtOH, which may contribute to nicotine and EtOH coabuse. PMID:27517088

  6. Tolerance to Ethanol or Nicotine Results in Increased Ethanol Self-Administration and Long-Term Depression in the Dorsolateral Striatum

    PubMed Central

    Abburi, Chandrika; Wolfman, Shannon L.; Metz, Ryan A. E.; Kamber, Rinya

    2016-01-01

    Abstract Ethanol (EtOH) and nicotine are the most widely coabused drugs. Tolerance to EtOH intoxication, including motor impairment, results in greater EtOH consumption and may result in a greater likelihood of addiction. Previous studies suggest that cross-tolerance between EtOH and nicotine may contribute to the abuse potential of these drugs. Here we demonstrate that repeated intermittent administration of either EtOH or nicotine in adult male Sprague Dawley rats results in tolerance to EtOH-induced motor impairment and increased EtOH self-administration. These findings suggest that nicotine and EtOH cross-tolerance results in decreased aversive and enhanced rewarding effects of EtOH. Endocannabinoid signaling in the dorsolateral striatum (DLS) has been implicated in both EtOH tolerance and reward, so we investigated whether nicotine or EtOH pretreatment might modulate endocannabinoid signaling in this region. Using similar EtOH and nicotine pretreatment methods resulted in increased paired-pulse ratios of evoked EPSCs in enkephalin-positive medium spiny neurons in DLS slices. Thus, EtOH and nicotine pretreatment may modulate glutamatergic synapses in the DLS presynaptically. Bath application of the CB1 receptor agonist Win 55,2-212 increased the paired-pulse ratio of evoked EPSCs in control slices, while Win 55,2-212 had no effect on paired-pulse ratio in slices from either EtOH- or nicotine-pretreated rats. Consistent with these effects, nicotine pretreatment occluded LTD induction by high-frequency stimulation of the corticostriatal inputs to the dorsolateral striatum. These results suggest that nicotine and EtOH pretreatment modulates striatal synapses to induce tolerance to the motor-impairing effects of EtOH, which may contribute to nicotine and EtOH coabuse. PMID:27517088

  7. Effects of chronic ethanol (EtOH) administration on pro-inflammatory cytokines of the hypothalamic-pituitary-gonadal (HPG) axis in female rats.

    PubMed

    Emanuele, Nicholas; LaPaglia, Nancy; Kovacs, Elizabeth J; Emanuele, Mary Ann

    2005-01-01

    We and others have investigated the effects of acute and chronic ethanol (EtOH) administration on function of the hypothalamic-pituitary-gonadal (HPG) axis in female rats, consistently finding EtOH to be detrimental. There are now substantial data that pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6), have anti-reproductive effects. If EtOH increased levels of these cytokines, such data would be consistent with, though not necessarily prove, a cytokine mediated mechanism for EtOH's deleterious effects on reproduction. Young adult female Sprague Dawley rats were used. In the experiment reported here, the Lieber DeCarli diet was used, with animals fed a 36% EtOH containing diet or pair fed an identical diet which contained dextrimaltose instead of EtOH. This was done for 4 to 6 weeks. TNFalpha and IL-6 were measured in the hypothalamus, pituitary, and ovary by ELISA. EtOH exposure resulted in significant increases in TNFalpha and IL-6 in hypothalami, pituitaries, and ovaries. The data reported here are the first to show consistent stimulatory effects of EtOH exposure on cytokines in the reproductive axis of female rats. Because the effects of these cytokines are generally anti-reproductive, these data provide a rational for more rigorous testing of the notion that part of EtOH's deleterious HPG effects may be due to such immuno-endocrine interactions.

  8. Amelioration of alcohol-induced hepatotoxicity by the administration of ethanolic extract of Sida cordifolia Linn.

    PubMed

    Rejitha, S; Prathibha, P; Indira, M

    2012-10-01

    Sida cordifolia Linn. (Malvaceae) is a plant used in folk medicine for the treatment of the inflammation of oral mucosa, asthmatic bronchitis, nasal congestion and rheumatism. We studied the hepatoprotective activity of 50 % ethanolic extract of S. cordifolia Linn. against alcohol intoxication. The duration of the experiment was 90 d. The substantially elevated levels of toxicity markers such as alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase due to the alcohol treatment were significantly lowered in the extract-treated groups. The activity of antioxidant enzymes and glutathione content, which was lowered due to alcohol toxicity, was increased to a near-normal level in the co-administered group. Lipid peroxidation products, protein carbonyls, total collagen and hydroxyproline, which were increased in the alcohol-treated group, were reduced in the co-administered group. The mRNA levels of cytochrome P450 2E1, NF-κB, TNF-α and transforming growth factor-β1 were found to be increased in the alcohol-treated rats, and their expressions were found to be decreased in the co-administered group. These observations were reinforced by histopathological analysis. Thus, the present study clearly indicates that 50 % ethanolic extract of the roots of S. cordifolia Linn. has a potent hepatoprotective action against alcohol-induced toxicity, which was mediated by lowering oxidative stress and by down-regulating the transcription factors.

  9. Long-term Behavioral Impairment Following Acute Embryonic Ethanol Exposure in Zebrafish

    PubMed Central

    Bailey, JM; Oliveri, AN; Zhang, C; Frazier, JM; Mackinnon, S; Cole, GJ; Levin, ED

    2015-01-01

    BACKGROUND Developmental exposure to ethanol has long been known to cause persisting neurobehavioral impairment. However, the neural and behavioral mechanisms underlying these deficits and the importance of exposure timing are not well-characterized. Given the importance of timing and sequence in neurodevelopment it would be expected that alcohol intoxication at different developmental periods would result in distinct neurobehavioral consequences. METHODS Zebrafish embryos were exposed to ethanol (0%, 1%, 3%) at either 8-10 or 24-27 hours post-fertilization (hpf) then reared to adolescence and evaluated on several behavioral endpoints. Habituation to a repeated environmental stimulus and overall sensorimotor function were assessed using a tap startle test; measurements of anxiety and exploration behavior were made following introduction to a novel tank; and spatial discrimination learning was assessed using aversive control in a three-chambered apparatus. Overt signs of dysmorphogenesis were also scored (i.e. craniofacial malformations, including eye diameter and midbrain-hindbrain boundary morphology). RESULTS Ethanol treated fish were more active both at baseline and following a tap stimulus compared to the control fish and were hyperactive when placed in a novel tank. These effects were more prominent following exposure at 24-27 hpf than with the earlier exposure window, for both dose groups. Increases in physical malformation were only present in the 3% ethanol group; all malformed fish were excluded from behavioral testing. DISCUSSION These results suggest specific domains of behavior are affected following ethanol exposure, with some but not all of the tests revealing significant impairment. The behavioral phenotypes following distinct exposure windows described here can be used to help link cellular and molecular mechanisms of developmental ethanol exposure to functional neurobehavioral effects. PMID:25599606

  10. Ethanol and development of disease and injury to tha alimentary tract.

    PubMed Central

    Krawitt, E L

    1977-01-01

    Effects of ethanol on the gastrointestinal tract are reviewed, and an overview of possible mechanisms of ethanol damage to the alimentary tract is presented. Ethanol toxicity most commonly results in metabsorption. Mechanisms contributing to ethanol-induced calcium malabsorption are considered in detail as a prototype for problems encountered in evaluating effects of toxicants on intestinal function. Effects at the local level in the intestine must be differentiated from systemic effects. The mechanism of suppression of calcium absorption by chronic ethanol ingestion differs from that produced by acute administration. Effects of acute administration appear to be due to local mucosal damage and are reversed in 18 hr. Such damage is not present with chronic administration, which affects only duodenal transport. Treatment with vitamin D and its metabolites does not reverse the inhibition of calcium transport. The overall findings suggest that ethanol inhibition of calcium transport is mediated at the intestinal level, probably affecting vitamid D independent mechanisms. PMID:598353

  11. Ethanol and development of disease and injury to tha alimentary tract.

    PubMed

    Krawitt, E L

    1977-10-01

    Effects of ethanol on the gastrointestinal tract are reviewed, and an overview of possible mechanisms of ethanol damage to the alimentary tract is presented. Ethanol toxicity most commonly results in metabsorption. Mechanisms contributing to ethanol-induced calcium malabsorption are considered in detail as a prototype for problems encountered in evaluating effects of toxicants on intestinal function. Effects at the local level in the intestine must be differentiated from systemic effects. The mechanism of suppression of calcium absorption by chronic ethanol ingestion differs from that produced by acute administration. Effects of acute administration appear to be due to local mucosal damage and are reversed in 18 hr. Such damage is not present with chronic administration, which affects only duodenal transport. Treatment with vitamin D and its metabolites does not reverse the inhibition of calcium transport. The overall findings suggest that ethanol inhibition of calcium transport is mediated at the intestinal level, probably affecting vitamid D independent mechanisms.

  12. Brain and muscle redox imbalance elicited by acute ethylmalonic acid administration.

    PubMed

    Schuck, Patrícia Fernanda; Milanez, Ana Paula; Felisberto, Francine; Galant, Leticia Selinger; Machado, Jéssica Luca; Furlanetto, Camila Brulezi; Petronilho, Fabricia; Dal-Pizzol, Felipe; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2',7'-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy.

  13. Brain and muscle redox imbalance elicited by acute ethylmalonic acid administration.

    PubMed

    Schuck, Patrícia Fernanda; Milanez, Ana Paula; Felisberto, Francine; Galant, Leticia Selinger; Machado, Jéssica Luca; Furlanetto, Camila Brulezi; Petronilho, Fabricia; Dal-Pizzol, Felipe; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2',7'-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy. PMID:26010931

  14. Brain and Muscle Redox Imbalance Elicited by Acute Ethylmalonic Acid Administration

    PubMed Central

    Schuck, Patrícia Fernanda; Milanez, Ana Paula; Felisberto, Francine; Galant, Leticia Selinger; Machado, Jéssica Luca; Furlanetto, Camila Brulezi; Petronilho, Fabricia; Dal-Pizzol, Felipe; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2’,7’-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy. PMID:26010931

  15. [Pecularities of correction of alcohol affctions of liver in patients with acute ethanol poisoning in the setting of consequence of toxic effect of ethanol].

    PubMed

    Shilov, V V; batotsyrenov, B V; Vasil'ev, S A; Shikalova, I A; Kuznetsov, O A

    2012-06-01

    The aim of this work was to test the usage of infusion of hepatoprotector "remaxol" in intensive therapy of acute ethanol poisoning accompanied with severe alcohol affections of the lever. In the result of the examination and treatment of 130 patients it was established that severe alcohol poisonings registered on alcohol abused patients with toxic hepatopathy, are always accompanied with serious metabolic violations. In the process of a comparative valuation of the using of heptral (ademethionin) and remaxol in the intensive therapy of alcohol poisonings it has been revealed that the using of remaxol led to improvement of the clinic of that poisonings, what had been registered as a decrease of frequency and duration of an alcohol delirium from 33,9% to 10,8%, a decrease of frequency of secondary lung complication from 18,5 to 3,1%, a decrease of a duration of treatment in intensive care unit from 7,3 +/- 0,6 to 5,6 +/- 0,3 and a hospital treatment duration from 11,8 +/- 0,5 to 9,0 +/- 0,3 days. Biochemical investigation has shown that using as heptral, as remaxol led to improvement of lever damages due to alcohol. However remaxol compared with heptral was better in the treatment of metabolic violations.

  16. Chronic and acute alcohol administration induced neurochemical changes in the brain: comparison of distinct zebrafish populations.

    PubMed

    Chatterjee, Diptendu; Shams, Soaleha; Gerlai, Robert

    2014-04-01

    The zebrafish is increasingly utilized in the analysis of the effects of ethanol (alcohol) on brain function and behavior. We have shown significant population-dependent alcohol-induced changes in zebrafish behavior and have started to analyze alterations in dopaminergic and serotoninergic responses. Here, we analyze the effects of alcohol on levels of selected neurochemicals using a 2 × 3 (chronic × acute) between-subject alcohol exposure paradigm randomized for two zebrafish populations, AB and SF. Each fish first received the particular chronic treatment (0 or 0.5 vol/vol% alcohol) and subsequently the acute exposure (0, 0.5 or 1.0% alcohol). We report changes in levels of dopamine, DOPAC, serotonin, 5HIAA, glutamate, GABA, aspartate, glycine and taurine as quantified from whole brain extracts using HPLC. We also analyze monoamine oxidase and tyrosine hydroxylase enzymatic activity. The results demonstrate that compared to SF, AB is more responsive to both acute alcohol exposure and acute alcohol withdrawal at the level of neurochemistry, a finding that correlates well with prior behavioral observations and one which suggests the involvement of genes in the observed alcohol effects. We discuss correlations between the current results and prior behavioral findings, and stress the importance of characterization of zebrafish strains for future behavior genetic and psychopharmacology studies.

  17. TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE AFTER ACUTE ORAL ADMINISTRATION

    EPA Science Inventory

    TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE
    AFTER ACUTE ORAL ADMINISTRATION

    Michael F. Hughes, Ph.D., Brenda C. Edwards, Carol T. Mitchell and Elaina M. Kenyon, Ph.D. United States Environmental Protection Agency, Office of Research and Development, Nation...

  18. Acute and subchronic administration of anandamide or oleamide increases REM sleep in rats.

    PubMed

    Herrera-Solís, Andrea; Vásquez, Khalil Guzmán; Prospéro-García, Oscar

    2010-03-01

    Anandamide and oleamide, induce sleep when administered acutely, via the CB1 receptor. Their subchronic administration must be tested to demonstrate the absence of tolerance to this effect, and that the sudden withdrawal of these endocannabinoids (eCBs) does not affect sleep negatively. The sleep-waking cycle of rats was evaluated for 24h, under the effect of an acute or subchronic administration of eCBs, and during sudden eCBs withdrawal. AM251, a CB1 receptor antagonist (CB1Ra) was utilized to block eCBs effects. Our results indicated that both acute and subchronic administration of eCBs increase REMS. During eCBs withdrawal, rats lack the expression of an abstinence-like syndrome. AM251 was efficacious to prevent REMS increase caused by both acute and subchronic administration of these eCBs, suggesting that this effect is mediated by the CB1 receptor. Our data further support a role of the eCBs in REMS regulation.

  19. The effects of acute alcohol administration on the human brain: insights from neuroimaging.

    PubMed

    Bjork, James M; Gilman, Jodi M

    2014-09-01

    Over the last quarter century, researchers have peered into the living human brain to develop and refine mechanistic accounts of alcohol-induced behavior, as well as neurobiological mechanisms for development and maintenance of addiction. These in vivo neuroimaging studies generally show that acute alcohol administration affects brain structures implicated in motivation and behavior control, and that chronic intoxication is correlated with structural and functional abnormalities in these same structures, where some elements of these decrements normalize with extended sobriety. In this review, we will summarize recent findings about acute human brain responses to alcohol using neuroimaging techniques, and how they might explain behavioral effects of alcohol intoxication. We then briefly address how chronic alcohol intoxication (as inferred from cross-sectional differences between various drinking populations and controls) may yield individual brain differences between drinking subjects that may confound interpretation of acute alcohol administration effects. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'.

  20. 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. PMID:27154534

  1. 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.

  2. 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

  3. Acute encephalomyelitis complicated with severe neurological sequelae after intrathecal administration of methotrexate in a patient with acute lymphoblastic leukemia.

    PubMed

    Nishikawa, Takuro; Okamoto, Yasuhiro; Maruyama, Shinsuke; Tanabe, Takayuki; Kurauchi, Koichiro; Kodama, Yuichi; Nakagawa, Shunsuke; Shinkoda, Yuichi; Kawano, Yoshifumi

    2014-11-01

    A four-year-old girl on maintenance therapy for acute lymphoblastic leukemia (ALL) complained of a headache and low back pain on the day she received her 21st intrathecal methotrexate (it-MTX) administration, and the next day experienced numbness and pain in her foot. This numbness gradually spread to her hand. She thereafter developed a fever and was hospitalized on day 8. After antibiotic therapy, the fever disappeared. However, her lower limbs became paralyzed, and she also developed urinary retention. On day 12, her paralysis progressed upwards, and she also developed paralysis of the upper limbs. Finally, she experienced convulsions with an impairment of consciousness. A magnetic resonance imaging study of the brain and spinal cord showed abnormal signals in the brain cortex and anterior horn. Accordingly, we diagnosed acute encephalomyelitis associated with it-MTX. High-dose intravenous immunoglobulin, steroid pulse therapy, plasma exchange, and dextromethorphan administration were initiated, while she received mechanical ventilation. Despite this intensive treatment, she suffered severe neurological damage and had to be maintained on mechanical ventilation due to persistent flaccid quadriplegia one year after the onset. When patients have symptoms of ascending paralysis during it-MTX treatment, clinicians should carefully consider the possibility of acute encephalomyelitis due to it-MTX. PMID:25501412

  4. 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.

  5. Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Copper (II) Complex against Ethanol-Induced Acute Gastric Lesions in Rats

    PubMed Central

    Hassandarvish, Pouya; Gwaram, Nura Suleiman; A. Hadi, A. Hamid; Mohd Ali, Hapipah; Majid, Nazia; Abdulla, Mahmood Ameen

    2012-01-01

    Background Copper is an essential element in various metabolisms. The investigation was carried out to evaluate acute gastroprotective effects of the Copper (II) complex against ethanol-induced superficial hemorrhagic mucosal lesions in rats. Methodology/Principal Findings Rats were divided into 7 groups. Groups 1 and 2 were orally administered with Tween 20 (10% v/v). Group 3 was orally administered with 20 mg/kg omeprazole (10% Tween 20). Groups 4–7 received 10, 20, 40, and 80 mg/kg of the complex (10% Tween 20), respectively. Tween 20 (10% v/v) was given orally to group 1 and absolute ethanol was given orally to groups 2–7, respectively. Rats were sacrificed after 1 h. Group 2 exhibited severe superficial hemorrhagic mucosal lesions. Gastric wall mucus was significantly preserved by the pre-treatment complex. The results showed a significant increase in glutathione (GSH), superoxide dismutase (SOD), nitric oxide (NO), and Prostaglandin E2 (PGE2) activities and a decrease in malondialdehyde (MDA) level. Histology showed marked reduction of hemorrhagic mucosal lesions in groups 4–7. Immunohistochemical staining showed up-regulation of Hsp70 and down-regulation of Bax proteins. PAS staining of groups 4–7 showed intense stain uptake of gastric mucosa. The acute toxicity revealed the non-toxic nature of the compound. Conclusions/Significance The gastroprotective effect of the Copper (II) complex may possibly be due to preservation of gastric wall mucus; increase in PGE2 synthesis; GSH, SOD, and NO up-regulation of Hsp70 protein; decrease in MDA level; and down-regulation of Bax protein. PMID:23251568

  6. A case of acute respiratory failure in a rheumatoid arthritis patient after the administration of abatacept

    PubMed Central

    Doğu, Birsen; Atilla, Nurhan; Çetin, Gözde Yıldırım; Yılmaz, Nezir; Öksüz, Hafize

    2016-01-01

    Drug-induced pulmonary disease is an important consideration in the differential diagnosis of patients with rheumatoid arthritis (RA) who present with respiratory symptoms. We report a patient with RA who developed acute respiratory failure two weeks after the administration of abatacept. The clinical findings were consistent with drug-induced acute respiratory failure, most likely acute eosinophilic pneumonia. Pulse steroid was administered at 1000 mg/kg/day in the emergency department. Chest X-ray and arterial blood gas values revealed significant improvement on the second day of hospitalization. However, in the second week, the patient’s fever rose up to 40°C, procalcitonin level increased to 15 ng/mL (<0.5 ng/mL is normal), and the patient died because of sepsis in the fourth week. This is the second report of respiratory failure, after the abatacept administration in the literature. We have reported an acute respiratory failure that occurred after use of the biological agent abatacept. With the increasing use of novel immunomodulatory agents, it is important for clinicians and pathologists to add the possibility of a drug reaction to the traditional differentials of acute respiratory failures occurring in these settings. PMID:27733944

  7. A major QTL for acute ethanol sensitivity in the alcohol tolerant and non-tolerant selected rat lines.

    PubMed

    Radcliffe, R A; Erwin, V G; Bludeau, P; Deng, X; Fay, T; Floyd, K L; Deitrich, R A

    2009-08-01

    The Alcohol Tolerant and Alcohol Non-Tolerant rats (AT, ANT) were selectively bred for ethanol-induced ataxia as measured on the inclined plane. Here we report on a quantitative trait locus (QTL) study in an F(2) intercross population derived from inbred AT and ANT (IAT, IANT) and a follow-up study of congenics that were bred to examine one of the mapped QTLs. Over 1200 F(2) offspring were tested for inclined plane sensitivity, acute tolerance on the inclined plane, duration of the loss of righting reflex (LORR) and blood ethanol at regain of the righting reflex (BECRR). F(2) rats that were in the upper and lower 20% for inclined plane sensitivity were genotyped with 78 SSLP markers. Significant QTLs for inclined plane sensitivity were mapped on chromosomes 8 and 20; suggestive QTLs were mapped on chromosomes 1, 2 and 3. Highly significant QTLs for LORR duration (LOD = 12.4) and BECRR (LOD = 5.7) were mapped to the same locus on chromosome 1. Breeding and testing of reciprocal congenic lines confirmed the chromosome 1 LORR/BECRR QTL. A series of recombinant congenic sub-lines were bred to fine-map this QTL. Current results have narrowed the QTL to an interval of between 5 and 20 Mb. We expect to be able to narrow the interval to less than 5 Mb with additional genotyping and continued breeding of recombinant sub-congenic lines.

  8. Laryngeal choking on food and acute ethanol intoxication in adults--An autopsy study.

    PubMed

    Nikolić, Slobodan; Zivković, Vladimir; Dragan, Babic; Juković, Fehim

    2011-01-01

    The retrospective autopsy study included 98 adults who died because of laryngeal choking on a bolus of food: 67 men and 31 women (χ(2)=6.843, p<0.01), average age 58.61±15.87 years (range 26-92 years). Most of the subjects had poor dentition (χ(2) =34.327, p<0.01). Twenty individuals died in medical institutions, and 78 were nonhospitalized individuals. More than a third of the nonhospitalized individuals were under the influence of ethanol at the moment of death: average blood concentration 8.3g/dL (SD=11.0), ranged from 5.0 to 36.0. Nonhospitalized persons were at the moment of event more often under influence of ethanol than the subjects in control group (χ(2)= 38.874, p<0.01), and at the same time significantly more intoxicated (z=-7.126, p<0.01). Our study pointed out that poor dentition and impairment of the swallowing reflex, as a consequence of ethanol intoxication in individuals without mental disorders, were the most important risk factors for bolus death.

  9. Ethanol and membrane lipids.

    PubMed

    Sun, G Y; Sun, A Y

    1985-01-01

    Although ethanol is known to exert its primary mode of action on the central nervous system, the exact molecular interaction underlying the behavioral and physiological manifestations of alcohol intoxication has not been elucidated. Chronic ethanol administration results in changes in organ functions. These changes are reflective of the adaptive mechanisms in response to the acute effects of ethanol. Biophysical studies have shown that ethanol in vitro disorders the membrane and perturbs the fine structural arrangement of the membrane lipids. In the chronic state, these membranes develop resistance to the disordering effects. Tolerance development is also accompanied by biochemical changes. Although ethanol-induced changes in membrane lipids have been implicated in both biophysical and biochemical studies, measurements of membrane lipids, such as cholesterol content, fatty acid unsaturation, phospholipid distribution, and ganglioside profiles, have not produced conclusive evidence that any of these parameters are directly involved in the action of ethanol. On the other hand, there is increasing evidence indicating that although ethanol in vitro produces a membrane-fluidizing effect, the chronic response to this effect is not to change the membrane bulk lipid composition. Instead, changes in membrane lipids may pertain to small metabolically active pools located in certain subcellular fractions. Most likely, these lipids are involved in important membrane functions. For example, the increase in PS in brain plasma membranes may provide an explanation for the adaptive increase in synaptic membrane ion transport activity, especially (Na,K)-ATPase. There is also evidence that the lipid pool involved in the deacylation-reacylation mechanism (i.e., PI and PC with 20:4 groups) is altered after ethanol administration. An increase in metabolic turnover of these phospholipid pools may have important implications for the membrane functional changes. Obviously, there are other

  10. A Standardized Composition from Extracts of Myristica Fragrans, Astragalus Membranaceus, and Poria Cocos Protects Liver from Acute Ethanol Insult.

    PubMed

    Yimam, Mesfin; Jiao, Ping; Hong, Mei; Jia, Qi

    2016-08-01

    Despite the promising advances in therapeutic discovery, there still is a major challenge in the development of a safe, effective, and economical intervention for managing alcohol-related liver disorders. In this study, we describe the potential use of "MAP," a standardized composition comprising three extracts from Myristica fragrans, Astragalus membranaceus, and Poria cocos, in ameliorating alcohol-induced acute liver toxicity. Ethanol-induced acute hepatotoxicity as an animal model of binge drinking was utilized. Mice received oral doses of MAP at 300 mg/kg for four consecutive days. Mice were orally gavaged with 50% ethanol in 12 mL/kg dosing volume following the third dose of MAP every 12 h thereafter for a total of three doses. Hepatic functional tests from serum collected at T12, and hepatic glutathione (GSH), superoxide dismutases (SODs), and triglyceride from liver homogenates were evaluated. Histopathology analysis and alcoholic steatohepatitis (ASH) scoring were also determined. Excessive increases of serum alanine aminotransferase and aspartate aminotransferase were significantly inhibited at 46.3% and 43.6%, respectively, when mice were treated with MAP. MAP replenished the depleted SOD by more than 60%, while causing significant stimulation of GSH productions. MAP showed statistically significant reduction in ballooning degeneration, vascular steatosis, cytoplasmic or nuclear condensation, and shrinkage, as well as inflammations when compared to vehicle-treated alcohol-induced liver toxicity model. Mice treated with MAP showed statistically significant reduction in ASH scoring when compared to vehicle control. Therefore, the composition MAP could be potentially utilized as an effective hepatic-detoxifying agent for the protection of liver damage caused by alcohol consumptions.

  11. A Standardized Composition from Extracts of Myristica Fragrans, Astragalus Membranaceus, and Poria Cocos Protects Liver from Acute Ethanol Insult.

    PubMed

    Yimam, Mesfin; Jiao, Ping; Hong, Mei; Jia, Qi

    2016-08-01

    Despite the promising advances in therapeutic discovery, there still is a major challenge in the development of a safe, effective, and economical intervention for managing alcohol-related liver disorders. In this study, we describe the potential use of "MAP," a standardized composition comprising three extracts from Myristica fragrans, Astragalus membranaceus, and Poria cocos, in ameliorating alcohol-induced acute liver toxicity. Ethanol-induced acute hepatotoxicity as an animal model of binge drinking was utilized. Mice received oral doses of MAP at 300 mg/kg for four consecutive days. Mice were orally gavaged with 50% ethanol in 12 mL/kg dosing volume following the third dose of MAP every 12 h thereafter for a total of three doses. Hepatic functional tests from serum collected at T12, and hepatic glutathione (GSH), superoxide dismutases (SODs), and triglyceride from liver homogenates were evaluated. Histopathology analysis and alcoholic steatohepatitis (ASH) scoring were also determined. Excessive increases of serum alanine aminotransferase and aspartate aminotransferase were significantly inhibited at 46.3% and 43.6%, respectively, when mice were treated with MAP. MAP replenished the depleted SOD by more than 60%, while causing significant stimulation of GSH productions. MAP showed statistically significant reduction in ballooning degeneration, vascular steatosis, cytoplasmic or nuclear condensation, and shrinkage, as well as inflammations when compared to vehicle-treated alcohol-induced liver toxicity model. Mice treated with MAP showed statistically significant reduction in ASH scoring when compared to vehicle control. Therefore, the composition MAP could be potentially utilized as an effective hepatic-detoxifying agent for the protection of liver damage caused by alcohol consumptions. PMID:27355692

  12. Effects of acute and chronic administration of methylprednisolone on oxidative stress in rat lungs* **

    PubMed Central

    Torres, Ronaldo Lopes; Torres, Iraci Lucena da Silva; Laste, Gabriela; Ferreira, Maria Beatriz Cardoso; Cardoso, Paulo Francisco Guerreiro; Belló-Klein, Adriane

    2014-01-01

    Objective: To determine the effects of acute and chronic administration of methylprednisolone on oxidative stress, as quantified by measuring lipid peroxidation (LPO) and total reactive antioxidant potential (TRAP), in rat lungs. Methods: Forty Wistar rats were divided into four groups: acute treatment, comprising rats receiving a single injection of methylprednisolone (50 mg/kg i.p.); acute control, comprising rats i.p. injected with saline; chronic treatment, comprising rats receiving methylprednisolone in drinking water (6 mg/kg per day for 30 days); and chronic control, comprising rats receiving normal drinking water. Results: The levels of TRAP were significantly higher in the acute treatment group rats than in the acute control rats, suggesting an improvement in the pulmonary defenses of the former. The levels of lung LPO were significantly higher in the chronic treatment group rats than in the chronic control rats, indicating oxidative damage in the lung tissue of the former. Conclusions: Our results suggest that the acute use of corticosteroids is beneficial to lung tissue, whereas their chronic use is not. The chronic use of methylprednisolone appears to increase lung LPO levels. PMID:25029646

  13. Nicotine decreases ethanol-induced dopamine signaling and increases self-administration via stress hormones.

    PubMed

    Doyon, William M; Dong, Yu; Ostroumov, Alexey; Thomas, Alyse M; Zhang, Tao A; Dani, John A

    2013-08-01

    Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement.

  14. Naloxone and ethanol intoxication.

    PubMed

    Askenasi, R; Fontaine, J

    1982-01-01

    Naloxone has been said to be an antidote of acute ethanol intoxication in man. Experimental and clinical studies are however not convincing and contradictory. We have used naloxone to antagonize the effect of ethanol in mice. Results are compared to those obtained with morphine intoxication. Even at high doses (5 mg/kg) naloxone is not a good antagonist of ethanol intoxication in mice.

  15. Nongenomic effects of estrogen mediate the dose-related myocardial oxidative stress and dysfunction caused by acute ethanol in female rats

    PubMed Central

    El-Mas, Mahmoud M.

    2013-01-01

    Acute ethanol lowers blood pressure (BP) and cardiac output in proestrus and after chronic estrogen (E2) replacement in ovariectomized (OVX) female rats. However, whether rapid nongenomic effects of estrogen mediate these hemodynamic effects of ethanol remains unanswered. To test this hypothesis, we investigated the effect of ethanol (0.5 or 1.5 g/kg iv) on left ventricular (LV) function and oxidative markers in OVX rats pretreated 30 min earlier with 1 μg/kg E2 (OVXE2) or vehicle (OVX) and in proestrus sham-operated (SO) rats. In SO rats, ethanol caused significant and dose-related reductions in BP, rate of rise in LV pressure (LV dP/dtmax), and LV developed pressure (LVDP). These effects of ethanol disappeared in OVX rats and were restored in OVXE2 rats, suggesting rapid estrogen receptor signaling mediates the detrimental effects of ethanol on LV function. Ex vivo studies revealed that the estrogen-dependent myocardial dysfunction caused by ethanol was coupled with higher LV 1) generation of reactive oxygen species (ROS), 2) expression of malondialdehyde and 4-hydroxynonenal protein adducts, 3) phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2), and 4) catalase activity. ERK1/2 inhibition by PD-98059 (1 mg/kg iv) abrogated the myocardial dysfunction, hypotension, and the elevation in myocardial ROS generation caused by ethanol. We conclude that rapid estrogen receptor signaling is implicated in cellular events that lead to the generation of aldehyde protein adducts and Akt/ERK1/2 phosphorylation, which ultimately mediate the estrogen-dependent LV oxidative stress and dysfunction caused by ethanol in female rats. PMID:24368668

  16. 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. PMID:25432283

  17. RAB GTPASES ASSOCIATE WITH ISOLATED LIPID DROPLETS (LDS) AND SHOW ALTERED CONTENT AFTER ETHANOL ADMINISTRATION: POTENTIAL ROLE IN ALCOHOL-IMPAIRED LD METABOLISM

    PubMed Central

    Rasineni, Karuna; McVicker, Benita L.; Tuma, Dean J.; McNiven, Mark A.; Casey, Carol A.

    2013-01-01

    Background Alcoholic liver disease is manifested by the presence of fatty liver, primarily due to accumulation of hepatocellular lipid droplets (LDs). The presence of membrane-trafficking proteins (e.g. Rab GTPases) with LDs indicates that LDs may be involved in trafficking pathways known to be altered in ethanol damaged hepatocytes. Since these Rab GTPases are crucial regulators of protein trafficking, we examined the effect ethanol administration has on hepatic Rab protein content and association with LDs. Methods Male Wistar rats were pair-fed Lieber-DeCarli diets for 5 to 8 weeks. Whole liver and isolated LD fractions were analyzed. Identification of LDs and associated Rab proteins was performed in frozen liver or paraffin-embedded sections followed by immunohistochemical analysis. Results Lipid accumulation was characterized by larger LD vacuoles and increased total triglyceride content in ethanol-fed rats. Rabs 1, 2, 3d, 5, 7 and 18 were analyzed in post-nuclear supernatant (PNS) as well as LDs. All of the Rabs were found in the PNS, and Rabs 1, 2, 5 and 7 did not show alcohol-altered content, while Rab 3d content was reduced by over 80%, and Rab 18 also showed ethanol-induced reduction in content. Rab 3d was not found to associate with LDs, while all other Rabs were found in the LD fractions, and several showed an ethanol-related decrease (Rabs 2, 5, 7, 18). Immunohistochemical analysis revealed the enhanced content of a LD-associated protein, perilipin 2 (PLIN2) that was paralleled with an associated decrease of Rab 18 in ethanol-fed rat sections. Conclusion Chronic ethanol feeding was associated with increased PLIN2 and altered Rab GTPase content in enriched LD fractions. Although mechanisms driving these changes are not established, further studies on intracellular protein trafficking and LD biology after alcohol administration will likely contribute to our understanding of fatty liver disease. PMID:24117505

  18. Acute versus subchronic pyridostigmine administration: Effects on the anticholinergic properties of atropine

    SciTech Connect

    Matthew, C.B.; Glenn, J.F.; Bowers, W.D.

    1993-05-13

    Acute, subchronic and chronic exposures to cholinergic compounds may result in differing effects. The efficacy of pyridostigmine bromide (PY) prophylaxis against organophosphorus poisoning depends on post exposure atropine (AT) administration. AT induces a dose-dependent increase in rate of rise of core temperature in heat exposed humans and rats. To determine whether AT's anticholinergic potency is altered following PY administration, we examined AT's effects following acute or subchronic (2 weeks) PY administration in the sedentary heat-stressed rat. Unrestrained rats were used in the following 8 groups of 12: acute (a,2 injections via tail vein) aSAL+SAL, aSAL+AT, aPY+SAL, aPY+AT; subchronic (c, osmotic pump + tail vein) cSAL+SAL, cSAL+AT, cPY+SAL, cPY+AT (SAL- saline, AT- 200 ug/kg, aPY- 100 ug/kg, cPY- 20 ug/hr.) Fifteen minutes following the final injection, rats were subjected to an ambient temperature of 41.5 deg C until a core temperature of 42.6 deg C was attained.

  19. [Characteristics of the pharmacological treatment of toxic liver damage in patients with an alcohol abused syndrome and an acute severe ethanol poison].

    PubMed

    Shilov, V V; Shikalova, I A; Vasil'ev, S A; Loladze, A T; Batotsyrenov, B V

    2012-01-01

    The examination of 130 patients with an alcohol abused syndrome and a severe ethanol poison have revealed that ethanol action are accompanied by significant metabolic disturbances. The comparative evaluation of the inclusion of heptral and remaxol in the treatment has shown that remaxol improves the clinical course of mentioned disorders decreasing the frequency and duration of alcohol delirium. Patients treated with this drug spent less time in acute care and their treatment duration was shorter. Remaxol reduces more effectively the severity of metabolic disorders.

  20. Retrobulbar blood flow and visual field alterations after acute ethanol ingestion

    PubMed Central

    Weber, Anke; Remky, Andreas; Bienert, Marion; der Velden, Klaudia Huber-van; Kirschkamp, Thomas; Rennings, Corinna; Roessler, Gernot; Plange, Niklas

    2013-01-01

    Background The purpose of this study was to test the effect of ethyl alcohol on the koniocellular and magnocellular pathway of visual function and to investigate the relationship between such visual field changes and retrobulbar blood flow in healthy subjects. Methods In 12 healthy subjects (mean age 32 ± 4 years), color Doppler imaging, short-wavelength automated perimetry, and frequency doubling perimetry was performed before and 60 minutes after oral intake of 80 mL of 40 vol% ethanol. Mean and pattern standard deviations for short-wavelength automated and frequency doubling perimetry were assessed. End diastolic velocity (EDV) and peak systolic velocity (PSV) were measured in the central retinal and ophthalmic arteries using color Doppler imaging. Systemic blood pressure, heart rate, intraocular pressure, and blood alcohol concentration were determined. Results Mean PSV and EDV in the central retinal artery showed a significant increase after alcohol intake (P = 0.03 and P = 0.02, respectively). Similarly, we found a significant acceleration of blood flow velocity in the ophthalmic artery (P = 0.02 for PSV; P = 0.04 for EDV). Mean intraocular pressure decreased by 1.0 mmHg after alcohol ingestion (P = 0.01). Retinal sensitivity in short-wavelength automated perimetry did not alter, whereas in frequency doubling perimetry, the mean deviation decreased significantly. Systolic and diastolic blood pressure did not change significantly. Mean blood alcohol concentration was 0.38 ± 0.16 g/L. Conclusion Although ethanol is known to cause peripheral vasodilation, our subjects had no significant drop in systemic blood pressure. However, a significant increase of blood flow velocity was seen in the retrobulbar vessels. Regarding visual function, moderate alcohol consumption led to reduced performance in the magnocellular visual system tested by frequency doubling perimetry, but had no effect on short-wavelength automated perimetry. PMID:23990703

  1. Time-course of extracellular nicotine and cotinine levels in rat brain following administration of nicotine: effects of route and ethanol coadministration

    PubMed Central

    Katner, Simon N.; Toalston, Jamie E.; Smoker, Michael P.; Rodd, Zachary A.; McBride, William J.

    2015-01-01

    Rationale Nicotine and ethanol are commonly coabused drugs, and nicotine-laced ethanol products are growing in popularity. However, little is known about time-course changes in extracellular nicotine and cotinine levels in rat models of ethanol and nicotine coabuse. Objectives The objective of the present study was to determine the time-course changes in brain levels of nicotine and cotinine following subcutaneous (SC) and intragastric (IG) nicotine administration in alcohol-preferring (P) and Wistar rats. Methods In vivo microdialysis was used to collect dialysate samples from the nucleus accumbens shell (NACsh) for nicotine and cotinine determinations, following SC administration of (−)-nicotine (0.18, 0.35, and 0.70 mg/kg) in female P and Wistar rats or IG administration of (−)-nicotine (0.35 and 0.70 mg/kg) in 15 % (v/v) ethanol or water in female P rats. Results SC nicotine produced nicotine and cotinine dialysate levels as high as 51 and 14 ng/ml, respectively. IG administration of 15 % EtOH + 0.70 mg/kg nicotine in P rats resulted in maximal nicotine and cotinine dialysate levels of 19 and 14 ng/ml, respectively, whereas administration of 0.70 mg/kg nicotine in water resulted in maximal nicotine and cotinine levels of 21 and 25 ng/ml, respectively. Nicotine and cotinine levels were detectable within the first 15 and 45 min, respectively, after IG administration. Conclusions Overall, the results of this study suggest that nicotine is rapidly adsorbed and produces relevant extracellular brain concentrations of nicotine and its pharmacologically active metabolite, cotinine. The persisting high brain concentrations of cotinine may contribute to nicotine addiction. PMID:25038869

  2. Chronic administration of ethanol leads to an increased incidence of hepatocellular adenoma by promoting H-ras-mutated cells

    PubMed Central

    Jeannot, Emmanuelle; Pogribny, Igor P.; Beland, Frederick A.; Rusyn, Ivan

    2010-01-01

    This study used tissue samples from male B6C3F1 mice treated with ethanol in drinking water (0, 2.5, or 5%) for 4 or 104 weeks. We tested whether chronic alcohol drinking promotes oxidative stress in the liver and characterized the mutation profile of spontaneous and ethanol-induced tumors. We show that ethanol does not cause detectable oxidative stress in the liver at any time point and acts by promoting H-ras mutated cells. PMID:21168264

  3. Effects of acute and chronic administration of neurosteroid dehydroepiandrosterone sulfate on neuronal excitability in mice

    PubMed Central

    Svob Strac, Dubravka; Vlainic, Josipa; Samardzic, Janko; Erhardt, Julija; Krsnik, Zeljka

    2016-01-01

    Background Neurosteroid dehydroepiandrosterone sulfate (DHEAS) has been associated with important brain functions, including neuronal survival, memory, and behavior, showing therapeutic potential in various neuropsychiatric and cognitive disorders. However, the antagonistic effects of DHEAS on γ-amino-butyric acidA receptors and its facilitatory action on glutamatergic neurotransmission might lead to enhanced brain excitability and seizures and thus limit DHEAS therapeutic applications. The aim of this study was to investigate possible age and sex differences in the neuronal excitability of the mice following acute and chronic DHEAS administration. Methods DHEAS was administered intraperitoneally in male and female adult and old mice either acutely or repeatedly once daily for 4 weeks in a 10 mg/kg dose. To investigate the potential proconvulsant properties of DHEAS, we studied the effects of acute and chronic DHEAS treatment on picrotoxin-, pentylentetrazole-, and N-methyl-D-aspartate-induced seizures in mice. The effects of acute and chronic DHEAS administration on the locomotor activity, motor coordination, and body weight of the mice were also studied. We also investigated the effects of DHEAS treatment on [3H]flunitrazepam binding to the mouse brain membranes. Results DHEAS did not modify the locomotor activity, motor coordination, body weight, and brain [3H]flunitrazepam binding of male and female mice. The results failed to demonstrate significant effects of single- and long-term DHEAS treatment on the convulsive susceptibility in both adult and aged mice of both sexes. However, small but significant changes regarding sex differences in the susceptibility to seizures were observed following DHEAS administration to mice. Conclusion Although our findings suggest that DHEAS treatment might be safe for various potential therapeutic applications in adult as well as in old age, they also support subtle interaction of DHEAS with male and female hormonal status

  4. Is albumin administration in the acutely ill associated with increased mortality? Results of the SOAP study

    PubMed Central

    Vincent, Jean-Louis; Sakr, Yasser; Reinhart, Konrad; Sprung, Charles L; Gerlach, Herwig; Ranieri, V Marco

    2005-01-01

    Introduction Albumin administration in the critically ill has been the subject of some controversy. We investigated the use of albumin solutions in European intensive care units (ICUs) and its relationship to outcome. Methods In a cohort, multicenter, observational study, all patients admitted to one of the participating ICUs between 1 May and 15 May 2002 were followed up until death, hospital discharge, or for 60 days. Patients were classified according to whether or not they received albumin at any time during their ICU stay. Results Of 3,147 admitted patients, 354 (11.2%) received albumin and 2,793 (88.8%) did not. Patients who received albumin were more likely to have cancer or liver cirrhosis, to be surgical admissions, and to have sepsis. They had a longer length of ICU stay and a higher mortality rate, but were also more severely ill, as manifested by higher simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) scores than the other patients. A Cox proportional hazard model indicated that albumin administration was significantly associated with decreased 30-day survival. Moreover, in 339 pairs matched according to a propensity score, ICU and hospital mortality rates were higher in the patients who had received albumin than in those who had not (34.8 versus 20.9% and 41.3 versus 27.7%, respectively, both p < 0.001). Conclusion Albumin administration was associated with decreased survival in this population of acutely ill patients. Further prospective randomized controlled trials are needed to examine the effects of albumin administration in sub-groups of acutely ill patients. PMID:16356223

  5. Reduced fear-recognition sensitivity following acute buprenorphine administration in healthy volunteers.

    PubMed

    Ipser, Jonathan C; Terburg, David; Syal, Supriya; Phillips, Nicole; Solms, Mark; Panksepp, Jaak; Malcolm-Smith, Susan; Thomas, Kevin; Stein, Dan J; van Honk, Jack

    2013-01-01

    In rodents, the endogenous opioid system has been implicated in emotion regulation, and in the reduction of fear in particular. In humans, while there is evidence that the opioid antagonist naloxone acutely enhances the acquisition of conditioned fear, there are no corresponding data on the effect of opioid agonists in moderating responses to fear. We investigated whether a single 0.2mg administration of the mu-opioid agonist buprenorphine would decrease fear sensitivity with an emotion-recognition paradigm. Healthy human subjects participated in a randomized placebo-controlled within-subject design, in which they performed a dynamic emotion recognition task 120min after administration of buprenorphine and placebo. In the recognition task, basic emotional expressions were morphed between their full expression and neutral in 2% steps, and presented as dynamic video-clips with final frames of different emotional intensity for each trial, which allows for a fine-grained measurement of emotion sensitivity. Additionally, visual analog scales were used to investigate acute effects of buprenorphine on mood. Compared to placebo, buprenorphine resulted in a significant reduction in the sensitivity for recognizing fearful facial expressions exclusively. Our data demonstrate, for the first time in humans, that acute up-regulation of the opioid system reduces fear recognition sensitivity. Moreover, the absence of an effect of buprenorphine on mood provides evidence of a direct influence of opioids upon the core fear system in the human brain. PMID:22651957

  6. The effects of time following acute growth hormone administration on metabolic and power output measures during acute exercise.

    PubMed

    Irving, Brian A; Patrie, James T; Anderson, Stacey M; Watson-Winfield, Deidre D; Frick, Kirsten I; Evans, William S; Veldhuis, Johannes D; Weltman, Arthur

    2004-09-01

    We examined the effects of GH infusion on metabolism and performance measures during acute exercise. Nine males [(X+/-SEM): age 23.7+/-1.9 yr, height 182.6+/-1.6 cm, weight 77.3+/- 2.6 kg, percent fat 17.7+/-1.9%, peak oxygen consumption 37.9 +/- 2.9 ml/kg.min] completed six 30-min randomly assigned bicycle ergometer exercise trials at a power output midway between the lactate threshold and peak oxygen consumption. In five of the six trials, the subjects received a recombinant humanGHinfusion (10 microg/kg, 6-min square wave pulse) at 0800 h, followed by a 30-min exercise trial initiated at one of the following times: 0845, 0930, 1015, 1100, or 1145 h. During one of the six trials, the subject received a saline infusion followed by a 30-min exercise trial initiated at 0845 h. Mixed-effect, repeated-measures ANOVA analyses corrected for multiple comparisons revealed that there were no significant condition effects for total work, caloric expenditure, heart rate response, the blood lactate response, or ratings of perceived exertion response. However, acute GH administration resulted in a lower exercise oxygen consumption without a drop-off in power output. We conclude that the time of exercise initiation after GH infusion does not affect total work, caloric expenditure, heart rate response, blood lactate response, or ratings of perceived exertion but reduces oxygen consumption in response to 30 min of constant load exercise at an intensity above the lactate threshold. The last outcome may suggest that GH administration can improve exercise economy.

  7. The impact of acute ethanol on reproductive hormone synthesis, processing, and secretion in female rats at proestrous.

    PubMed

    LaPaglia, N; Steiner, J; Kirsteins, L; Emanuele, M A; Emanuele, N

    1997-12-01

    It is the purpose of this study to investigate the effects of acute ethanol (EtOH) on the female rat hypothalamic-pituitary-gonadal (HPG) axis. The molecular and cellular mechanistic details of such effects have been studied intensively in the male rat. However, there has been relatively little in-depth study of EtOH's effects on the adult, postpubertal female rat. Adult female rats with confirmed 4- or 5-day estrous cycles were given a single injection of EtOH or saline between noon and 1:00 PM on proestrous and were killed at 4:00 PM. EtOH caused a sharp 97% reduction in luteinizing hormone (LH) serum levels (p < 0.001), compared with controls with no concomitant change in LH mRNA. EtOH also significantly reduced hypothalamic LH releasing hormone (LHRH) by 49% (p < 0.01), with no change in content of the precursor pro-LHRH compared with saline-injected controls. The ratio of LHRH to pro-LHRH was also significantly reduced by EtOH (p < 0.05), compared with control. There was no EtOH-induced change in LHRH mRNA. Compared with saline, EtOH reduced both serum estradiol by 37% (p < 0.02) and progesterone by 47% (p < 0.001). These results show that EtOH has profound disruptive effects on the female HPG axis. Our data suggests that EtOH decreases the releasable LHRH pool either by decreasing conversion of pro-LHRH to LHRH and/or by increasing local LHRH degradation. This acutely restricts the release of LH and subsequent estradiol and progesterone secretion.

  8. Acute hemodynamic effects and blood pool kinetics of polystyrene microspheres following intravenous administration

    SciTech Connect

    Slack, J.D.; Kanke, M.; Simmons, G.H.; DeLuca, P.P.

    1981-06-01

    The acute hemodynamic effect of intravenous administration of polystyrene microspheres was investigated and correlated with their distribution pattern and kinetics. Microspheres of three diameters (3.4, 7.4, and 11.6 micrometer) were administered. The 7.4- and 11.6-micrometer diameter microspheres were filtered by the pulmonary capillary network following intravenous administration, the majority during the first pass. There was no significant hemodynamic effect following administrations of the 7.4- and 11.6-micrometer diameter microspheres in doses as high as 3.0 X 10(9) and 6.1 X 10(8) respectively (total cross-sectional area of 1.3 X 10(11) and 6.4 X 10(10) micrometer2, respectively). Intravenous administration of 3.4-micrometer diameter microspheres produced significant dose-dependent systemic hypotension and depression of myocardial performance at dosages as slow as 1.0 X 10(10) (cross-sectional area of 9.1 X 10(10) micrometer2). These differences in acute hemodynamic effect from the 7.4- and 11.6-micrometer diameter microspheres may be due to the differences in distribution kinetics and fate of the 3.4-micrometer diameter microspheres, which readily pass through the lungs to the spleen. Although elimination of the smaller spheres from the blood during the first 6-8 min was rapid, i.e., t 1/2 . 1.62 and 1.72 min from the venous and arterial blood circulation, respectively, levels of 10(3) spheres/g of blood were present in the circulation for greater than 1 hr. These findings must be considered in the planning of intravenous administration of microspheres as a drug delivery system to target organs.

  9. 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

  10. Alterations in ethanol-induced accumbal transmission after acute and long-term zinc depletion.

    PubMed

    Morud, Julia; Adermark, Louise; Ericson, Mia; Söderpalm, Bo

    2015-01-01

    Alcoholism is subject to extensive research, but the role of changes in metabolism caused by alcohol consumption has been poorly investigated. Zinc (Zn(2+) ) deficiency is a common metabolic aberration among alcoholics and Zn(2+) influences the function of ligand-gated ion channels, known pharmacological targets of ethanol (EtOH). Here, we investigate whether manipulation of extracellular levels of Zn(2+) modulates EtOH-induced increases of dopamine (DA) output, as measured by in vivo microdialysis in the rat, and whether voluntary EtOH consumption is altered by Zn(2+) deficiency. Our findings show that the Zn(2+) -chelating agent tricine slowly raises DA levels when perfused in the nucleus accumbens (nAc), whereas the more potent Zn(2+) chelator TPEN reduces DA levels. We also show that pre-treatment with either tricine or TPEN blocks the EtOH-induced DA elevation. Chronic Zn(2+) deficiency induced by a Zn(2+) -free diet did not affect EtOH consumption, but excitatory transmission, assessed by striatal field-potential recordings in the nAc shell, was significantly modulated both by Zn(2+) -free diet and by EtOH consumption, as compared with the EtOH naïve controls. The present study indicates that Zn(2+) influences EtOH's interaction with the brain reward system, possibly by interfering with glycine receptor and GABAA receptor function. This also implies that Zn(2+) deficiency among alcoholics may be important to correct in order to normalize important aspects of brain function.

  11. Effect of acute ethanol on beta-endorphin secretion from rat fetal hypothalamic neurons in primary cultures

    SciTech Connect

    Sarkar, D.K.; Minami, S. )

    1990-01-01

    To characterize the effect of ethanol on the hypothalamic {beta}-endorphin-containing neurons, rat fetal hypothalamic neurons were maintained in primary culture, and the secretion of {beta}-endorphin ({beta}-EP) was determined after ethanol challenges. Constant exposure to ethanol at doses of 6-50 mM produced a dose-dependent increase in basal secretion of {beta}-EP from these cultured cells. These doses of ethanol did not produce any significant effect on cell viability, DNA or protein content. The stimulated secretion of {beta}-EP following constant ethanol exposure is short-lasting. However, intermittent ethanol exposures maintained the ethanol stimulatory action on {beta}-EP secretion for a longer time. The magnitude of the {beta}-EP response to 50 mM ethanol is similar to that of the {beta}-EP response to 56 mM of potassium. Ethanol-stimulated {beta}-EP secretion required extracellular calcium and was blocked by a calcium channel blocker; a sodium channel blocker did not affect ethanol-stimulated secretion. These results suggest that the neuron culture system is a useful model for studying the cellular mechanisms involved in the ethanol-regulated hypothalamic opioid secretion.

  12. Differential effects of acute and chronic fructose administration on pyruvate dehydrogenase activity and lipogenesis

    SciTech Connect

    Wilson, L.

    1988-01-01

    These studies were undertaken to distinguish between the acute and chronic effects of fructose administration. In vivo, liver lipogenesis, as measured by {sup 3}H{sub 2}O incorporation, was greater in rats fed 60% fructose than in their glucose fed controls. Both fructose feeding, and fructose feeding plus intraperitoneal fructose injection increased the activities of 6-phosphogluconate dehydrogenase and malic enzyme. Liver PDH activity was increased by fructose feeding, and was increased even more by fructose feeding and injection of fructose, but this was not associated with any changes in hepatic ATP concentrations.

  13. The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking.

    PubMed

    Sabino, Valentina; Cottone, Pietro; Zhao, Yu; Iyer, Malliga R; Steardo, Luca; Steardo, Luca; Rice, Kenner C; Conti, Bruno; Koob, George F; Zorrilla, Eric P

    2009-05-01

    Sigma-Receptors (SigRs) have been implicated in behavioral and appetitive effects of psychostimulants and may also modulate the motivating properties of ethanol. This study tested the hypothesis that SigRs modulate ethanol reinforcement and contribute to excessive ethanol intake. The effects of subcutaneous treatment with the potent, selective Sig-1R antagonist BD-1063 on operant ethanol self-administration were studied in two models of excessive drinking-Sardinian alcohol-preferring (sP) rats and acutely withdrawn ethanol-dependent Wistar rats-and compared to ethanol self-administration in nondependent Wistar controls. To assess the specificity of action, the effects of BD-1063 on self-administration of an equally reinforcing saccharin solution were determined in Wistar and sP rats. Gene expression of Sig-1R in reward-related brain areas implicated in ethanol reinforcement was compared between ethanol-naive sP and Wistar rats and withdrawn ethanol-dependent Wistar rats. BD-1063 dose dependently reduced ethanol self-administration in sP rats (3.3-11 mg/kg) and withdrawn, dependent Wistar rats (4-11 mg/kg) at doses that did not modify mean ethanol self-administration in nondependent Wistar controls. BD-1063 did not reduce concurrent water self-administration and did not comparably suppress saccharin self-administration, suggesting selectivity of action. BD-1063 also reduced the breakpoints of sP rats to work for ethanol under a progressive-ratio reinforcement schedule. Ethanol-naive sP rats and 24-h withdrawn, dependent Wistar rats showed reduced Sig-1R mRNA expression in the nucleus accumbens. The results suggest that SigR systems may contribute to innate or ethanol-induced increases in susceptibility to self-administer high ethanol levels, identifying a potential neuroadaptive mechanism contributing to excessive drinking and a therapeutic target for alcohol abuse and dependence.

  14. Ethanol and Acetaldehyde After Intraperitoneal Administration to Aldh2-Knockout Mice-Reflection in Blood and Brain Levels.

    PubMed

    Jamal, Mostofa; Ameno, Kiyoshi; Tanaka, Naoko; Ito, Asuka; Takakura, Ayaka; Kumihashi, Mitsuru; Kinoshita, Hiroshi

    2016-05-01

    This paper reports, for the first time, on the analysis of ethanol (EtOH) and acetaldehyde (AcH) concentrations in the blood and brains of Aldh2-knockout (Aldh2-KO) and C57B6/6J (WT) mice. Animals were administrated EtOH (1.0, 2.0 or 4.0 g/kg) or 4-methylpyrazole (4-MP, 82 mg/kg) plus AcH (50, 100 or 200 mg/kg) intraperitoneally. During the blood tests, samples from the orbital sinus of the eye were collected. During the brain tests, dialysates were collected every 5 min (equal to a 15 µl sample) from the striatum using in vivo brain microdialysis. Samples were collected at 5, 10, 15, 20, 25, 30 and 60 min intervals post-EtOH and -AcH injection, and then analyzed by head-space GC. In the EtOH groups, high AcH levels were found in the blood and brains of Aldh2-KO mice, while only small traces of AcH were seen in the blood and brains of WT mice. No significant differences in EtOH levels were observed between the WT and the Aldh2-KO mice for either the EtOH dose. EtOH concentrations in the brain were comparable to the EtOH concentrations in the blood, but the AcH concentrations in the brain were four to five times lower compared to the AcH concentrations in the blood. In the AcH groups, high AcH levels were found in both WT and Aldh2-KO mice. Levels reached a sharp peak at 5 min and then quickly declined for 60 min. Brain AcH concentrations were almost equal to the concentrations found in the blood, where the AcH concentrations were approximately two times higher in the Aldh2-KO mice than in the WT mice, both in the blood and the brain. Our results suggest that systemic EtOH and AcH administration can cause a greater increase in AcH accumulation in the blood and brains of Aldh2-KO mice, where EtOH concentrations in the Aldh2-KO mice were comparable to the EtOH concentrations in the WT mice. Furthermore, detection of EtOH and AcH in the blood and brain was found to be dose-dependent in both genotypes. PMID:26646001

  15. The role of oestradiol in sexually dimorphic hypothalamic-pituitary-adrena axis responses to intracerebroventricular ethanol administration in the rat.

    PubMed

    Larkin, J W; Binks, S L; Li, Y; Selvage, D

    2010-01-01

    Systemic ethanol (EtOH) administration activates the hypothalamic-pituitary-adrenal (HPA) axis of rats in a sexually dimorphic manner. The present studies tested the role played by the central nervous system (CNS) in this phenomenon. To localise the effects of the drug to the brain, we utilised an experimental paradigm whereby a small, nontoxic amount of the drug was delivered via intracerebroventricular (i.c.v.) injection. EtoH administered i.c.v. rapidly diffuses throughout the cerebrospinal fluid and brain, and does not cause neuronal damage or have any long-term physiological or behavioural effects. Experimental groups included intact males, intact cycling females, and ovariectomised (OVX) animals with or without replacement oestradiol (E(2)). Intracerebroventricular EtOH-induced HPA hormonal activation was determined by measuring plasma adrenocorticotrophin (ACTH) levels. Activation of brain areas that both regulate HPA function and are responsive to gonadal hormones was determined using expression of the transcription factor c-fos (Fos) as a marker of neuronal activity. We observed sex- and oestrous cycle- dependent differences in HPA activation by EtOH as measured by both these parameters. ACTH secretion was highest in females in pro-oestrus or oestrus, just prior to or after the endogenous peak of E(2), as was Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and the locus coreuleus (LC) of the brainstem. In OVX animals, E(2) replacement caused an increase in PVN and LC Fos expression in response to i.c.v. EtOH compared to OVX controls, but a decrease in ACTH secretion. Taken together, these results indicate that at the level of the CNS, EtOH stimulates HPA activity more robustly at times when the effects of E(2) are high, but that E(2) alone is not responsible for this effect. The data further suggest that the LC plays an important role in the circuitry, which appears to be different from that activated following the systemic

  16. Synergistic Self-Administration of Ethanol and Cocaine Directly into the Posterior Ventral Tegmental Area: Involvement of Serotonin-3 Receptors

    PubMed Central

    Oster, Scott M.; Hauser, Sheketha R.; Toalston, Jamie E.; Bell, Richard L.; McBride, William J.; Rodd, Zachary A.

    2012-01-01

    Ethanol (EtOH) and cocaine are both self-administered into the posterior ventral tegmental area (VTA). Self-administration of either drug is prevented by coadministration of a serotonin (5-HT3) receptor antagonist. Electrophysiological studies indicated that cocaine and EtOH can act synergistically to stimulate VTA dopamine neurons. The current experiment assessed whether cocaine and EtOH would synergistically interact to produce a reinforcing action within the posterior VTA. Adult female Wistar rats were randomly assigned to one of 13 groups. There were three control groups: artificial cerebrospinal fluid (aCSF), a subthreshold EtOH (100 mg%) group, and a subthreshold cocaine (25 pmol/100 nl) group. The other groups self-administered 50 or 75 mg% EtOH containing 6.25, 12.5, or 25 pmol/100 nl cocaine or 100 mg% EtOH containing 3.12, 6.25, 12.5, or 25 pmol/100 nl cocaine. All rats received the assigned infusate for sessions 1 through 4, aCSF alone in sessions 5 and 6, and the original infusate during session 7. The effects of adding a 5-HT3 receptor antagonist [tropisetron, C17H20N2O2 (ICS 205,930) and C17H22N4O.C4H4O4 (LY278-584)] on coadministration of EtOH and cocaine (75 mg% + 12.5 pmol/100 nl) were determined. Rats failed to self-administer aCSF or the subthreshold concentration of EtOH or cocaine. All three concentrations of EtOH (50, 75, and 100 mg%) combined with cocaine (12.5 and 25 pmol/100 nl) supported self-administration. Adding a 5HT3 receptor antagonist attenuated coadministration of EtOH + cocaine. Overall, the data indicate that the reinforcing properties of EtOH and cocaine interacted synergistically within the posterior VTA, and these synergistic effects were mediated, at least in part, by activation of local 5-HT3 receptors. PMID:22011435

  17. Acute Ethanol Effects on Brain Activation in Low- and High-Level Responders to Alcohol

    PubMed Central

    Trim, Ryan S.; Simmons, Alan N.; Tolentino, Neil J.; Hall, Shana A.; Matthews, Scott C.; Robinson, Shannon K.; Smith, Tom L.; Padula, Claudia B.; Paulus, Martin P.; Tapert, Susan F.; Schuckit, Marc A.

    2013-01-01

    Background A low level of response (LR) to alcohol is an important endophenotype associated with an increased risk for alcoholism. However, little is known about how neural functioning may differ between individuals with low and high LRs to alcohol. This study examined whether LR group effects on neural activity varied as a function of acute alcohol consumption. Methods 30 matched high- and low-LR pairs (N=60 healthy young adults) were recruited from the University of California, San Diego and administered a structured diagnostic interview and laboratory alcohol challenge followed by two fMRI sessions under placebo and alcohol conditions, in randomized order. Task performance and BOLD response contrast to high relative to low working memory load in an event-related visual working memory (VWM) task was examined across 120 fMRI sessions. Results Both LR groups performed similarly on the VWM task across conditions. A significant LR group by condition interaction effect was observed in inferior frontal and cingulate regions, such that alcohol attenuated the LR group differences found under placebo (p<.05). The LR group by condition effect remained even after controlling for cerebral blood flow, age, and typical drinking quantity. Conclusions Alcohol had differential effects on brain activation for low and high LR individuals within frontal and cingulate regions. These findings represent an additional step in the search for physiological correlates of a low LR, and identify brain regions that may be associated with the low LR response. PMID:20477775

  18. 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.

  19. Moderate ethanol administration accentuates cardiomyocyte contractile dysfunction and mitochondrial injury in high fat diet-induced obesity.

    PubMed

    Yuan, Fang; Lei, Yonghong; Wang, Qiurong; Esberg, Lucy B; Huang, Zaixing; Scott, Glenda I; Li, Xue; Ren, Jun

    2015-03-18

    Light to moderate drinking confers cardioprotection although it remains unclear with regards to the role of moderate drinking on cardiac function in obesity. This study was designed to examine the impact of moderate ethanol intake on myocardial function in high fat diet intake-induced obesity and the mechanism(s) involved with a focus on mitochondrial integrity. C57BL/6 mice were fed low or high fat diet for 16 weeks prior to ethanol challenge (1g/kg/d for 3 days). Cardiac contractile function, intracellular Ca(2+) homeostasis, myocardial histology, and mitochondrial integrity [aconitase activity and the mitochondrial proteins SOD1, UCP-2 and PPARγ coactivator 1α (PGC-1α)] were assessed 24h after the final ethanol challenge. Fat diet intake compromised cardiomyocyte contractile and intracellular Ca(2+) properties (depressed peak shortening and maximal velocities of shortening/relengthening, prolonged duration of relengthening, dampened intracellular Ca(2+) rise and clearance without affecting duration of shortening). Although moderate ethanol challenge failed to alter cardiomyocyte mechanical property under low fat diet intake, it accentuated high fat diet intake-induced changes in cardiomyocyte contractile function and intracellular Ca(2+) handling. Moderate ethanol challenge failed to affect fat diet intake-induced cardiac hypertrophy as evidenced by H&E staining. High fat diet intake reduced myocardial aconitase activity, downregulated levels of mitochondrial protein UCP-2, PGC-1α, SOD1 and interrupted intracellular Ca(2+) regulatory proteins, the effect of which was augmented by moderate ethanol challenge. Neither high fat diet intake nor moderate ethanol challenge affected protein or mRNA levels as well as phosphorylation of Akt and GSK3β in mouse hearts. Taken together, our data revealed that moderate ethanol challenge accentuated high fat diet-induced cardiac contractile and intracellular Ca(2+) anomalies as well as mitochondrial injury.

  20. 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.

  1. Cyproheptadine resembles clozapine in vivo following both acute and chronic administration in rats.

    PubMed

    Goudie, Andrew J; Cooper, Gillian D; Cole, Jon C; Sumnall, Harry R

    2007-03-01

    Cyproheptadine is a cheap, widely available anti-allergy drug with a broad receptor binding profile which resembles that of clozapine. In rats discriminating clozapine from vehicle cyproheptadine mimicked clozapine very closely. Acutely it induced full generalization in the absence of response suppression, as observed with clozapine. Chronic administration of clozapine and cyproheptadine induced tolerance and cross-tolerance respectively to the clozapine stimulus. This was characterized by circa 3.5-fold parallel shifts to the right in the clozapine generalization curves. Such tolerance and cross-tolerance was spontaneously reversible, suggesting that it was pharmacodynamic, and that clozapine and cyproheptadine induce similar neuroadaptations when administered chronically. Administration of chlordiazepoxide at a very high dose induced no cross-tolerance to the clozapine stimulus showing the pharmacological specificity of tolerance. The clozapine stimulus is a compound cue involving actions at various receptors, and various clozapine-like antipsychotic (APD) drugs generalize fully to it. These data demonstrate that in vivo cyproheptadine resembles clozapine both acutely and chronically. Our findings, in conjunction with other actions of cyproheptadine -- induction of weight gain, alleviation of clozapine withdrawal, anxiolytic actions, alleviation of 'typical' APD-induced motoric side effects, and some preliminary clinical findings -- suggest that further study of cyproheptadine in conjunction with a 'typical' APD for the possible treatment of schizophrenia is merited at both pre-clinical and clinical levels.

  2. Combined administration of hyperbaric oxygen and hydroxocobalamin improves cerebral metabolism after acute cyanide poisoning in rats.

    PubMed

    Hansen, M B; Olsen, N V; Hyldegaard, O

    2013-11-01

    Hyperbaric oxygen therapy (HBOT) or intravenous hydroxocobalamin (OHCob) both abolish cyanide (CN)-induced surges in interstitial brain lactate and glucose concentrations. HBOT has been shown to induce a delayed increase in whole blood CN concentrations, whereas OHCob may act as an intravascular CN scavenger. Additionally, HBOT may prevent respiratory distress and restore blood pressure during CN intoxication, an effect not seen with OHCob administration. In this report, we evaluated the combined effects of HBOT and OHCob on interstitial lactate, glucose, and glycerol concentrations as well as lactate-to-pyruvate ratio in rat brain by means of microdialysis during acute CN poisoning. Anesthetized rats were allocated to three groups: 1) vehicle (1.2 ml isotonic NaCl intra-arterially); 2) potassium CN (5.4 mg/kg intra-arterially); 3) potassium CN, OHCob (100 mg/kg intra-arterially) and subsequent HBOT (284 kPa in 90 min). OHCob and HBOT significantly attenuated the acute surges in interstitial cerebral lactate, glucose, and glycerol concentrations compared with the intoxicated rats given no treatment. Furthermore, the combined treatment resulted in consistent low lactate, glucose, and glycerol concentrations, as well as in low lactate-to-pyruvate ratios compared with CN intoxicated controls. In rats receiving OHCob and HBOT, respiration improved and cyanosis disappeared, with subsequent stabilization of mean arterial blood pressure. The present findings indicate that a combined administration of OHCob and HBOT has a beneficial and persistent effect on the cerebral metabolism during CN intoxication.

  3. Administration of Reconstituted Polyphenol Oil Bodies Efficiently Suppresses Dendritic Cell Inflammatory Pathways and Acute Intestinal Inflammation

    PubMed Central

    Cavalcanti, Elisabetta; Vadrucci, Elisa; Delvecchio, Francesca Romana; Addabbo, Francesco; Bettini, Simona; Liou, Rachel; Monsurrò, Vladia; Huang, Alex Yee-Chen; Pizarro, Theresa Torres

    2014-01-01

    Polyphenols are natural compounds capable of interfering with the inflammatory pathways of several in vitro model systems. In this study, we developed a stable and effective strategy to administer polyphenols to treat in vivo models of acute intestinal inflammation. The in vitro suppressive properties of several polyphenols were first tested and compared for dendritic cells (DCs) production of inflammatory cytokines. A combination of the polyphenols, quercetin and piperine, were then encapsulated into reconstituted oil bodies (OBs) in order to increase their stability. Our results showed that administration of low dose reconstituted polyphenol OBs inhibited LPS-mediated inflammatory cytokine secretion, including IL-6, IL-23, and IL-12, while increasing IL-10 and IL-1Rα production. Mice treated with the polyphenol-containing reconstituted OBs (ROBs) were partially protected from dextran sodium sulfate (DSS)-induced colitis and associated weight loss, while mortality and inflammatory scores revealed an overall anti-inflammatory effect that was likely mediated by impaired DC immune responses. Our study indicates that the administration of reconstituted quercetin and piperine-containing OBs may represent an effective and potent anti-inflammatory strategy to treat acute intestinal inflammation. PMID:24558444

  4. Brain energy consumption in ethanol-treated, Long-Evans rats.

    PubMed

    Viña, J R; Salus, J E; DeJoseph, M R; Pallardo, F; Towfighi, J; Hawkins, R A

    1991-06-01

    The cerebral metabolic rate of glucose utilization (CMRGlc) was measured in rats fed liquid diets containing ethanol for 8 wk, after removal of ethanol from the diet and after acute ethanol intoxication. Control rats were pair fed the liquid diets containing isoenergetic amounts of dextrin-maltose. Quantitative autogradiography using [6-14C]glucose measured CMRGlc at the level of individual structures. Digital image techniques created stereograms of brain energy consumption from the autoradiographs. These techniques provided information about CMRGlc throughout the brain. Rats given the ethanol liquid diet drank constantly throughout the day and night. Neuropathological examination of brain revealed no abnormalities from ethanol consumption. Acute ethanol administration to control rats produced a decrease in CMRGlc throughout the brain that was most prominent in structures concerning auditory, visual, memory and motor functions. Chronic ethanol consumption did not reduce CMRGlc to the same degree as acute ethanol intoxication; in fact, it affected only a few structures. The removal of ethanol from chronic ethanol-treated rats for a period of 18 h caused CMRGlc to rise above control values throughout the brain. However, there were no seizures or other evidence of brain dysfunction.

  5. Differential peptidomics assessment of strain and age differences in mice in response to acute cocaine administration.

    PubMed

    Romanova, Elena V; Rubakhin, Stanislav S; Ossyra, John R; Zombeck, Jonathan A; Nosek, Michael R; Sweedler, Jonathan V; Rhodes, Justin S

    2015-12-01

    Neurochemical differences in the hypothalamic-pituitary axis between individuals and between ages may contribute to differential susceptibility to cocaine abuse. This study measured peptide levels in the pituitary gland (Pit) and lateral hypothalamus (LH) in adolescent (age 30 days) and adult (age 65 days) mice from four standard inbred strains, FVB/NJ, DBA/2J, C57BL/6J, and BALB/cByJ, which have previously been characterized for acute locomotor responses to cocaine. Individual peptide profiles were analyzed using mass spectrometric profiling and principal component analysis. Sequences of assigned peptides were verified by tandem mass spectrometry. Principal component analysis classified all strains according to their distinct peptide profiles in Pit samples from adolescent mice, but not adults. Select pro-opiomelanocortin-derived peptides were significantly higher in adolescent BALB/cByJ and DBA/2J mice than in FVB/NJ or C57BL/6J mice. A subset of peptides in the LH, but not in the Pit, was altered by cocaine in adolescents. A 15 mg/kg dose of cocaine induced greater peptide alterations than a 30 mg/kg dose, particularly in FVB/NJ animals, with larger differences in adolescents than adults. Neuropeptides in the LH affected by acute cocaine administration included pro-opiomelanocortin-, myelin basic protein-, and glutamate transporter-derived peptides. The observed peptide differences could contribute to differential behavioral sensitivity to cocaine among strains and ages. Peptides were measured using mass spectrometry (MALDI-TOF) in individual lateral hypothalamus and pituitary samples from four strains and two ages of inbred mice in response to acute cocaine administration. Principal component analyses (PCA) classified the strains according to their peptide profiles from adolescent mice, and a subset of peptides in the lateral hypothalamus was altered by cocaine in adolescents.

  6. 17β-Estradiol administration attenuates seawater aspiration-induced acute lung injury in rats.

    PubMed

    Fan, Qixin; Zhao, Pengtao; Li, Jiahuan; Xie, Xiaoyan; Xu, Min; Zhang, Yong; Mu, Deguang; Li, Wangping; Sun, Ruilin; Liu, Wei; Nan, Yandong; Zhang, Bo; Jin, Faguang; Li, Zhichao

    2011-12-01

    There is very little evidence on the value of administering estrogen in cases of seawater drowning which can induce acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Therefore, this study aimed to investigate whether 17β-estradiol (E2) treatment can attenuate seawater aspiration-induced ALI in rats. In the experiment, ALI was induced by endotracheal instillation of seawater (4mL/kg) and the rats were then given intraperitoneal injection of E2 (5mg/kg) 20min after seawater instillation. Finally, the changes of arterial blood gases which contained hydrogen ion concentration (pH), arterial oxygen tension (PaO(2)) and arterial carbon dioxide tension (PaCO(2)) were measured and the measurement of extravascular lung water (EVLW) was observed. The pulmonary histological changes were evaluated by hematoxylin-eosin stain. The expression of aquaporins (AQPs) 1, AQP5, and estrogen receptor-β (ERβ) was measured by western blotting and immunohistochemical methods. The results showed that compared with normal saline water, seawater aspiration induced more serious ALI in rats which was markedly alleviated by E2 treatment. Meanwhile, the ERβ in lung tissues was activated after E2 administration. The seawater aspiration group also presented with severe pulmonary edema which was paralleled with over expressed AQP1 and AQP5. However, the up-regulation of AQP1 and AQP5 was suppressed by the administration of E2, resulting in an attenuation of lung edema. In conclusion, E2 treatment could effectively attenuate seawater aspiration-induced acute lung injury in rats by the down-regulation of AQP1 and AQP5.

  7. Acute caffeine administration effect on brain activation patterns in mild cognitive impairment.

    PubMed

    Haller, Sven; Montandon, Marie-Louise; Rodriguez, Cristelle; Moser, Dominik; Toma, Simona; Hofmeister, Jeremy; Sinanaj, Indrit; Lovblad, Karl-Olof; Giannakopoulos, Panteleimon

    2014-01-01

    Previous studies showed that acute caffeine administration enhances task-related brain activation in elderly individuals with preserved cognition. To explore the effects of this widely used agent on cognition and brain activation in early phases of cognitive decline, we performed a double-blinded, placebo-controlled functional magnetic resonance imaging (fMRI) study during an n-back working memory task in 17 individuals with mild cognitive impairment (MCI) compared to 17 age-matched healthy controls (HC). All individuals were regular caffeine consumers with an overnight abstinence and given 200 mg caffeine versus placebo tablets 30 minutes before testing. Analyses included assessment of task-related activation (general linear model), functional connectivity (tensorial-independent component analysis, TICA), baseline perfusion (arterial spin labeling, ASL), grey matter density (voxel-based morphometry, VBM), and white matter microstructure (tract-based spatial statistics, TBSS). Acute caffeine administration induced a focal activation of the prefrontal areas in HC with a more diffuse and posteromedial activation pattern in MCI individuals. In MCI, TICA documented a significant caffeine-related enhancement in the prefrontal cortex, supplementary motor area, ventral premotor and parietal cortex as well as the basal ganglia and cerebellum. The absence of significant group differences in baseline ASL perfusion patterns supports a neuronal rather than a purely vascular origin of these differences. The VBM and TBSS analyses excluded potentially confounding differences in grey matter density and white matter microstructure between MCI and HC. The present findings suggest a posterior displacement of working memory-related brain activation patterns after caffeine administration in MCI that may represent a compensatory mechanism to counterbalance a frontal lobe dysfunction.

  8. 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.

  9. Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

    PubMed Central

    Faccidomo, Sara; Salling, Michael C; Galunas, Christina; Hodge, Clyde W

    2015-01-01

    Rationale Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown. Objective To pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC) and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2). Methods Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9% ethanol+2% sucrose (ethanol) or 2% sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0–1.7 μg/side) in PFC, NAC or AMY prior to self-administration. Results pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg=1.21 g/kg; BAC=54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions. Conclusions Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug. PMID:26123321

  10. Hibiscus sabdariffa ethanolic extract protects against dyslipidemia and oxidative stress induced by chronic cholesterol administration in rabbits.

    PubMed

    Ekor, M; Adesanoye, O A; Udo, I E; Adegoke, O A; Raji, J; Farombi, E O

    2010-12-01

    Excessive intake of cholesterol (CHOL) and induction of free radical production play a critical role in the pathophysiology of several human diseases. Dietary therapy with plant products rich in flavonoids has been shown to provide benefits without the adverse effects of agents used in clinical practice. Hibiscus sabdariffa (HS) has been used for various purposes due to myriads of flavonoids present in it. In this study, the chemopreventive property of HS ethanolic extract (HSE) was investigated in dyslipidemia and oxidant stress associated with prolonged CHOL administration in rabbits. Twenty-five (25) adult male rabbits weighing between 1.5 and 1.7 kg were used and randomly divided into five groups of five rabbits per group. The CHOL-fed rabbits received 1 g/kg/day of CHOL suspended in 1 ml of corn oil for 8 weeks. Group 1 received 1 ml of corn oil and served as control. Group 2 was fed with CHOL only while groups 3, 4 and 5 received daily doses ofcholestyramine (questran, 260 mg/kg), HSE 200 mg/kg and HSE 300 mg/kg respectively along with CHOL. Animals were sacrificed by cervical dislocation 24-hours after last dose. Enzymic and non-enzymic markers of oxidative stress and lipid profile were analysed in serum, liver, kidney and heart of rabbits. HSE significantly attenuated the alteration in lipid levels and antioxidant status induced by high CHOL intake in rabbits in this study. Both serum and tissue levels of low density lipoprotein-CHOL, triglycerides, phospholipids, and total CHOL decreased with increase in high density lipoprotein-CHOL except in the heart, following treatment with HSE in CHOL-fed rabbits when compared with the untreated group (p<0.05). Similarly, HSE prevented CHOL-induced depletion of enzymic (superoxide dismutase, catalase) and non-enzymic (reduced glutathione, vitamin C) antioxidants with the attendant increases in lipid peroxidation and xanthine oxidase activity in these animals. The effectiveness of HSE in this condition was comparable

  11. Acute Sodium Arsenite-Induced Hematological and Biochemical Changes in Wistar Rats: Protective Effects of Ethanol Extract of Ageratum conyzoides

    PubMed Central

    Ola-Davies, Olufunke Eunice; Akinrinde, Akinleye Stephen

    2016-01-01

    Background: Ageratum conyzoides L. (Asteraceae) is an annual herbaceous plant used in folklore medicine for the treatment of a wide range of diseases. Objective: To investigate the protective effect of the ethanol leaf extract of A. conyzoides (EEAC) against hematological, serum biochemical and histological alterations induced by Sodium arsenite administration to Wistar rats. Materials and Methods: Twenty male Wistar rats were randomly assigned into four groups of five rats each. Group I received propylene glycol and Group II rats were given the (EEAC, 100 mg/kg b.w.) orally for 7 days. Group III were given a single oral dose of sodium arsenite (NaAsO2, 2.5 mg/kg b.w.). Animals in Group IV were pretreated with 100 mg/kg EEAC for 7 days followed by a single oral dose of sodium arsenite. Results: Arsenic exposure resulted in significant reductions (P < 0.05) in values of packed cell volume (PCV), hemoglobin concentration (Hb) and red blood cell (RBC) count, and elevation in total white blood cell (WBC) count with insignificant reductions in serum total protein, albumin, and globulin levels. Alterations in aspartate aminotransferase, alanine transferase, alkaline phosphatase, and gamma glutamyl transferase activities, as well as in serum levels of urea, creatinine, glucose, cholesterol, and triglyceride levels, were not statistically significant. EEAC significantly restored (P < 0.05) the PCV, Hb, RBC, and WBC as well as serum albumin, globulin, and total protein to normal values. Conclusion: The results of this study indicate that EEAC possess strong potentials to protect against toxicities induced by sodium arsenite. SUMMARY Ageratum conyzoides produced significant reversal of the reduction in the erythrocytic indices (packed cell volume, red blood cell, and Hb) caused by sodium arseniteSodium arsenite-induced slight elevations in serum aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), correlating with the

  12. Effects of a new administration form of oxymetazoline on maxillary ostial patency in healthy individuals and patients with acute rhinitis.

    PubMed

    Ackerhans, M; Jannert, M; Tönnesson, M

    1994-01-01

    A new administration form of the nasal decongestant oxymetazoline and its effects on maxillary ostial patency were investigated in 5 healthy individuals and 20 patients with acute rhinitis. Registration and comparison of ostial patency after administration of placebo spray and oxymetazoline spray, placebo solution and oxymetazoline solution, were performed in healthy individuals. Patients with acute rhinitis were treated with either oxymetazoline solution or placebo solution, preceded and followed by registration of the equivalent maxillary ostial diameter. In both studies, solution was administered with a nasal bellows container. The results suggest that the administration of oxymetazoline solution with the nasal bellows container is a more effective way of increasing maxillary ostial patency in healthy individuals than oxymetazoline spray. In patients with acute rhinitis it also seems to be a way of increasing maxillary ostial patency.

  13. Acute ethanol intoxication shows no effect on Ca sup 2+ -uptake of Ca sup 2+ -dependent ATPase activity in myocardial sarcoplasmic reticulum vesicles

    SciTech Connect

    McAllister, K.P.; Horton, J.W.; Kaufman, T.M.; White, D.J. )

    1989-02-09

    We have previously shown that acute ethanolism impairs left ventricular (LV) function. We hypothesized that cardiac dysfunction may be related to altered Ca{sup 2+} pump function by the sarcoplasmic reticulum (SR). In this study, LV function (in isolated perfused hearts) was compared to Ca{sup 2+} transport in SR vesicles isolated from nonperfused hearts in control (C) and acutely intoxicated (ETOH, 2.5 ml/kg IV) guinea pigs. Compared to control hearts, ETOH hearts had significantly lower LV systolic pressure maximal rate of LV pressure rise and fall. Ca{sup 2+}-ATPase activity was not significantly different in either group of animals. Although maximum Ca{sup 2+} uptake tended to be slightly lower in ETOH compared to control hearts coupling ratios (mol Ca{sup 2+} transported/mol ATP hydrolyzed) were not significantly different. We conclude that changes in SR Ca{sup 2+} pump function are not responsible for the depressed LV function seen in acute ethanolism.

  14. Effects of acute administration of brotizolam in subjects with disturbed sleep

    PubMed Central

    Roehrs, T.; Zorick, F.; Koshorek, G. L.; Wittig, R.; Roth, T.

    1983-01-01

    1 Effects of ingestion of brotizolam (0.25 and 0.50 mg) over 1-3 days on polysomnographic measures of sleep were assessed in patients complaining of insomnia. 2 Brotizolam reduced latency to sleep, number of awakenings and wake during sleep, and increased total sleep time. It also increased stage 2 sleep and decreased slow wave and rapid eye movement sleep. 3 Increasing the dose from 0.25 to 0.50 mg increased hypnotic efficacy, and there was a more consistent and reliable effect. 4 Discontinuation of brotizolam had minimal effects on sleep compared with placebo over the 3 nights after acute administration. 5 No side-effects or disruption of daytime function was found using questionnaires and objective tests of performance. PMID:6661383

  15. Behavioral consequences of chelator administration in acute cadmium toxicity (journal version)

    SciTech Connect

    Peele, D.B.; Farmer, J.D.; MacPhail, R.C.

    1988-01-01

    The conditioned flavor-aversion paradigm was used to assess the toxicity of acutely administered cadmium and the interaction of cadmium with the heavy-metal chelating agents dimercaprol (BAL) and dimercaptosuccinic acid (DMSA). Shortly after consuming saccharin, rats received cadmium either alone or in combination with BAL or DMSA. When compared to rats receiving either nothing or the vehicle, rats receiving cadmium displayed significant reductions in saccharin preference (i.e., conditioned flavor aversions). BAL and DMSA were also capable of producing conditioned flavor aversions when given alone. Rats receiving cadmium in combination with either BAL or DMSA displayed significant, but not complete, attenuations of conditioned flavor aversions when compared to rats receiving cadmium alone. Chelator-induced blockade of cadmium-induced flavor-aversion conditioning was not obtained when BAL or DMSA administration was delayed by 4 hrs.

  16. Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity.

    PubMed

    Tiradentes, R V; Pires, J G P; Silva, N F; Ramage, A G; Santuzzi, C H; Futuro Neto, H A

    2014-07-01

    Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33 ± 4.7 and -31 ± 5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35 ± 5.4 and -31 ± 5.5%, respectively, with an increase in blood pressure +26.3 ± 2.5; 3 mg/kg sertraline reduced RSNA by -59.4 ± 8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central. PMID:25003632

  17. [Ethanol metabolism and pathobiochemistry of organ damage--1992. II. Relation between ethanol metabolism and free radicals, and the metabolism of saccharides and amino acids. Ethanol as a carcinogen. Drug interactions with ethanol].

    PubMed

    Zima, T

    1993-01-01

    Ethanol metabolism induces formation of free radicals which are responsible for lipid peroxidation of biological membranes with subsequent aldehyde formation (malondialdehyde,4-hydroxy-nonenal). These aldehydes are competitive or mixed inhibitors of aldehyde dehydrogenase, and they cause an increase in hepatocellular toxicity of aldehydes. The activity of antioxidative systems in human body after chronic as well as acute ethanol intake is being reduced. Interference of ethanol metabolism and gluconeogenesis is caused by inhibition of intake substrates or by decrease NADH/NAD+, ratio in hepatocyte. The blood level of glucose decreases, lactate level increases as well as the ration of lactate, pyruvate and NADH/NAD+ which inhibit cytosole pyruvate carboxykinase. An acute ethanol administration reduces the concentration of most amino acids in plasma by ethanol oxidation impacts on increase of NADH/NAD+ ratio or by mechanism mediated by beta-adrenergic receptors. Chronic alcoholics develop tolerance to decreased plasmatic levels of amino acids. Accumulation of proteins in liver may be explained by larger amount of proteins binding to fatty acids, and also by diminished degradation of proteins with decreasing autophagosome and autolysosome formations. Alcohol is one of carcinogenic factors. Ethanol, acetaldehyde and originating free radicals impaired the DNA repairing enzyme. Binding itself to DNA, acetaldehyde changes DNA properties. Ethanol may also function as a co-carcinogen due to its ability to increase disolution and absorption of carcinogens. Chronic alcoholism induces cytochrome P450 which takes part in the activation and metabolism of carcinogens. Mutual interaction of drugs metabolism and ethanol is connected mainly with cytochrome P450-MEOS. Acute ethanol intake inhibits MEOS, as MEOS gives preference to ethanol as a substrate, however, chronic alcoholism induces MEOS.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Progesterone inhibits behavioral responses and estrogen increases corticosterone levels after acute cocaine administration.

    PubMed

    Niyomchai, Tipyamol; Russo, Scott J; Festa, Eugene D; Akhavan, Alaleh; Jenab, Shirzad; Quiñones-Jenab, Vanya

    2005-04-01

    Accumulating evidence suggests that estrogen and progesterone contribute to the sexually dimorphic behavioral response to cocaine. In this study, we tested the hypothesis that varying the level of estrogen or progesterone affects cocaine-induced locomotive behavior in female rats. Ovariectomized (OVX) rats received estrogen (0, 5, 10, 20, or 50 microg) 48 h or progesterone (0, 50, 100, 250, or 500 microg) 24 h before acute saline or cocaine (15 mg/kg) administration. Although estrogen did not affect cocaine-induced ambulatory and rearing behaviors, it affected stereotypic behaviors regardless of cocaine administration (animals receiving 50 microg had higher stereotypic counts than did the OVX group). In contrast, progesterone affected rearing activity dose-dependently: 50 and 500 microg of progesterone inhibited, whereas 100 microg and 250 microg stimulated, rearing in response to cocaine. That estrogen and progesterone did not affect overall baseline behavioral activity suggests their effects are mediated in part through interactions with cocaine. Progesterone administration did not affect corticosterone levels in saline- or cocaine-treated rats. Estrogen administration, however, affected levels of corticosterone both at baseline and after cocaine treatment. After accounting for baseline differences, we found that rats receiving 5 or 10 microg of estrogen and cocaine had higher percentage increases in serum corticosterone levels than did the control group that did not receive estrogen. On the basis of these observations, we suggest that progesterone fluctuations during the estrous cycle impact cocaine-induced behavioral responses, whereas estrogen may affect activity in the hypothalamic-pituitary-adrenal axis. Thus, dose-dependent effects of gonadal hormones may underlie some of the reported sex differences and reproductive cycle effects of cocaine.

  19. Synergism of organic zinc salts and sulfhydryl compounds (thiols) in the protection of mice against acute ethanol toxicity, and protective effects of various metal salts.

    PubMed

    Floersheim, G L

    1987-06-01

    Organic zinc salts such as zinc aspartate, zinc orotate, zinc histidine and zinc acetate protected mice against the lethality of an acute intraperitoneal challenge with ethanol. A similar activity was also provided by salts of cobalt, zirconium, lithium and magnesium. Organic zinc salts acted synergistically with sulfhydryl compounds in protecting the mice and potentiation between the two categories of agents was seen. The results are in analogy to radioprotective effects by zinc and thiols and imply that organic zinc salts may, alone or in conjunction with thiols, reduce in a wider context tissue injury caused by free radical-mediated mechanisms. PMID:3630856

  20. Comparison of ethanol toxicity to Daphnia magna and Ceriodaphnia dubia tested at two different temperatures: static acute toxicity test results

    SciTech Connect

    Takahashi, I.T.; Cowgill, U.M.; Murphy, P.G.

    1987-08-01

    Ethanol is a commonly used solvent in toxicity testing, yet there are few studies in the literature devoted to its toxicity to zooplankton. The purpose of this study was to compare the response of Daphnia magna Straus 1820 and Ceriodaphnia dubia J. Richard 1894 to ethanol. Two temperatures were selected because most toxicity data involving D. magna has been carried out at 20/sup 0/C while all discussions concerning C. dubia appear to relate to temperatures oscillating around 25/sup 0/C. Thus, the response of these two organisms to ethanol was examined at 20/sup 0/C and at 24/sup 0/C.r

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

    PubMed

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

    2016-01-01

    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. PMID:27537918

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

    PubMed Central

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

    2016-01-01

    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. PMID:27537918

  3. Interactions between diltiazem and ethanol: differences from those seen with dihydropyridine calcium channel antagonists.

    PubMed

    Watson, W P; Little, H J

    1994-03-01

    It has previously been shown that dihydropyridine calcium channel antagonists prevent the ethanol withdrawal syndrome and potentiate the acute effects of ethanol and other central depressant drugs. We now report that, in contrast, the benzothiazepine calcium channel antagonist, diltiazem, gave no protection against the behavioural hyperexcitability seen during ethanol withdrawal, when given either acutely, on withdrawal, or chronically, during the ethanol treatment. A significant increase in convulsive behaviour on handling was seen during the withdrawal period when diltiazem was given on cessation of a mild chronic ethanol treatment schedule. Diltiazem decreased the acute general anaesthetic effects of ethanol, and did not appear to potentiate the ataxic action of ethanol. Centrally administered diltiazem did not enhance the hypothermic action of ethanol, but this effect was significantly increased by diltiazem when the calcium channel antagonist was given peripherally. When given alone by the intraperitoneal route, diltiazem decreased spontaneous locomotor activity and lowered body temperature. When the intracerebral route was used for administration of diltiazem, a significantly decrease in body temperature was seen when this compound was given alone, accompanied by a brief hyperexcitability. The interactions between ethanol and diltiazem therefore appear to differ from those seen with other calcium channel antagonists.

  4. The effect of acute stress and long-term corticosteroid administration on plasma metabolites in an urban and desert songbird.

    PubMed

    Davies, Scott; Rodriguez, Natalie S; Sweazea, Karen L; Deviche, Pierre

    2013-01-01

    In response to stressful stimuli, animals activate the hypothalamic-pituitary-adrenal axis, which can result in transition to the "emergency life history stage." A key adaptive characteristic of this life history stage is the mobilization of energy stores. However, few data are available on the metabolic response to acute stress in wild-caught, free-ranging birds. We quantified the effect of acute capture and restraint stress on plasma glucose, free fatty acid, and uric acid in free-ranging Abert's towhees Melozone aberti. Furthermore, birds were caught from urban and desert localities of Phoenix, Arizona, to investigate potential effects of urban versus desert habitats on the corticosterone (CORT) and metabolic response to acute stress. Complementing work on free-ranging birds, captive towhees received CORT-filled Silastic capsules to investigate the response of urban and desert conspecifics to long-term CORT administration. We quantified the effect of CORT administration on baseline plasma glucose and uric acid, liver and pectoralis muscle glycogen stores, kidney phosphoenolpyruvate carboxykinase (PEPCK-C, a key gluconeogenic enzyme), and body mass. Acute stress increased plasma CORT and glucose and decreased plasma uric acid but had no effect on plasma free fatty acid. There was no difference between urban and desert localities in body mass, fat scores, and the response to acute stress. CORT administration decreased body mass but had no effect on glucose and uric acid, pectoral muscle glycogen, or kidney PEPCK-C. However, liver glycogen of CORT-treated urban birds increased compared with corresponding controls, whereas glycogen decreased in CORT-treated desert birds. This study suggests that Abert's towhees principally mobilize glucose during acute stress but urban and desert towhees do not differ in their CORT and metabolic response to acute stress or long-term CORT administration.

  5. Effects of Nitric oxide synthase blockade on the acute response of the reproductive axis to ethanol in pubertal male rats.

    PubMed

    Emanuele, M A; LaPaglia, N; Steiner, J; Kirsteins, L; Emanuele, N V

    1999-05-01

    The effects of ethanol (EtOH) and nitric oxide (NO) are well known in the adult male rat reproductive axis. In the present study, we investigate the effects of EtOH, NO, and their interaction on key genes and reproductive hormone levels in mid- (45-day) and late pubertal (55-day) male rats. Using three different NO synthase blockers--N'omega-nitro-L-arginine methyl ester (L-NAME), N'omega-nitro-L-arginine (L-NA), and 7-nitroindazole--we show that it is possible to block, in part, some of the disruptive effects of EtOH. L-NAME totally prevented the EtOH-induced fall in serum testosterone in both 45- and 55-day-old rats (p < 0.05 and p < 0.001, respectively). On the other hand, the D-NAME, an inactive isomer of L-NAME, did not protect testosterone from suppression caused by EtOH. Similarly, L-NA and 7-nitroindazole prevented the suppression of testosterone caused by EtOH in 55-day-old animals (p < 0.001 L-NA and p < 0.05 for 7-nitroindazole), but not in the 45-day-old rats. Serum luteinizing hormone (LH) was significantly reduced by EtOH in all the studies in both age groups. L-NAME (but not D-NAME) and L-NA prevented this inhibition in 55-day-old animals (p < 0.001 for L-NAME and p < 0.01 for L-NA). However, only L-NA was able to prevent the effects of EtOH on LH in the 45-day-old rats. 7-Nitroindazole was unable to prevent the decrease in LH in either age group. Despite changes in the other reproductive hormones, there were no consistent changes in hypothalamic concentrations of either LH releasing hormone (LHRH) or its precursor, pro-LHRH. No treatment caused any change in steady-state levels of beta-LH mRNA. There were no consistent changes in pro-LHRH mRNA; but, interestingly, in 45-day-old rats, L-NA given with or without EtOH lead to a significant fall in LHRH gene expression. Our findings indicate that the acute suppressive effects of EtOH on the hypothalamic-pituitary-gonadal axis of the pubertal male rat can be at least partially prevented by NO synthase

  6. Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress.

    PubMed

    Granjeiro, Erica M; Gomes, Felipe V; Guimarães, Francisco S; Corrêa, Fernando M A; Resstel, Leonardo B M

    2011-10-01

    Systemic administration of cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, attenuates the cardiovascular and behavioral responses to restraint stress. Although the brain structures related to CBD effects are not entirely known, they could involve brainstem structures responsible for cardiovascular control. Therefore, to investigate this possibility the present study verified the effects of CBD (15, 30 and 60 nmol) injected into the cisterna magna on the autonomic and behavioral changes induced by acute restraint stress. During exposure to restraint stress (1h) there was a significant increase in mean arterial pressure (MAP) and heart rate (HR). Also, 24h later the animals showed a decreased percentage of entries onto the open arms of the elevated plus-maze. These effects were attenuated by CBD (30 nmol). The drug had no effect on MAP and HR baseline values. These results indicate that intracisternal administration of CBD can attenuate autonomic responses to stress. However, since CBD decreased the anxiogenic consequences of restraint stress, it is possible that the drug is also acting on forebrain structures. PMID:21771609

  7. GABAA receptor regulation of voluntary ethanol drinking requires PKCepsilon.

    PubMed

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

    2006-11-01

    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 epsilon-isoform of PKC (PKCepsilon) self-administer 75% less ethanol and exhibit supersensitivity to acute ethanol and allosteric positive modulators of GABA(A) receptors when compared with wild-type controls. The purpose of the present study was to examine involvement of PKCepsilon in GABA(A) receptor regulation of voluntary ethanol drinking. To address this question, PKCepsilon 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 GABA(A) BZ positive modulator), zolpidem (GABA(A) alpha1 agonist), L-655,708 (BZ-sensitive GABA(A) alpha5 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 PKCepsilon 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 PKCepsilon null mice. Thus, results of the present study show that PKCepsilon null mice do not respond to doses of GABA(A) BZ receptor ligands that regulate ethanol drinking by wild-type control mice. This suggests that PKCepsilon may be required for GABA(A) receptor regulation of chronic ethanol drinking.

  8. Displacement of Cortisol From Human Heart by Acute Administration of a Mineralocorticoid Receptor Antagonist

    PubMed Central

    Iqbal, Javaid; Andrew, Ruth; Cruden, Nicholas L.; Kenyon, Christopher J.; Hughes, Katherine A.; Newby, David E.; Hadoke, Patrick W. F.; Walker, Brian R.

    2015-01-01

    Context Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with heart failure and myocardial infarction, often attributed to blocking aldosterone action in the myocardium. However, binding of aldosterone to MR requires local activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol to cortisone and thereby prevents receptor occupancy by cortisol. In vivo activity of 11β-HSD2 and potential occupancy of MR by cortisol in human heart have not been quantified. Objective This study aimed to measure in vivo activity of 11β-HSD2 and to establish whether cortisol binds MR in human heart. Participants and Interventions Nine patients without heart failure undergoing diagnostic coronary angiography were infused to steady state with the stable isotope tracers 9,11,12,12-[2H]4-cortisol and 1,2-[2H]2-cortisone to quantify cortisol and cortisone production. Samples were obtained from the femoral artery and coronary sinus before and for 40 minutes after bolus iv administration of an MR antagonist, potassium canrenoate. Coronary sinus blood flow was measured by venography and Doppler flow wire. Results There was no detectable production of cortisol or cortisone across the myocardium. After potassium canrenoate administration, plasma aldosterone concentrations increased substantially but aldosterone was not detectably released from the myocardium. In contrast, plasma cortisol concentrations did not change in the systemic circulation but tissue-bound cortisol was released transiently from the myocardium after potassium canrenoate administration. Conclusions Human cardiac 11β-HSD2 activity appears too low to inactivate cortisol to cortisone. Cortisol is displaced acutely from the myocardium by MR antagonists and may contribute to adverse MR activation in human heart. PMID:24423282

  9. Effect of acute lithium administration on penile erection: involvement of nitric oxide system

    PubMed Central

    Sandoughdaran, Saleh; Sadeghipour, Hamed; Sadeghipour, Hamid Reza

    2016-01-01

    Background: Lithium has been the treatment of choice for bipolar disorder (BD) for many years. Although erectile dysfunction is a known adverse effect of this drug, the mechanism of action by which lithium affects erectile function is still unknown. Objective: The aim was to investigate the possible involvement of nitric oxide (NO) in modulatory effect of lithium on penile erection (PE). We further evaluated the possible role of Sildenafil in treatment of lithium-induced erectile dysfunction. Materials and Methods: Erectile function was determined using rat model of apomorphine-induced erections. For evaluating the effect of lithium on penile erection, rats received intraperitoneal injection of graded doses of lithium chloride 30 mins before subcutaneous injection of apomorphine. To determine the possible role of NO pathway, sub-effective dose of N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, was administered 15 min before administration of sub-effective dose of lithium chloride. In other separate experimental groups, sub- effective dose of the nitric oxide precursor, L-arginine, or Sildenafil was injected into the animals 15 min before administration of a potent dose of lithium. 30 min after administration of lithium chloride, animals were assessed in apomorphine test. Serum lithium levels were measured 30 min after administration of effective dose of lithium. Results: Lithium at 50 and 100 mg/kg significantly decreased number of PE (p<0.001), whereas at lower doses (5, 10 and 30 mg/kg) had no effect on apomorphine induced PE. The serum Li+ level of rats receiving 50 mg/kg lithium was 1±0.15 mmol/L which is in therapeutic range of lithium. The inhibitory effect of Lithium was blocked by administration of sub-effective dose of nitric oxide precursor L-arginine (100 mg/kg) (p<0.001) and sildenafil (3.5 mg/kg) (p<0.001) whereas pretreatment with a low and sub-effective dose of L-NAME (10mg/kg) potentiated sub-effective dose of

  10. Social Isolation Blunted the Response of Mesocortical Dopaminergic Neurons to Chronic Ethanol Voluntary Intake

    PubMed Central

    Lallai, Valeria; Manca, Letizia; Dazzi, Laura

    2016-01-01

    Previous studies have shown that stress can increase the response of mesolimbic dopaminergic neurons to acute administration of drugs of abuse included ethanol. In this study, we investigated the possible involvement of the mesocortical dopaminergic pathway in the development of ethanol abuse under stress conditions. To this aim we trained both socially isolated (SI) and group housed (GH) rats to self administer ethanol which was made available only 2 ha day (from 11:00 to 13:00 h). Rats have been trained for 3 weeks starting at postnatal day 35. After training, rats were surgically implanted with microdialysis probes under deep anesthesia, and 24 hlater extracellular dopamine concentrations were monitored in medial prefrontal cortex (mPFC) for the 2 hpreceding ethanol administration (anticipatory phase), during ethanol exposure (consummatory phase) and for 2 hafter ethanol removal. Results show that, in GH animals, dopamine extracellular concentration in the mPFC increased as early as 80 min before ethanol presentation (+50% over basal values) and remained elevated for 80 min during ethanol exposure. In SI rats, on the contrary, dopamine extracellular concentration did not show any significant change at any time point. Ethanol consumption was significantly higher in SI than in GH rats. Moreover, mesocortical dopaminergic neurons in SI animals also showed a decreased sensitivity to an acute administration of ethanol with respect to GH rats. Our results show that prolonged exposure to stress, as in social isolation, is able to induce significant changes in the response of mesocortical dopaminergic neurons to ethanol exposure and suggest that these changes might play an important role in the compulsivity observed in ethanol addiction. PMID:27378852

  11. Social Isolation Blunted the Response of Mesocortical Dopaminergic Neurons to Chronic Ethanol Voluntary Intake.

    PubMed

    Lallai, Valeria; Manca, Letizia; Dazzi, Laura

    2016-01-01

    Previous studies have shown that stress can increase the response of mesolimbic dopaminergic neurons to acute administration of drugs of abuse included ethanol. In this study, we investigated the possible involvement of the mesocortical dopaminergic pathway in the development of ethanol abuse under stress conditions. To this aim we trained both socially isolated (SI) and group housed (GH) rats to self administer ethanol which was made available only 2 ha day (from 11:00 to 13:00 h). Rats have been trained for 3 weeks starting at postnatal day 35. After training, rats were surgically implanted with microdialysis probes under deep anesthesia, and 24 hlater extracellular dopamine concentrations were monitored in medial prefrontal cortex (mPFC) for the 2 hpreceding ethanol administration (anticipatory phase), during ethanol exposure (consummatory phase) and for 2 hafter ethanol removal. Results show that, in GH animals, dopamine extracellular concentration in the mPFC increased as early as 80 min before ethanol presentation (+50% over basal values) and remained elevated for 80 min during ethanol exposure. In SI rats, on the contrary, dopamine extracellular concentration did not show any significant change at any time point. Ethanol consumption was significantly higher in SI than in GH rats. Moreover, mesocortical dopaminergic neurons in SI animals also showed a decreased sensitivity to an acute administration of ethanol with respect to GH rats. Our results show that prolonged exposure to stress, as in social isolation, is able to induce significant changes in the response of mesocortical dopaminergic neurons to ethanol exposure and suggest that these changes might play an important role in the compulsivity observed in ethanol addiction. PMID:27378852

  12. Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol.

    PubMed

    Ortega-Álvaro, Antonio; Ternianov, Alexander; Aracil-Fernández, Auxiliadora; Navarrete, Francisco; García-Gutiérrez, Maria Salud; Manzanares, Jorge

    2015-01-01

    This study examines the role of the cannabinoid CB2 receptor (CB2 r) on the vulnerability to ethanol consumption. The time-related and dose-response effects of ethanol on rectal temperature, handling-induced convulsions (HIC) and blood ethanol concentrations were evaluated in CB2 KO and wild-type (WT) mice. The reinforcing properties of ethanol were evaluated in conditioned place preference (CPP), preference and voluntary ethanol consumption and oral ethanol self-administration. Water-maintained behavior schedule was performed to evaluate the degree of motivation induced by a natural stimulus. Preference for non-alcohol tastants assay was performed to evaluate the differences in taste sensitivity. Tyrosine hydroxylase (TH) and μ-opioid receptor gene expressions were also measured in the ventral tegmental area and nucleus accumbens (NAcc), respectively. CB2 KO mice presented increased HIC score, ethanol-CPP, voluntary ethanol consumption and preference, acquisition of ethanol self-administration, and increased motivation to drink ethanol compared with WT mice. No differences were found between genotypes in the water-maintained behavior schedule or preference for non-alcohol tastants. Naïve CB2 KO mice presented increased μ-opioid receptor gene expression in NAcc. Acute ethanol administration (1-2 g/kg) increased TH and μ-opioid receptor gene expressions in CB2 KO mice, whereas the lower dose of ethanol decreased TH gene expression in WT mice. These results suggest that deletion of the CB2 r gene increased preference for and vulnerability to ethanol consumption, at least in part, by increased ethanol-induced sensitivity of the TH and μ-opioid receptor gene expressions in mesolimbic neurons. Future studies will determine the role of CB2 r as a target for the treatment of problems related with alcohol consumption.

  13. Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats.

    PubMed

    Gonçalves, Cinara L; Rezin, Gislaine T; Ferreira, Gabriela K; Jeremias, Isabela C; Cardoso, Mariane R; Valvassori, Samira S; Munhoz, Bruna J P; Borges, Gabriela D; Bristot, Bruno N; Leffa, Daniela D; Andrade, Vanessa M; Quevedo, João; Streck, Emilio L

    2013-08-01

    Obesity is a chronic and multifactorial disease, whose prevalence is increasing in many countries. Pharmaceutical strategies for the treatment of obesity include drugs that regulate food intake, thermogenesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine, which is associated with neurotoxicity. In this context, the present study evaluated DNA damage parameters in the peripheral blood of young and adult rats submitted to an acute administration and chronic administration of fenproporex. In the acute administration, both young and adult rats received a single injection of fenproporex (6.25, 12.5 or 25 mg/kg i.p.) or vehicle. In the chronic administration, both young and adult rats received one daily injection of fenproporex (6.25, 12.5, or 25 mg/kg i.p.) or Tween for 14 days. 2 h after the last injection, the rats were killed by decapitation and their peripheral blood removed for evaluation of DNA damage parameters by alkaline comet assay. Our study showed that acute administration of fenproporex in young and adult rats presented higher levels of damage index and frequency in the DNA. However, chronic administration of fenproporex in young and adult rats did not alter the levels of DNA damage in both parameters of comet assay. The present findings showed that acute administration of fenproporex promoted damage in DNA, in both young and adult rats. Our results are consistent with other reports which showed that other amphetamine-derived drugs also caused DNA damage. We suggest that the activation of an efficient DNA repair mechanism may occur after chronic exposition to fenproporex. Our results are consistent with other reports that showed some amphetamine-derived drugs also caused DNA damage. PMID:23636618

  14. Impact of acute guanfacine administration on stress and cue reactivity in cocaine-dependent individuals

    PubMed Central

    Moran-Santa Maria, Megan M.; Baker, Nathaniel L.; Ramakrishnan, Viswanathan; Brady, Kathleen T.; McRae-Clark, Aimee

    2014-01-01

    Background Stress and drug-paired cues increase drug craving and noradrenergic activity in cocaine-dependent individuals, thus medications that attenuate noradrenergic activity may be effective therapeutic treatment options for cocaine-dependent individuals. Objectives To examine the impact of acute administration of the α-2 adrenergic receptor agonist guanfacine on responses to multiple risk factors for relapse in cocaine-dependent individuals. Methods In a double-blind, placebo-controlled study, cocaine-dependent individuals (N=84), were randomized to receive either 2 mg guanfacine (n=50) or placebo (n=34). Within each treatment arm, subjects were randomized to either a stress (guanfacine n=26; placebo n=15) or a no-stress (guanfacine n=24; placebo n=19) group. Participants in the stress group performed the Trier Social Stress Test. Subjects in each group were exposed to a neutral cue and then to cocaine-related cues. Plasma cortisol and subjective responses were compared between the four groups. Results The no-stress guanfacine group reported greater craving in response to cocaine-cues as compared to the neutral cue (p<0.001). The guanfacine stress group reported greater subjective stress at the neutral cue than at baseline (p=0.032). The cocaine-cue increased subjective stress in the guanfacine (p<0.001) no-stress group. There were no effects of guanfacine on cortisol levels in either the stress or no stress groups (all p>0.70). Conclusion This study found no effects of a single 2 mg dose of guanfacine on reactivity to stress and cues alone or on the interaction of stress and drug cues. In cocaine-dependent individuals an acute 2 mg dose of guanfacine may not be an effective therapeutic treatment strategy. PMID:25140866

  15. Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial

    PubMed Central

    Hill, Michael D.; Martin, Renee H.; Palesch, Yuko Y.; Moy, Claudia S.; Tamariz, Diego; Ryckborst, Karla J.; Jones, Elizabeth B.; Weisman, David; Pettigrew, Creed; Ginsberg, Myron D.

    2015-01-01

    Background Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial. Methods Ischemic stroke patients, aged 18–83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism. Results Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI95 1.01–5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI95 4.3–26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%). Conclusions ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke. Trial Registration ClincalTrials.gov NCT00235495 PMID:26325387

  16. Effects of Gelam and Acacia honey acute administration on some biochemical parameters of Sprague Dawley rats

    PubMed Central

    2014-01-01

    Background Since ancient times, honey has been used for medicinal purposes in many cultures; it is one of the oldest and most enduring substances used in wound management. Scientific evidence for its efficacy is widely studied, but systemic safety studies are still lacking. It is essential to study the impact of consumption of honey on the health and proper development of the consumer. Therefore, the present study was designed to observe the effects of acute administration (14 days) of Gelam honey (GH), a wild harvesting honey and Acacia honey (AH), a beekeeping honey, on male and female Sprague Dawley (SD) rats. Methods An acute oral study was performed following OECD test guideline 423, with minor modifications. In the study, GH, AH and sucrose (S) were administered at 2000 mg/kg body weight. Animals were observed for the next 14 days. Gross pathology was performed at the end of the study. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Clinical biochemistry, gross pathology, relative organ weight and histopathological examination were performed. Results Rats fed with honey did not exhibit any abnormal signs or deaths. Results showed a decrease in weight gain and energy efficiency, but significantly increased in total food intake and total calories in female rats fed with GH, compared to control (p < 0.05). Nevertheless, a significant increase in body weight was observed in male rats in all honey-treated groups. Male rats fed with AH significantly decreased in total food intake, total calories and energy efficiency. Both male and female rats fed with GH displayed a significant decrease in triglycerides compared to control group. Hepatic and renal function levels were within acceptable range. The gross necropsy analysis did not reveal changes in any of the organs examined. Conclusions Our results suggest that acute consumption of GH and AH at 2000 mg/kg body weight of male and female SD rats has some discrepancy

  17. Acute toxicity and gastroprotective role of M. pruriens in ethanol-induced gastric mucosal injuries in rats.

    PubMed

    Golbabapour, Shahram; Hajrezaie, Maryam; 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.

  18. 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

  19. Up-regulation of gamma-aminobutyric acid transporter I mediates ethanol sensitivity in mice.

    PubMed

    Hu, J-H; Ma, Y-H; Yang, N; Mei, Z-T; Zhang, M-H; Fei, J; Guo, L-H

    2004-01-01

    Ethanol is among the most widely abused drugs in the world. Chronic ethanol consumption leads to ethanol tolerance and addiction, and impairs learning and memory. Na+/Cl- dependent GABA transporters play an important role in controlling the concentration of GABA in the synaptic cleft, and thus they control the intensity and duration of synaptic transmission of GABA. It has been suggested that GABAergic system is involved in ethanol consumption, tolerance and addiction, because chronic ethanol consumption alters the expression of GABAA receptors and drugs on GABA receptors affect ethanol actions. The results of the present study reveal that that activity of GABA transporters in mouse brain after 15-min acute ethanol injection or after chronic ethanol consumption is increased. Moreover, mice pre-injected with a competitive or a noncompetitive antagonist of gamma-aminobutyric acid transporter subtype 1 (GAT1) showed high sensitivity to the sedative/hypnotic effects of ethanol. In contrast, transgenic mice overexpressing GAT1 displayed low sensitivity to ethanol, as shown by the righting reflex test. Mice overexpressing GAT1 survived a lethal dose of ethanol (9 g/kg, i.p.) longer, maintained locomotor activity longer after a sub-lethal dose (1.75 g/kg, i.p.) and exhibited a higher median lethal dose than wild-type littermates. These results suggest that GAT1 plays an important role in sensitivity to ethanol, and might be a therapeutic target for alcoholism prevention and treatment. Acute and chronic ethanol administration resulted in the increase of GABA transporter function. Use of GAT1 selective inhibitors and GAT1 overexpressing mice thus demonstrate that GAT1 should be an important protein mediating sensitivity to ethanol in mice.

  20. Acute supra-therapeutic oral terbutaline administration has no ergogenic effect in non-asthmatic athletes.

    PubMed

    Sanchez, Anthony M J; Borrani, Fabio; Le Fur, Marie Amélie; Le Mieux, Anais; Lecoultre, Virgile; Py, Guillaume; Gernigon, Christophe; Collomp, Katia; Candau, Robin

    2013-02-01

    This study aimed to investigate the effects on a possible improvement in aerobic and anaerobic performance of oral terbutaline (TER) at a supra-therapeutic dose in 7 healthy competitive male athletes. On day 1, ventilatory threshold, maximum oxygen uptake [Formula: see text] and corresponding power output were measured and used to determine the exercise load on days 2 and 3. On days 2 and 3, 8 mg of TER or placebo were orally administered in a double-blind process to athletes who rested for 3 h, and then performed a battery of tests including a force-velocity exercise test, running sprint and a maximal endurance cycling test at Δ50 % (50 % between VT and [Formula: see text]). Lactatemia, anaerobic parameters and endurance performance ([Formula: see text] and time until exhaustion) were raised during the corresponding tests. We found that TER administration did not improve any of the parameters of aerobic performance (p > 0.05). In addition, no change in [Formula: see text] kinetic parameters was found with TER compared to placebo (p > 0.05). Moreover, no enhancement of the force-velocity relationship was observed during sprint exercises after TER intake (p > 0.05) and, on the contrary, maximal strength decreased significantly after TER intake (p < 0.05) but maximal power remained unchanged (p > 0.05). In conclusion, oral acute administration of TER at a supra-therapeutic dose seems to be without any relevant ergogenic effect on anaerobic and aerobic performances in healthy athletes. However, all participants experienced adverse side effects such as tremors. PMID:22767151

  1. Effects of Acute Cortisol Administration on Perceptual Priming of Trauma-Related Material

    PubMed Central

    Streb, Markus; Pfaltz, Monique; Michael, Tanja

    2014-01-01

    Intrusive memories are a hallmark symptom of posttraumatic stress disorder (PTSD). They reflect excessive and uncontrolled retrieval of the traumatic memory. Acute elevations of cortisol are known to impair the retrieval of already stored memory information. Thus, continuous cortisol administration might help in reducing intrusive memories in PTSD. Strong perceptual priming for neutral stimuli associated with a “traumatic” context has been shown to be one important learning mechanism that leads to intrusive memories. However, the memory modulating effects of cortisol have only been shown for explicit declarative memory processes. Thus, in our double blind, placebo controlled study we aimed to investigate whether cortisol influences perceptual priming of neutral stimuli that appeared in a “traumatic” context. Two groups of healthy volunteers (N = 160) watched either neutral or “traumatic” picture stories on a computer screen. Neutral objects were presented in between the pictures. Memory for these neutral objects was tested after 24 hours with a perceptual priming task and an explicit memory task. Prior to memory testing half of the participants in each group received 25 mg of cortisol, the other half received placebo. In the placebo group participants in the “traumatic” stories condition showed more perceptual priming for the neutral objects than participants in the neutral stories condition, indicating a strong perceptual priming effect for neutral stimuli presented in a “traumatic” context. In the cortisol group this effect was not present: Participants in the neutral stories and participants in the “traumatic” stories condition in the cortisol group showed comparable priming effects for the neutral objects. Our findings show that cortisol inhibits perceptual priming for neutral stimuli that appeared in a “traumatic” context. These findings indicate that cortisol influences PTSD-relevant memory processes and thus further support

  2. Ethanol-induced impairment of hepatic glycoprotein secretion in the isolated rat liver perfusion model

    SciTech Connect

    Volentine, G.D.; Ogden, K.A.; Tuma, D.J.; Sorrell, M.F.

    1987-05-01

    The authors have previously shown that acute administration of ethanol inhibits hepatic glycoprotein secretion in vivo. This ethanol-induced effect appears to be mediated by its reactive metabolite, acetaldehyde. Since hormonal influences and vascular changes can not be controlled in vivo during ethanol administration, they investigated the effect of ethanol in the isolated perfused liver model. Rat liver from fed animals was perfused with oxygenated KRB at 3 ml/min/g liver for 4 hrs. Since ethanol inhibits proteins synthesis in vitro, protein acceptor pool size was equalized in both ethanol and control perfused livers with 1 mM cycloheximide. /sup 3/H-glucosamine was used to label hepatic secretory glycoproteins in the perfusate. Colchicine, a known inhibitor of protein secretion, impaired the secretion of labeled glycoproteins with a concomitant retention of these export proteins in the liver; therefore, confirming the authors secretory model. Ethanol (50 mM) inhibited the appearance of glucosamine-labeled glycoproteins by 60% into the perfusate as compared to control livers. Pretreatment of animals with cyanamide (an aldehyde dehydrogenase inhibitor) further potentiated this effect of ethanol in the isolated perfused liver. These data suggest that ethanol inhibits hepatic glycoprotein secretion in the isolated liver perfusion model, and this ethanol-induced impairment appears to be mediated by acetaldehyde.

  3. Acute but not chronic administration of pioglitazone promoted behavioral and neurochemical protective effects in the MPTP model of Parkinson's disease.

    PubMed

    Barbiero, Janaína K; Santiago, Ronise M; Lima, Marcelo M S; Ariza, Deborah; Morais, Lívia H; Andreatini, Roberto; Vital, Maria A B F

    2011-01-01

    The present study investigated the neurochemical, motor and cognitive effects of pioglitazone in a rat model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the first experiment, we administered MPTP, and 1h later administered a single oral dose of pioglitazone (5, 15 and 30 mg/kg). The following day, we performed the open-field test and neurochemical dose response curve. We demonstrated that 30 mg/kg of pioglitazone was capable of restoring striatal dopamine (DA) concentrations and motor behaviors. A second experiment was conducted to test the effects of two protocols (acute and chronic) of pioglitazone (30 mg/kg) administration in the open-field test, two-way active avoidance task and in the DA and metabolites levels. The acute protocol consisted of a single oral administration 1 h after MPTP, whereas the chronic protocol was performed with daily administrations starting 1 h after MPTP and ending 22 days after that. Results showed that neither protocol was able to reverse the cognitive impairment promoted by MPTP. We also demonstrated that acute treatment generated some level of neuroprotection, as confirmed by the absence of DA reduction in the group treated with pioglitazone in comparison to the sham group. By contrast, chronic treatment leaded to a reduction of striatal DA, close to MPTP administration alone. These findings suggest that acute administration of pioglitazone (30 mg/kg) was more efficient in generating beneficial effects on motor behaviors and in striatal DA levels. Nevertheless, we failed to demonstrate that pioglitazone administration improved performance on a dopamine-related cognitive task after MPTP.

  4. Vitamin E administration at the onset of fever prevents renal scarring in acute pyelonephritis.

    PubMed

    Sadeghi, Zhina; Kajbafzadeh, Abdol-Mohammad; Tajik, Parvin; Monajemzadeh, Maryam; Payabvash, Seyedmehdi; Elmi, Azadeh

    2008-09-01

    We evaluated the protective effects of antioxidant at the onset of fever on renal damage in a rat model of acute pyelonephritis. Twenty rats were allocated to four groups. In groups 1 to 3, the animals were given direct inoculation of Escherichia coli into the right kidney, and group four served as control. All rats in groups 1 to 3 were given once-daily intraperitoneal injections of ceftriaxon for five consecutive days, beginning on the third day after inoculation. The animals' body temperatures were monitored; as soon as body temperature reaches 38 degrees C, the rats in group 2 were given allopurinol co-treatment, whereas, in group 3, vitamin E co-treatment was started at fever onset. Both kidneys were excised 6 weeks later, for the evaluation of histopathologic changes, apoptotic damage, and concentrations of transforming growth factor-beta (TGF-beta). Only minimal changes were found in control samples. Pathologic scores of inflammation and fibrosis in group 1 were higher than in the vitamin E and allopurinol groups (P < 0.05). Apoptosis index was also decreased in groups 2 and 3, compared to group 1 (P < 0.05). There was no significant difference in average TGF-beta levels between study groups. These findings suggest that administration of vitamin E or allopurinol following the onset of fever can reduce renal damage in pyelonephritis. PMID:18523811

  5. Acute toxicity, histopathology, and coagulopathy in American kestrels (Falco sparverius) following administration of the rodenticie diphacinone

    USGS Publications Warehouse

    Rattner, Barnett A.; Horak, Katherine E.; Warner, Sarah E.; Day, Daniel D.; Meteyer, Carol U.; Voler, Steven F.; Eisemann, John D.; Johnston, John J.

    2011-01-01

    The acute oral toxicity of the anticoagulant rodenticide diphacinone was found to be over 20 times greater in American kestrels (Falco sparverius; median lethal dose 96.8 mg/kg body weight) compared with Northern bobwhite (Colinus virginianus) and mallards (Anas platyrhynchos). Modest evidence of internal bleeding was observed at necropsy, although histological examination of heart, liver, kidney, lung, intestine, and skeletal muscle revealed hemorrhage over a wide range of doses (35.1-675 mg/kg). Residue analysis suggests that the half-life of diphacinone in the liver of kestrels that survived was relatively short, with the majority of the dose cleared within 7 d of exposure. Several precise and sensitive clotting assays (prothrombin time, Russell's viper venom time, thrombin clotting time) were adapted for use in this species, and oral administration of diphacinone at 50 mg/kg increased prothrombin time and Russell?s viper venom time at 48 and 96 h postdose compared with controls. Prolongation of in vitro clotting time reflects impaired coagulation complex activity, and generally corresponded with the onset of overt signs of toxicity and lethality. In view of the toxicity and risk evaluation data derived from American kestrels, the involvement of diphacinone in some raptor mortality events, and the paucity of threshold effects data following short-term dietary exposure for birds of prey, additional feeding trials with captive raptors are warranted to characterize more fully the risk of secondary poisoning.

  6. Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis.

    PubMed

    Vieira, Erica L M; Leonel, Alda J; Sad, Alexandre P; Beltrão, Nathália R M; Costa, Thaís F; Ferreira, Talita M R; Gomes-Santos, Ana C; Faria, Ana M C; Peluzio, Maria C G; Cara, Denise C; Alvarez-Leite, Jacqueline I

    2012-05-01

    Butyrate is a four-carbon short-chain fatty acid that improves colonic trophism. Although several studies have shown the benefits of butyrate enemas in ulcerative colitis (UC), studies using the oral route are rare in the literature. In the present study, we evaluated the effect of butyrate intake in the immune response associated to UC. For that, mice were fed control or butyrate (0.5% sodium butyrate) diets for 14 days. Acute UC was induced by dextran sulphate sodium (DSS, 2.5%), replacing drinking water. The results showed that, in UC animals, oral butyrate significantly improved trophism and reduced leukocyte (eosinophil and neutrophil) infiltration in the colon mucosa and improved the inflammatory profile (activated macrophage, B and T lymphocytes) in cecal lymph nodes. In the small intestine, although mucosa histology was similar among groups, DSS treatment reduced duodenal transforming growth factor-β, increased interleukin-10 concentrations and increased memory T lymphocytes and dendritic cells in Peyer's patches. Butyrate supplementation was able to revert these alterations. When cecal butyrate concentration was analyzed in cecal content, it was still higher in the healthy animals receiving butyrate than in the UC+butyrate and control groups. In conclusion, our results show that oral administration of sodium butyrate improves mucosa lesion and attenuates the inflammatory profile of intestinal mucosa, local draining lymph nodes and Peyer's patches of DSS-induced UC. Our results also highlight the potential use of butyrate supplements as adjuvant in UC treatment.

  7. Medicinal Mushroom Cracked-Cap Polypore, Phellinus rimosus (Higher Basidiomycetes) Attenuates Acute Ethanol-Induced Lipid Peroxidation in Mice.

    PubMed

    Ajith, Thekkuttuparambil A; Janardhanan, Kainoor K

    2015-01-01

    Alcohol abuse and alcoholism remain one of the major health issues worldwide, especially in developing countries. The protective effect of Phellinus rimosus against acute alcohol-induced lipid peroxidation in the liver, kidney, and brain as well as its effect against antioxidant enzyme activity such as superoxide (SOD) and catalase (CAT) in the liver was evaluated in mice. Ethyl acetate extract of Ph. Rimosus (50 mg/kg body wt, p.o.) 1 h before each administration of alcohol (3 mL/kg, p.o.; total 2 doses at 24-h intervals) protected against lipid peroxidation in all organs and attenuated the decline of SOD and CAT activity in the liver. The fold increase in lipid peroxidation, including conjugated diene and thiobarbituric acid reactive substance (TBARS) levels, was highest in the liver. There were 2.6- and 1.5- fold increases in TBARS levels in the liver of the alcohol alone- and alcohol+Ph. Rimosus-treated groups, compared with that of the normal group. Activity of SOD and CAT in the liver of alcohol- and alcohol+Ph. Rimosus- treated animals was 9.05±1.38, 18.76±1.71, and 11.26±1.02, 31.58±3.35 IU/mg protein, respectively. Extract at 1 mg/mL inhibited 50.6% activity of aniline hydroxylase (CYP2E1) in liver homogenate. From these results, we concluded that the extract significantly protected against the lipid peroxidation. Protection in the liver may be due to the inhibitory effect on CYP2E1 as well as the direct radical scavenging effect of Ph. Rimosus, which warrants further research.

  8. Reversed Scototaxis during Withdrawal after Daily-Moderate, but Not Weekly-Binge, Administration of Ethanol in Zebrafish

    PubMed Central

    Holcombe, Adam; Howorko, Adam; Powell, Russell A.; Schalomon, Melike; Hamilton, Trevor J.

    2013-01-01

    Alcohol abuse can lead to severe psychological and physiological damage. Little is known, however, about the relative impact of a small, daily dose of alcohol (daily-moderate schedule) versus a large, once per week dose (weekly-binge schedule). In this study, we examined the effect of each of these schedules on behavioural measures of anxiety in zebrafish (Danio rerio). Adult wild-type zebrafish were administered either 0.2% ethanol on a daily-moderate schedule or 1.4% ethanol on a weekly-binge schedule for a period of 21 days, and then tested for scototaxis (preference for darkness) during withdrawal. Compared to a control group with no alcohol exposure, the daily-moderate group spent significantly more time on the light side of the arena (indicative of decreased anxiety) on day two of withdrawal, but not day 9 of withdrawal. The weekly-binge group was not significantly different from the control group on either day of withdrawal and showed no preference for either the light or dark zones. Our results indicate that even a small dose of alcohol on a daily basis can cause significant, though reversible, changes in behaviour. PMID:23675478

  9. Oral administration of lactulose: a novel therapy for acute carbon monoxide poisoning via increasing intestinal hydrogen production.

    PubMed

    Fan, Dan-Feng; Hu, Hui-Jun; Sun, Xue-Jun; Meng, Xiang-En; Zhang, Yu; Pan, Shu-Yi

    2016-01-01

    It has been known that the pathophysiology of carbon monoxide (CO) poisoning is related to hypoxia, the increased production of reactive oxygen species (ROS) and oxidative stress. Studies have shown that the novel, safe and effective free radical scavenger, hydrogen, has neuroprotective effects in both acute CO poisoning and delayed neuropsychological sequelae in CO poisoning. Orally administered lactulose, which may be used by some intestinal bacteria as a food source to produce endogenous hydrogen, can ameliorate oxidative stress. Based on the available findings, we hypothesize that oral administration of lactulose may be a novel therapy for acute CO poisoning via increasing intestinal hydrogen production.

  10. Effect of acute administration of L-tyrosine on oxidative stress parameters in brain of young rats.

    PubMed

    Macêdo, Livia G R P; Carvalho-Silva, Milena; Ferreira, Gabriela K; Vieira, Júlia S; Olegário, Natália; Gonçalves, Renata C; Vuolo, Francieli S; Ferreira, Gustavo C; Schuck, Patrícia F; Dal-Pizzol, Felipe; Streck, Emilio L

    2013-12-01

    Tyrosinemia type II, also known as Richner-Hanhart syndrome, is an autosomal recessive inborn error of metabolism caused by a deficiency of hepatic cytosolic tyrosine aminotransferase, and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that studies demonstrated that high concentrations of tyrosine provoke oxidative stress in vitro and in vivo in the cerebral cortex of rats, in the present study we investigate the oxidative stress parameters (enzymatic antioxidant defenses, thiobarbituric acid-reactive substances and protein carbonyl content) in cerebellum, hippocampus and striatum of 30-old-day rats after acute administration of L-tyrosine. Our results demonstrated that the acute administration of L-tyrosine increased the thiobarbituric acid reactive species levels in hippocampus and the carbonyl levels in cerebellum, hippocampus and striatum. In addition, acute administration of L-tyrosine significantly decreased superoxide dismutase activity in cerebellum, hippocampus and striatum, while catalase was increased in striatum. In conclusion, the oxidative stress may contribute, along with other mechanisms, to the neurological dysfunction characteristic of hypertyrosinemia and the administration of antioxidants may be considered as a potential adjuvant therapy for tyrosinemia, especially type II. PMID:24135880

  11. Effect of acute administration of L-tyrosine on oxidative stress parameters in brain of young rats.

    PubMed

    Macêdo, Livia G R P; Carvalho-Silva, Milena; Ferreira, Gabriela K; Vieira, Júlia S; Olegário, Natália; Gonçalves, Renata C; Vuolo, Francieli S; Ferreira, Gustavo C; Schuck, Patrícia F; Dal-Pizzol, Felipe; Streck, Emilio L

    2013-12-01

    Tyrosinemia type II, also known as Richner-Hanhart syndrome, is an autosomal recessive inborn error of metabolism caused by a deficiency of hepatic cytosolic tyrosine aminotransferase, and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that studies demonstrated that high concentrations of tyrosine provoke oxidative stress in vitro and in vivo in the cerebral cortex of rats, in the present study we investigate the oxidative stress parameters (enzymatic antioxidant defenses, thiobarbituric acid-reactive substances and protein carbonyl content) in cerebellum, hippocampus and striatum of 30-old-day rats after acute administration of L-tyrosine. Our results demonstrated that the acute administration of L-tyrosine increased the thiobarbituric acid reactive species levels in hippocampus and the carbonyl levels in cerebellum, hippocampus and striatum. In addition, acute administration of L-tyrosine significantly decreased superoxide dismutase activity in cerebellum, hippocampus and striatum, while catalase was increased in striatum. In conclusion, the oxidative stress may contribute, along with other mechanisms, to the neurological dysfunction characteristic of hypertyrosinemia and the administration of antioxidants may be considered as a potential adjuvant therapy for tyrosinemia, especially type II.

  12. Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults

    PubMed Central

    Derry, Christopher J; Derry, Sheena; Moore, R Andrew

    2014-01-01

    Background Migraine is a highly disabling condition for the individual and also has wide-reaching implications for society, healthcare services, and the economy. Sumatriptan is an abortive medication for migraine attacks, belonging to the triptan family. Subcutaneous administration may be preferable to oral for individuals experiencing nausea and/or vomiting Objectives To determine the efficacy and tolerability of subcutaneous sumatriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults. Search methods We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, online databases, and reference lists for studies through 13 October 2011. Selection criteria We included randomised, double-blind, placebo- and/or active-controlled studies using subcutaneous sumatriptan to treat a migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or ‘risk ratio’) and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. Main results Thirty-five studies (9365 participants) compared subcutaneous sumatriptan with placebo or an active comparator. Most of the data were for the 6 mg dose. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 6 mg versus placebo the NNTs were 2.9, 2.3, 2.2, and 2.1 for pain-free at one and two hours, and headache relief at one and two hours, respectively, and 6.1 for sustained pain-free at 24 hours. Results for the 4 mg and 8 mg doses were similar to the 6 mg dose, with 6 mg significantly better than 4 mg only for pain-free at one hour, and 8 mg significantly better than 6 mg only for headache relief at one hour. There was no evidence of increased migraine relief if a second dose of sumatriptan 6

  13. Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood.

    PubMed

    Gass, Justin T; Glen, William Bailey; McGonigal, Justin T; Trantham-Davidson, Heather; Lopez, Marcelo F; Randall, Patrick K; Yaxley, Richard; Floresco, Stan B; Chandler, L Judson

    2014-10-01

    The prefrontal cortex (PFC) is a brain region that is critically involved in cognitive function and inhibitory control of behavior, and adolescence represents an important period of continued PFC development that parallels the maturation of these functions. Evidence suggests that this period of continued development of the PFC may render it especially vulnerable to environmental insults that impact PFC function in adulthood. Experimentation with alcohol typically begins during adolescence when binge-like consumption of large quantities is common. In the present study, we investigated the effects of repeated cycles of adolescent intermittent ethanol (AIE) exposure (postnatal days 28-42) by vapor inhalation on different aspects of executive functioning in the adult rat. In an operant set-shifting task, AIE-exposed rats exhibited deficits in their ability to shift their response strategy when the rules of the task changed, indicating reduced behavioral flexibility. There were no differences in progressive ratio response for the reinforcer suggesting that AIE did not alter reinforcer motivation. Examination of performance on the elevated plus maze under conditions designed to minimize stress revealed that AIE exposure enhanced the number of entries into the open arms, which may reflect either reduced anxiety and/or disinhibition of exploratory-like behavior. In rats that trained to self-administer ethanol in an operant paradigm, AIE increased resistance to extinction of ethanol-seeking behavior. This resistance to extinction was reversed by positive allosteric modulation of mGluR5 during extinction training, an effect that is thought to reflect promotion of extinction learning mechanisms within the medial PFC. Consistent with this, CDPPB was also observed to reverse the deficits in behavioral flexibility. Finally, diffusion tensor imaging with multivariate analysis of 32 brain areas revealed that while there were no differences in the total brain volume, the volume of

  14. 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

  15. Acute cadmium administration to rats exerts both immunosuppressive and proinflammatory effects in spleen.

    PubMed

    Demenesku, Jelena; Mirkov, Ivana; Ninkov, Marina; Popov Aleksandrov, Aleksandra; Zolotarevski, Lidija; Kataranovski, Dragan; Kataranovski, Milena

    2014-12-01

    Conflicting data (both suppression and augmentation as well as lack of the effect) exist in respect to cadmium (Cd) and splenic T cell-based immune cell activity. Spleen is also the site of innate immune responses but impact of Cd on this type of immunity has been less explored. In the present study the effects of acute Cd administration on basic aspects of both T cell-based and innate immune spleen cell activity were examined in rats. Intraperitoneal injection of 1mg of Cd/kg resulted in decrease in concanavalin A (ConA) induced proliferation which seems to be more related to altered spleen cells responsiveness to IL-2 than to apoptosis. Differential effects on proinflammatory T cell derived cytokines were observed (decreases of IFN-γ gene expression and ConA-stimulated production, but increases in IL-17 mRNA levels with no effect on concentrations of protein product). Reduction of IFN-γ production seemed not to rely on IL-4 and IL-10, but at least partly on nitric oxide (NO). Increased activity relevant for innate immunity (granulocyte and CD11b(+) cell accumulation in the spleen, inducible nitric oxide synthase/iNOS expression and NO production by spleen cells) was observed, but there was a decrease in respiratory burst (dihydrorhodamine/DHR oxidation and nitroblue tetrazolium/NBT reduction). Increases of TNF-α and IL-1β gene expression and IL-1β protein product were noted as well. Administration of 0.5mg Cd/kg resulted in less pronounced (ConA-induced proliferation) or lack of the effect (IFN-γ production) on spleen T cell activities and on innate activities (granulocyte accumulation, NO production) as well. However, increases of spleen cell respiratory burst activity and IL-1β production were observed. Effects of lower cadmium doses (5ppm and 50ppm) on several aspects of spleen cell immune activity were observed in intermediate period of exposure (30 days, oral intake) as well. Differential effects of Cd on immune activities of spleen cells might

  16. Ethanol reduces evoked dopamine release and slows clearance in the rat medial prefrontal cortex

    PubMed Central

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

    2014-01-01

    Background Ethanol intoxication affects cognitive performance, contributing to attentional deficits and poor decision making, which may occur via actions in the medial prefrontal cortex (mPFC). mPFC function is modulated by the catecholamines dopamine and norepinephrine. In this study, we examine the acute effects of ethanol on electrically-evoked dopamine release and clearance in the mPFC of anaesthetized rats naïve to alcohol or chronically exposed to alcohol during adolescence. Methods Dopamine release and clearance was evoked by electrical stimulation of the VTA and measured in the mPFC of anaesthetized rats with fast-scan cyclic voltammetry. In Experiments 1 and 2, effects of a high dose of ethanol (4g/kg, i.p.) on dopamine neurotransmission in the mPFC of ethanol-naïve rats and rats given ethanol exposure during adolescence were investigated. Effects of cumulative dosing of ethanol (0.5–4g/kg) on the dopamine release and clearance were investigated in Experiment 3. Experiment 4 studied effects of ethanol locally applied to the ventral tegmental area (VTA) on the dopamine neurotransmission in the mPFC of ethanol-naïve rats. Results A high dose of ethanol decreased evoked dopamine release within 10 min of administration in ethanol-naïve rats. When tested via cumulative dosing from 0.5–4g/kg, both 2 and 4g/kg ethanol inhibited evoked dopamine release in the mPFC of ethanol-naïve rats, while 4g/kg ethanol also slowed dopamine clearance. A similar effect on electrically-evoked dopamine release in the mPFC was observed after infusion of ethanol into the VTA. Interestingly, intermittent ethanol exposure during adolescence had no effect on observed changes in mPFC dopamine release and clearance induced by acute ethanol administration. Conclusions Taken together, these data describe ethanol-induced reductions in the dynamics of VTA-evoked mPFC dopamine release and clearance, with the VTA contributing to the attenuation of evoked mPFC dopamine release induced

  17. Acute third ventricular administration of leptin decreases protein and fat in self-selecting rats.

    PubMed

    Wetzler, Sandrine; Jean-Joseph, Gwladys; Even, Patrick; Tomé, Daniel; Larue-Achagiotis, Christiane

    2005-04-15

    The peripheral administration of leptin reduces food intake (FI) body weight gain (BWG) and modifies food choice. The aim of this study was to examine the effect of acute cerebral injections of leptin on food selection in rats. Male rats were first adapted to the food choice paradigm (protein, carbohydrate, fat) for 3 weeks. They were then implanted with a cannula in the third ventricle. Leptin (leptin group=L) or saline (control group=C) injections were performed at either the beginning or the end of the night at 4-day intervals. FI was recorded continuously, 3 days before, during and then after injections. Rats were sacrificed 86 h after the second injection. After both injections, BWG and FI were reduced. The reduction in FI concerned only nocturnal intake, whatever the timing of the injection. When the injection was given at the beginning of the night, the reductions after a 1-h latency period were -45% and -27.5% during the first and second days, respectively. Following the second injection, the same effects were observed immediately (-16% and -41%, respectively). Only the fat and protein intakes were significantly reduced. This lower FI was due to a reduction in meal size and duration. The reduction resulted in a lower BWG and total white adipose tissue mass. At the time of sacrifice, 6 h after food deprivation, leptinemia and insulinemia were reduced in leptin-treated rats. Glycemia values were identical. It was thus demonstrated that central leptin was a satiation factor rather than a satiety factor.

  18. Acute Administration of Methionine Affects Performance of Swiss Mice in Learning and Memory Paradigms.

    PubMed

    Abi, I; Magaji, R A; Magaji, M G

    2015-12-20

    Methionine, an essential amino acid, plays an essential role in the central nervous system CNS development. It serves as a crucial intermediate in the methylation, trans-sulfuration and amino- phosphorylationpathways,necessary for the synthesis of nucleic acids, phospholipids, hormones, neurotransmitters, antioxidants, polyamines, catecholamines and other biogenic amines. The effect of methionine on learning and memory in mice was investigated using Morris water maze (MWM), Elevated plus maze(EPM) and Y maze (YM). Animals were administered with distilled water (control), methionine (1,700mg/kg); folate (3mg/kg) or methionine (1700mg/kg) plus folate (3mg/kg) for 14 days. Escape latency and time spent in target quadrants; transfer latency and percentage spontaneous alternations were measured in the MWM, EPM and YM respectively. The animals were anaesthetized with inhalational chloroform and their brains subsequently harvested, homogenized and assayed for acetylcholinesterase24 hours after the experiment.Folate significantly(p<0.05) increased transfer latency (53.33 ± 12.62) as compared to control (20.1 ± 5.01) and reduced spontaneous alternations significantly (25.0 ± 8.9) when compared to control (44.33 ± 3.07). When folate was combined with methionine there was also a significant increase in transfer latency (43.0 ± 14.39) when compared with control (20.1 ± 5.01). Folate-methionine combination also significantly reduced spontaneous alternations (20.4 ± 8.4) as compared to the control (44.33 ± 3.07) much more than folate alone. Acetylcholinesterase activities in all groups were not statistically significant. It can be concluded that acute methionine administration has some benefits in memory enhancement. However, a short course folate supplementation impairslearning and working memory especially when combined with methioninewhich may be as a result of sudden overwhelming of the methylation cycle, leading to homocysteinemia which is pro-dementia.

  19. Acute Administration of Methionine Affects Performance of Swiss Mice in Learning and Memory Paradigms.

    PubMed

    Abi, I; Magaji, R A; Magaji, M G

    2015-01-01

    Methionine, an essential amino acid, plays an essential role in the central nervous system CNS development. It serves as a crucial intermediate in the methylation, trans-sulfuration and amino- phosphorylationpathways,necessary for the synthesis of nucleic acids, phospholipids, hormones, neurotransmitters, antioxidants, polyamines, catecholamines and other biogenic amines. The effect of methionine on learning and memory in mice was investigated using Morris water maze (MWM), Elevated plus maze(EPM) and Y maze (YM). Animals were administered with distilled water (control), methionine (1,700mg/kg); folate (3mg/kg) or methionine (1700mg/kg) plus folate (3mg/kg) for 14 days. Escape latency and time spent in target quadrants; transfer latency and percentage spontaneous alternations were measured in the MWM, EPM and YM respectively. The animals were anaesthetized with inhalational chloroform and their brains subsequently harvested, homogenized and assayed for acetylcholinesterase24 hours after the experiment.Folate significantly(p<0.05) increased transfer latency (53.33 ± 12.62) as compared to control (20.1 ± 5.01) and reduced spontaneous alternations significantly (25.0 ± 8.9) when compared to control (44.33 ± 3.07). When folate was combined with methionine there was also a significant increase in transfer latency (43.0 ± 14.39) when compared with control (20.1 ± 5.01). Folate-methionine combination also significantly reduced spontaneous alternations (20.4 ± 8.4) as compared to the control (44.33 ± 3.07) much more than folate alone. Acetylcholinesterase activities in all groups were not statistically significant. It can be concluded that acute methionine administration has some benefits in memory enhancement. However, a short course folate supplementation impairslearning and working memory especially when combined with methioninewhich may be as a result of sudden overwhelming of the methylation cycle, leading to homocysteinemia which is pro-dementia. PMID

  20. Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm).

    PubMed

    Kennedy, D O; Scholey, Andrew B; Tildesley, N T J; Perry, E K; Wesnes, K A

    2002-07-01

    Melissa officinalis (lemon balm) is a traditional herbal medicine, which enjoys contemporary usage as a mild sedative, spasmolytic and antibacterial agent. It has been suggested, in light of in vitro cholinergic binding properties, that Melissa extracts may effectively ameliorate the cognitive deficits associated with Alzheimer's disease. To date, no study has investigated the effects on cognition and mood of administration of Melissa to healthy humans. The present randomised, placebo-controlled, double-blind, balanced-crossover study investigated the acute effects on cognition and mood of a standardised extract of M. officinalis. Twenty healthy, young participants received single doses of 300, 600 and 900 mg of M. officinalis (Pharmaton) or a matching placebo at 7-day intervals. Cognitive performance was assessed using the Cognitive Drug Research (CDR) computerised test battery and two serial subtraction tasks immediately prior to dosing and at 1, 2.5, 4 and 6 h thereafter. In vitro IC(50) concentrations for the displacement of [3H]-(N)-nicotine and [3H]-(N)-scopolamine from nicotinic and muscarinic receptors in human occipital cortex tissue were also calculated. Results, utilising the cognitive factors previously derived from the CDR battery, included a sustained improvement in Accuracy of Attention following 600 mg of Melissa and time- and dose-specific reductions in both Secondary Memory and Working Memory factors. Self-rated "calmness," as assessed by Bond-Lader mood scales, was elevated at the earliest time points by the lowest dose, whilst "alertness" was significantly reduced at all time points following the highest dose. Both nicotinic and muscarinic binding were found to be low in comparison to the levels found in previous studies.

  1. Changes in brain oxidative metabolism induced by inhibitory avoidance learning and acute administration of amitriptyline.

    PubMed

    González-Pardo, Héctor; Conejo, Nélida M; Arias, Jorge L; Monleón, Santiago; Vinader-Caerols, Concepción; Parra, Andrés

    2008-05-01

    The effects of antidepressant drugs on memory have been somewhat ignored, having been considered a mere side effect of these compounds. However, the memory impairment caused by several antidepressants could be considered to form part of their therapeutic effects. Amitriptyline is currently one of the most prescribed tricyclic antidepressants, and exerts marked anticholinergic and antihistaminergic effects. In this study, we evaluated the effects of inhibitory avoidance (IA) learning and acute administration of amitriptyline on brain oxidative metabolism. Brain oxidative metabolism was measured in several limbic regions using cytochrome oxidase (CO) quantitative histochemistry. Amitriptyline produced a clear impairment in the IA task. In animals exposed only to the apparatus, amitriptyline decreased CO activity in nine brain regions, without affecting the remaining regions. In animals that underwent the IA training phase, amitriptyline reduced CO activity in only three of these nine regions. In animals treated with saline, IA acquisition increased CO activity in the medial prefrontal cortex, the prelimbic cortex, and the medial mammillary body, and diminished it in the medial septum and the nucleus basalis of Meynert with respect to animals exposed only to the IA apparatus. In animals treated with amitriptyline, IA acquisition did not modify CO activity in any of these regions, but increased it in the anteromedial nucleus of the thalamus, the diagonal band of Broca, and the dentate gyrus. The results reveal a pattern of changes in brain oxidative metabolism induced by IA training in saline-treated animals that was clearly absent in animals submitted to the same behavioural training but treated with amitriptyline. PMID:18313125

  2. Full-gestational exposure to nicotine and ethanol augments nicotine self-administration by altering ventral tegmental dopaminergic function due to NMDA receptors in adolescent rats.

    PubMed

    Roguski, Emily E; Sharp, Burt M; Chen, Hao; Matta, Shannon G

    2014-03-01

    In adult rats, we have shown full-gestational exposure to nicotine and ethanol (Nic + EtOH) augmented nicotine self-administration (SA) (increased nicotine intake) compared to pair-fed (PF) offspring. Therefore, we hypothesized that full-gestational exposure to Nic + EtOH disrupts control of dopaminergic (DA) circuitry by ventral tegmental area (VTA) NMDA receptors, augmenting nicotine SA and DA release in nucleus accumbens (NAcc) of adolescents. Both NAcc DA and VTA glutamate release were hyper-responsive to intra-VTA NMDA in Nic + EtOH offspring versus PF (p = 0.03 and 0.02, respectively). Similarly, DA release was more responsive to i.v. nicotine in Nic + EtOH offspring (p = 0.02). Local DL-2-Amino-5-phosphonopentanoic acid sodium salt (AP5) (NMDA receptor antagonist) infusion into the VTA inhibited nicotine-stimulated DA release in Nic + EtOH and PF offspring. Nicotine SA was augmented in adolescent Nic + EtOH versus PF offspring (p = 0.000001). Daily VTA microinjections of AP5 reduced nicotine SA by Nic + EtOH offspring, without affecting PF (p = 0.000032). Indeed, nicotine SA in Nic + EtOH offspring receiving AP5 was not different from PF offspring. Both VTA mRNA transcripts and NMDA receptor subunit proteins were not altered in Nic + EtOH offspring. In summary, adolescent offspring exposed to gestational Nic + EtOH show markedly increased vulnerability to become dependent on nicotine. This reflects the enhanced function of a subpopulation of VTA NMDA receptors that confer greater nicotine-induced DA release in NAcc. We hypothesized that concurrent gestational exposure to nicotine and ethanol would disrupt the control of VTA dopaminergic circuitry by NMDA receptors. Resulting in the augmented nicotine self-administration (SA) in adolescent offspring.

  3. Ethanol enhancement of cocaine- and amphetamine-regulated transcript mRNA and peptide expression in the nucleus accumbens.

    PubMed

    Salinas, Armando; Wilde, Jennifer D; Maldve, Regina E

    2006-04-01

    Cocaine- and amphetamine-regulated transcript (CART) is a peptide neurotransmitter that has been implicated in drug reward and reinforcement. CART mRNA and peptide expression are highly concentrated in several compartments of the mesolimbic reward pathway. Several lines of evidence suggest that CART peptides may contribute to rewarding behaviors and the addiction liability of psychostimulants; however, there are no reports of basic work concerning CART in relation to alcohol and mechanisms of alcohol dependence development. Therefore, in this study we investigated the response of CART transcript and peptide to acute ethanol administration in vivo. Rats were administered ethanol (1 g/kg or 3.5 g/kg, 1 h, ip) and CART expression was measured by RT-PCR in the nucleus accumbens (NAcc). Ethanol (3.5 g/kg) increased CART transcription markedly. The interactions of dopamine on ethanol-induced CART expression were further evaluated pharmacologically using D1 and D2/D3 receptor antagonists. Both SCH 23390 (0.25 mg/kg) or raclopride (0.2 mg/kg) pre-treatment significantly suppressed ethanol-enhancement of CART mRNA transcription. Confocal immunofluorescence microscopy revealed that CART peptide immunoreactivity was also enhanced in both the core and the shell of the NAcc by ethanol administration. These findings demonstrate that CART mRNA and peptide expression are responsive to acute ethanol administrated in vivo and suggests that CART peptides may be important in regulating the rewarding and reinforcing properties of ethanol. PMID:16539670

  4. Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat

    EPA Science Inventory

    Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat M.F. Hughes1, D.G. Ross1, J.M. Starr1, E.J. Scollon1,2, M.J. Wolansky1,3, K.M. Crofton1, M.J. DeVito1,4 1U.S. EPA, ORD, Research Triangle Park, NC, 2U.S. EPA,...

  5. Synergistic effect of Se-methylselenocysteine and vitamin E in ameliorating the acute ethanol-induced oxidative damage in rat.

    PubMed

    Yao, Zhao; Zhang, Yunlong; Li, Hongyan; Deng, Zeyuan; Zhang, Xiaoping

    2015-01-01

    The present study was conduced to investigate the synergistic effects of combined treatments with Se-methylselenocysteine (SeMSC) and vitamin E (Vit E) in reversing oxidative stress induced by ethanol in serum and different tissues of rats. Sixty female rats were randomly divided into six groups for 30 days' consecutive pretreatments as followed: control (I), physiological saline (II), 2.8μgkg(-1) Se as SeMSC (III), 2.8μgkg(-1) Se as sodium selenite (Na2SeO3, IV), 5mgkg(-1) α-tocopherol as α-tocopherol acetate (Vit E, V), 5mgkg(-1) α-tocopherol as α-tocopherol acetate and 2.8μgkg(-1) Se as SeMSC (VI). All animals in groups II-VI were treated by ethanol treatment to cause oxidative stress. After 6h of ethanol treatment, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), the contents of total antioxidant capacity (T-AOC), malondialdehyde (MDA), glutathione (GSH) and carbonyl protein (CP) in the serum, liver, heart and kidney were measured. The result showed that the individual SeSMC, Na2SeO3 and vitamin E could effectively increase the SOD, T-AOC, GSH-Px and GSH contents as well as significantly decrease the MDA and CP concentrations in the tissues of ethanol-induced rats. At the same dose on different forms of Se, SeMSC showed greater antioxidant activity than Na2SeO3. Moreover, group VI (SeMSC and α-tocopherol acetate) showed much better antioxidant activity than individual group III (SeMSC) and V (α-tocopherol acetate) due to the synergistic effect.

  6. Lack of effect of nucleus accumbens dopamine D1 receptor blockade on consumption during the first two days of operant self-administration of sweetened ethanol in adult Long-Evans rats.

    PubMed

    Doherty, James M; Gonzales, Rueben A

    2015-09-01

    The mechanisms underlying ethanol self-administration are not fully understood; however, it is clear that ethanol self-administration stimulates nucleus accumbens dopamine release in well-trained animals. During operant sweetened ethanol self-administration behavior, an adaptation in the nucleus accumbens dopamine system occurs between the first and second exposure, paralleling a dramatic increase in sweetened ethanol intake, which suggests a single exposure to sweetened ethanol may be sufficient to learn the association between sweetened ethanol cues and its reinforcing properties. In the present experiment, we test the effects of blockade of nucleus accumbens dopamine D1 receptors on operant sweetened ethanol self-administration behavior during the first 2 days of exposure. Adult male Long-Evans rats were first trained to self-administer 10% sucrose (10S) across 6 days in an appetitive and consummatory operant model (appetitive interval: 10-min pre-drinking wait period and a lever response requirement of 4; consummatory interval: 20-min access to the drinking solution). After training on 10S, the drinking solution was switched to 10% sucrose plus 10% ethanol (10S10E); control rats continued drinking 10S throughout the experiment. Bilateral nucleus accumbens microinjections of the dopamine D1 antagonist, SCH-23390 (0, 1.0, or 3.0 μg/side), immediately preceded the first two sessions of drinking 10S10E. Results show that blocking nucleus accumbens dopamine D1 receptors has little or no influence on consumption during the first 2 days of exposure to the sweetened ethanol solution or maintenance of sucrose-only drinking. Furthermore, the high dose of SCH-23390, 3.0 μg/side, reduced open-field locomotor activity. In conclusion, we found no evidence to suggest that nucleus accumbens D1 receptor activation is involved in consumption of a sweetened ethanol solution during the first 2 days of exposure or maintenance of sucrose drinking, but rather D1 receptors seem

  7. Lack of effect of nucleus accumbens dopamine D1 receptor blockade on consumption during the first two days of operant self-administration of sweetened ethanol in adult Long-Evans rats

    PubMed Central

    Doherty, James M.; Gonzales, Rueben A.

    2014-01-01

    The mechanisms underlying ethanol self-administration are not fully understood; however, it is clear that ethanol self-administration stimulates nucleus accumbens dopamine release in well trained animals. During operant sweetened ethanol self-administration behavior, an adaptation in the nucleus accumbens dopamine system occurs between the first and second exposure paralleling a dramatic increase in sweetened ethanol intake, which suggests a single exposure to sweetened ethanol may be sufficient to learn the association between sweetened ethanol cues and its reinforcing properties. In the present experiment, we test the effects of blockade of nucleus accumbens dopamine D1 receptors on operant sweetened ethanol self-administration behavior during the first two days of exposure. Adult male Long-Evans rats were first trained to self-administer 10% sucrose (10S) across six days in an appetitive and consummatory operant model (appetitive interval: 10 min pre-drinking wait period and a lever response requirement of 4; consummatory interval: 20 min access to the drinking solution). After training on 10S, the drinking solution was switched to 10% sucrose plus 10% ethanol (10S10E); control rats remained drinking 10S throughout the experiment. Bilateral nucleus accumbens microinjections of the dopamine D1 antagonist, SCH-23390 (0, 1.0, or 3.0 μg/side), immediately preceded the first two sessions of drinking 10S10E. Results show that blocking nucleus accumbens dopamine D1 receptors has little or no influence on consumption during the first two days of exposure to the sweetened ethanol solution or maintenance of sucrose only drinking. Furthermore, the high dose of SCH-23390, 3.0 μg/side, reduced open field locomotor activity. In conclusion, we found no evidence to suggest that nucleus accumbens D1 receptor activation is involved in consumption of a sweetened ethanol solution during the first two days of exposure or maintenance of sucrose drinking, but rather D1 receptors

  8. Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3α,5α-THP and reduces long-term operant ethanol self-administration.

    PubMed

    Cook, Jason B; Werner, David F; Maldonado-Devincci, Antoniette M; Leonard, Maggie N; Fisher, Kristen R; O'Buckley, Todd K; Porcu, Patrizia; McCown, Thomas J; Besheer, Joyce; Hodge, Clyde W; Morrow, A Leslie

    2014-04-23

    Neuroactive steroids are endogenous neuromodulators capable of altering neuronal activity and behavior. In rodents, systemic administration of endogenous or synthetic neuroactive steroids reduces ethanol self-administration. We hypothesized this effect arises from actions within mesolimbic brain regions that we targeted by viral gene delivery. Cytochrome P450 side chain cleavage (P450scc) converts cholesterol to pregnenolone, the rate-limiting enzymatic reaction in neurosteroidogenesis. Therefore, we constructed a recombinant adeno-associated serotype 2 viral vector (rAAV2), which drives P450scc expression and neuroactive steroid synthesis. The P450scc-expressing vector (rAAV2-P450scc) or control GFP-expressing vector (rAAV2-GFP) were injected bilaterally into the ventral tegmental area (VTA) or nucleus accumbens (NAc) of alcohol preferring (P) rats trained to self-administer ethanol. P450scc overexpression in the VTA significantly reduced ethanol self-administration by 20% over the 3 week test period. P450scc overexpression in the NAc, however, did not alter ethanol self-administration. Locomotor activity was unaltered by vector administration to either region. P450scc overexpression produced a 36% increase in (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone)-positive cells in the VTA, but did not increase 3α,5α-THP immunoreactivity in NAc. These results suggest that P450scc overexpression and the resultant increase of 3α,5α-THP-positive cells in the VTA reduces ethanol reinforcement. 3α,5α-THP is localized to neurons in the VTA, including tyrosine hydroxylase neurons, but not astrocytes. Overall, the results demonstrate that using gene delivery to modulate neuroactive steroids shows promise for examining the neuronal mechanisms of moderate ethanol drinking, which could be extended to other behavioral paradigms and neuropsychiatric pathology.

  9. Acute ethanol inhibits calcium influxes into esophageal smooth but not striated muscle: a possible mechanism for ethanol-induced inhibition of esophageal contractility.

    PubMed

    Keshavarzian, A; Zorub, O; Sayeed, M; Urban, G; Sweeney, C; Winship, D; Fields, J

    1994-09-01

    In both humans and cats, EtOH administered in vivo and acutely decreases contractility of smooth muscle of lower esophageal sphincter (LES) and lower esophagus (LE), but not striated muscle of upper esophagus. To see if these effects are associated with perturbation of Ca++ homeostasis, esophageal muscle slices were incubated in vitro with EtOH and then 45Ca++. At steady-state Ca++ uptake, some slices were exposed to 1 microM carbachol (CCH). Although 100 mM EtOH had no effect on Ca++ uptake into resting or stimulated striated muscle of upper esophagus, it significantly inhibited Ca++ uptake into smooth muscle of LES and LE. For unstimulated LE and resting LES, 100 mM EtOH significantly inhibited both initial uptake and steady-state levels, whereas lower doses had no significant effect. EtOH at 100 mM also affected changes in Ca++ content induced by CCH stimulation. CCH increased total exchangeable tissue Ca++ content in LE, whereas it decreased Ca++ content in LES. EtOH at 100 mM blunted these CCH-induced effects in both LES and LE. In contrast to resting muscle, inhibition of CCH-stimulated LE muscle was not limited to 100 mM EtOH, because substantial and significant inhibition was also seen at EtOH doses of 25 and 50 mM, doses which are relevant even in social drinking. Thus, EtOH inhibition of Ca++ influx into esophageal muscle is selective for smooth muscle, can occur at pharmacologically relevant EtOH doses and could be the underlying mechanism for EtOH's inhibition of contractility of esophageal smooth muscle. PMID:7932153

  10. Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny.

    PubMed

    Silveri, M M; Spear, L P

    1998-05-01

    Sensitivity to the hypnotic effects of ethanol was examined in Sprague-Dawley male and female rats at 16, 26, 36, 46, 56, or 96 days postnatally. Following administration of 3.5, 4.0, 4.5, or 5.0 g/kg of a 17% v/v ethanol solution, sleep times were recorded and blood alcohol levels (BALs) and brain alcohol levels (BrALs) were measured upon awakening. In addition to examining ethanol sleep time during ontogeny, data were used to estimate acute tolerance (indexed by the slope of the linear regressions of waking BALs and BrALs as a function of dose) and initial brain sensitivity to ethanol (indexed by calculating the y-intercept from the linear regression of BrALs as a function of sleep time). The results showed a marked increase in sensitivity to ethanol hypnosis during ontogeny, with young animals exhibiting shorter ethanol-induced sleep times and high waking BALs and BrALs. This ontogenetic increase in ethanol sensitivity was associated with a developmental decline in acute tolerance, with acute tolerance being most pronounced at postnatal day (P) 16 and evident only up to P36. Initial sensitivity conversely increased with age, with P16 pups showing lower initial brain sensitivity to ethanol than at all other ages. Gender differences emerged in adulthood, with males sleeping significantly longer than females at P56 and P96. These findings suggest that the marked insensitivity of young animals to the hypnotic effects of ethanol is related to both pronounced acute tolerance, as well as reduced initial brain sensitivity to ethanol early in life. PMID:9622449

  11. Gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves against acute gastric lesion models in rodents.

    PubMed

    Fernandes, Hélio B; Silva, Francilene V; Passos, Flávia Franceli B; Bezerra, Roosevelt D S; Chaves, Mariana H; Oliveira, Francisco A; Oliveira, Rita C Meneses

    2010-01-01

    Parkia platycephala Benth. (Leguminosae--Mimosoideae), popularly known as "visgueira", fava bean tree or "fava-de-bolota", is widely found in the Northern and Northeastern regions of Brazil. Its pods are used as cattle food supplement in the drought period. Compounds with a gastroprotective activity were obtained from the genus Parkia. Therefore, this study aimed at investigating the gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves (Pp-EtOH), as well as evaluating its possible mechanisms of action in experimental ulcer induction models. Lesions were induced by absolute ethanol, ethanol-HCl, ischemia-reperfusion and indomethacin in rodents. Pp-EtOH showed a protective effect in the lesion models (66, 48 and 52%, respectively), but it was not able to protect gastric mucosa against indomethacin-induced lesions. Results show a possible participation of the NO-synthase pathway in the gastroprotection and an antioxidant activity, by the increase of the catalase activity. The participation of prostaglandins and potassium channels sensitive to ATP in the gastroprotective effect of Pp-EtOH seems less likely to occur. More comprehensive studies, therefore, should be carried out to elucidate the antiulcerative effects of this promising natural product against this gastrointestinal disorder.

  12. A report of acute ethanol poisoning in a child: mouthwash versus cologne, perfume and after-shave.

    PubMed

    Hornfeldt, C S

    1992-01-01

    The ingestion of ethanol-containing products, such as cologne, perfume and after-shave, in children under six years of age is common, but serious poisoning is rarely reported. Thus, it has been recently suggested that children ingesting up to 3.5 ounces of these products may be safely observed at home as long as they remain asymptomatic. While it may be assumed that products with a significantly lower alcohol content represent a much smaller poisoning hazard, mouthwashes are a relatively frequent cause of serious poisoning in children. In the following case report, 75 milliliters of mouthwash caused hypoglycemia, coma and manifestations of tonic seizure activity. Because of the palatable nature of mouthwash, wine and liquor, it appears that children are more apt to drink large quantities, consuming dangerous amounts of ethanol. The apparent safety of cologne, perfume, and after-shave may be due to a lack of palatability as well as the irritant nature of high concentrations of ethanol. This case suggests that consumer items such as mouthwash should be packaged in child-resistant containers.

  13. Gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves against acute gastric lesion models in rodents.

    PubMed

    Fernandes, Hélio B; Silva, Francilene V; Passos, Flávia Franceli B; Bezerra, Roosevelt D S; Chaves, Mariana H; Oliveira, Francisco A; Oliveira, Rita C Meneses

    2010-01-01

    Parkia platycephala Benth. (Leguminosae--Mimosoideae), popularly known as "visgueira", fava bean tree or "fava-de-bolota", is widely found in the Northern and Northeastern regions of Brazil. Its pods are used as cattle food supplement in the drought period. Compounds with a gastroprotective activity were obtained from the genus Parkia. Therefore, this study aimed at investigating the gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves (Pp-EtOH), as well as evaluating its possible mechanisms of action in experimental ulcer induction models. Lesions were induced by absolute ethanol, ethanol-HCl, ischemia-reperfusion and indomethacin in rodents. Pp-EtOH showed a protective effect in the lesion models (66, 48 and 52%, respectively), but it was not able to protect gastric mucosa against indomethacin-induced lesions. Results show a possible participation of the NO-synthase pathway in the gastroprotection and an antioxidant activity, by the increase of the catalase activity. The participation of prostaglandins and potassium channels sensitive to ATP in the gastroprotective effect of Pp-EtOH seems less likely to occur. More comprehensive studies, therefore, should be carried out to elucidate the antiulcerative effects of this promising natural product against this gastrointestinal disorder. PMID:21526272

  14. Inhibitory effects of ethanol on phosphatidylinositol breakdown in pancreatic acini

    SciTech Connect

    Towner, S.J.; Peppin, J.F.; Tsukamoto, H.

    1986-03-01

    Recently the physiological relationship between the phospholipid effect and secretagogue-induced cellular function has begun to be understood. In this study, the authors investigated acute and chronic effects of ethanol on phosphatidylinositol (PI) synthesis and breakdown in pancreatic acini. Five pairs of male Wistar rats were intragastrically infused for 30 days with high fat diet (25% total calories) plus ethanol or isocaloric dextrose. After intoxication, isolated in HEPES media, followed by 30 min incubation with CCK-8 (0, 100, 300 or 600 pM) and ethanol (0 or 100 mM). Acinar lipids were extracted and counted for labeled PI. Incorporation of /sup 3/H-inositol into alcoholic acinar PI was reduced to 38.2% of that in controls. A percent maximal PI break down by CCK-8 was similar in the two groups (13-24% of basal). However, the magnitude of PI breakdown was markedly lower in alcoholic acini (482 vs 1081 dpm) due to the decreased PI synthesis rate. The presence of 100 mM ethanol in the media further inhibited the breakdown by 50% in this group. These results strongly indicate that chronic ethanol intoxication inhibits PI synthesis and breakdown in pancreatic acini, and that this inhibition can be potentiated by acute ethanol administration.

  15. Turning Rate Dynamics of Zebrafish Exposed to Ethanol

    NASA Astrophysics Data System (ADS)

    Mwaffo, Violet; Porfiri, Maurizio

    2015-06-01

    Zebrafish is emerging as a species of choice in alcohol-related pharmacological studies. In these studies, zebrafish are often exposed to acute ethanol treatments and their activity scored during behavioral assays. Computational modeling of zebrafish behavior is expected to positively impact these efforts by offering a predictive toolbox to plan hypothesis-driven studies, reduce the number of subjects, perform pilot trials, and refine behavioral screening. In this work, we demonstrate the use of the recently proposed jump persistent turning walker to model the turning rate dynamics of zebrafish exposed to acute ethanol administration. This modeling framework is based on a stochastic mean reverting jump process to capture the sudden and large changes in orientation of swimming zebrafish. The model is calibrated on an available experimental dataset of 40 subjects, tested at different ethanol concentrations. We demonstrate that model parameters are modulated by ethanol administration, whereby both the relaxation rate and jump frequency of the turning rate dynamics are influenced by ethanol concentration. This effort offers a first evidence for the possibility of complementing zebrafish pharmacological research with computational modeling of animal behavior.

  16. Sex differences in acute ethanol withdrawal severity after adrenalectomy and gonadectomy in Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant mice.

    PubMed

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

    2009-08-01

    Recent findings suggest that the ability of ethanol (EtOH) to increase the levels of neurosteroids with potent gamma-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 study 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 Withdrawal Seizure-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 2 weeks later, baseline handling-induced convulsions (HICs) were assessed, mice were given a 4 g/kg dose of EtOH, and HICs were measured hourly for 12 h and then at 24 h. 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. The 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 EtOH withdrawal severity in female WSP and WSR mice after 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.

  17. Central histaminergic transmission modulates the ethanol induced anxiolysis in mice.

    PubMed

    Verma, Lokesh; Jain, Nishant S

    2016-10-15

    Intrigued by the report demonstrating an increase in brain histamine levels by ethanol administration and central histamine transmission to affect the anxiety related behaviors, the present study examined the permissive role of central histaminergic transmission in the acute anxiolytic-like effect of the ethanol on elevated plus maze (EPM) in mice. Results demonstrated that prior administration of the agents that are known to enhance the brain histamine transmission, i.e. low dose of histamine (0.1μg/mouse, i.c.v.) or histamine precursor, l-histidine (500, 1000mg/kg, i.p.) or low dose of histamine releasing agent (H3 receptor inverse agonist), thioperamide (2μg/mouse) attenuated the acute anitanxiety-like effect of ethanol (2g/kg, i.p, 8% w/v) in mice on EPM. However, pre-treatment with the H1 receptor antagonist, cetirizine (0.1μg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50μg/mouse, i.c.v.) failed to affect the attenuating effect of low dose of histamine on ethanol induced anxiolysis. On the other hand, only H1 receptor antagonist, cetirizine (0.1μg/mouse, i.c.v.) was able to partially reverse the attenuation of ethanol induced anxiolysis by l-histidine (1000mg/kg, i.p.). Surprisingly, in mice pre-treated with the higher dose of histamine (50μg/mouse, i.c.v.) or thioperamide (10μg/mouse, i.c.v.), the ethanol (2g/kg, i.p.) induced antianxiety-like effect was further enhanced on EPM. Furthermore, this potentiating effect of high dose of histamine on the ethanol (2g/kg, i.p.) was exacerbated on pre-treatment with the H1 receptor antagonist, cetirizine, while H2 receptor antagonist, ranitidine completely reversed this action of high dose of histamine on ethanol. Supportive to these results, i.c.v. pre-treatment with H1 receptor agonist, FMPH (2, 6.5μg/mouse, i.c.v.) attenuated while H2 receptor agonist, amthamine (0.1, 0.5μg/mouse, i.c.v.) enhanced the ethanol induced anxiolysis in mice. Thus, it is reasonable to contemplate that central

  18. Zonal heterogeneity of the effects of chronic ethanol feeding on hepatic fatty acid metabolism.

    PubMed

    Guzman, M; Castro, J

    1990-11-01

    Periportal and perivenous hepatocytes were isolated from rats fed a high-fat, ethanol-containing diet to investigate the acinar heterogeneity of the effects of prolonged ethanol administration on lipid metabolism. Chronic feeding of ethanol caused a rather selective accumulation of triacylglycerols in the perivenous zone of the liver. In control animals the rate of lipogenesis and the activity of acetyl-CoA carboxylase were higher in perivenous than in periportal hepatocytes, whereas the rate of fatty acid oxidation and the activity of carnitine palmitoyltransferase I were higher in periportal than in perivenous cells; however, no zonation was evident for very-low-density-lipoprotein-lipid secretion. Prolonged ethanol administration abolished the zonal asymmetry of the lipogenic process and inverted the acinar distribution of the fatty acid-oxidative process (i.e., in ethanol-fed animals the rate of fatty acid oxidation and the activity of carnitine palmitoyltransferase I were higher in perivenous than in periportal hepatocytes). Moreover, chronic feeding of ethanol led to a marked and selective inhibition of very-low-density-lipoprotein-triacylglycerol secretion by the perivenous zone of the liver. Nevertheless, no zonal differences were observed between control and ethanol-fed animals with respect to the effects of acute doses of ethanol and acetaldehyde on lipid metabolism. In conclusion, our results show that chronic ethanol intake produces important alterations in the acinar distribution of the different fatty acid-metabolizing pathways.

  19. Intracranial self-administration of ethanol within the ventral tegmental area of male Wistar rats: evidence for involvement of dopamine neurons.

    PubMed

    Rodd, Zachary A; Melendez, Roberto I; Bell, Richard L; Kuc, Kelly A; Zhang, Ying; Murphy, James M; McBride, William J

    2004-02-01

    Previous work from our laboratory indicated that female Wistar rats will self-administer ethanol (EtOH) directly into the posterior ventral tegmental area (VTA). These results suggested that VTA dopamine (DA) neurons might be involved in mediating the reinforcing actions of EtOH within this region. The objectives of this study were to determine (1) the dose-response effects for the self-administration of EtOH into the VTA of male Wistar rats, and (2) the involvement of VTA DA neurons in the reinforcing actions of EtOH within the VTA. Adult male Wistar rats were implanted stereotaxically with guide cannulas aimed at the posterior or anterior VTA. After 1 week, rats were placed in standard two-lever (active and inactive) experimental chambers for a total of seven to eight sessions. The first experiment determined the intracranial self-administration of EtOH (0-400 mg%) into the posterior and anterior VTA. The second experiment examined the effects of coadministration of the D2/3 agonist quinpirole on the acquisition and maintenance of EtOH self-infusions into the posterior VTA. The final experiment determined the effects of a D2 antagonist (sulpiride) to reinstate self-administration behavior in rats given EtOH and quinpirole to coadminister. Male Wistar rats self-infused 100-300 mg% EtOH directly into the posterior, but not anterior, VTA. Coadministration of quinpirole prevented the acquisition and extinguished the maintenance of EtOH self-infusion into the posterior VTA, and addition of sulpiride reinstated EtOH self-administration. The results of this study indicate that EtOH is reinforcing within the posterior VTA of male Wistar rats and suggest that activation of VTA DA neurons is involved in this process.

  20. Effect of acute and chronic administration of L-tyrosine on nerve growth factor levels in rat brain.

    PubMed

    Ferreira, Gabriela K; Jeremias, Isabela C; Scaini, Giselli; Carvalho-Silva, Milena; Gomes, Lara M; Furlanetto, Camila B; Morais, Meline O; Schuck, Patrícia F; Ferreira, Gustavo C; Streck, Emilio L

    2013-08-01

    Most inborn errors of tyrosine catabolism produce hypertyrosinemia. Neurological manifestations are variable and some patients are developmentally normal, while others show different degrees of developmental retardation. Considering that current data do not eliminate the possibility that elevated levels of tyrosine and/or its derivatives may have noxious effects on central nervous system development in some patients, the present study evaluated nerve growth factor (NGF) levels in hippocampus, striatum and posterior cortex of young rats. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal administration of L-tyrosine (500 mg/kg) or saline. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); the rats were killed 12 h after the last injection. NGF levels were then evaluated. Our findings showed that acute administration of L-tyrosine decreased NGF levels in striatum of 10-day-old rats. In the 30-day-old rats, NGF levels were decreased in hippocampus and posterior cortex. On the other hand, chronic administration of L-tyrosine increased NGF levels in posterior cortex. Decreased NGF may impair growth, differentiation, survival and maintenance of neurons. PMID:23690230

  1. Role of neutrophilic elastase in ethanol induced injury to the gastric mucosa

    SciTech Connect

    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). 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.

  2. 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

  3. Repeated ethanol administration modifies the temporal structure of sucrose intake patterns in mice: effects associated with behavioral sensitization.

    PubMed

    Pastor, Raúl; Kamens, Helen M; McKinnon, Carrie S; Ford, Matthew M; Phillips, Tamara J

    2010-07-01

    Neuroadaptations supporting behavioral sensitization to abused drugs are suggested to underlie pathological, excessive motivation toward drugs and drug-associated stimuli. Drug-induced sensitization has also been linked to increased appetitive responses for non-drug, natural reinforcers. The present research investigated whether ethanol (EtOH)-induced neural changes, inferred from psychomotor sensitization, can modify consumption and intake dynamics for the natural reinforcer, sucrose. The effects of EtOH-induced sensitization in mice on the temporal structure of sucrose intake patterns were measured using a lickometer system. After sensitization, sucrose intake dynamics were measured for 1 hour daily for 7 days and indicated more rapid initial approach and consumption of sucrose in EtOH-sensitized groups; animals showed a shorter latency to the first intake bout and an increased number of sucrose bottle licks during the initial 15 minutes of the 1-hour sessions. This effect was associated with increased frequency and size of bouts. For the total 1-hour session, sucrose intake and bout dynamics were not different between groups, indicating a change in patterns of sucrose intake but not total consumption. When sensitization was prevented by the gamma-aminobutyric acid B receptor agonist, baclofen, the increased rate of approach and consumption of sucrose were also prevented. Thus, EtOH-induced sensitization, and not the mere exposure to EtOH, was associated with changes in sucrose intake patterns. These data are consistent with current literature suggesting an enhancing effect of drug-induced sensitization on motivational processes involved in reinforcement.

  4. Endogenous released ascorbic acid suppresses ethanol-induced hydroxyl radical production in rat striatum.

    PubMed

    Huang, Mei; Liu, Wen; Li, Qiang; Wu, Chun Fu

    2002-07-19

    Previous studies have shown that acute systemic administration of ethanol induced ascorbic acid release in the striatum. However, the pharmacological implications of ethanol-induced striatal ascorbic acid release are unclear. In the present study, ethanol-induced extracellular changes of ascorbic acid and hydroxyl radical levels were detected in rat striatum by using brain microdialysis coupled to high-performance liquid chromatography with electrochemical detection. It was found that both in male and female rats, ethanol (3.0 g/kg, i.p.) increased striatal ascorbic acid release in the first 60 min after ethanol administration. Meanwhile, the extracellular hydroxyl radical levels, detected as 2,3- and 2,5-DHBA, were significantly decreased. However, when the ascorbic acid levels returned to the baseline, hydroxyl radical levels rebounded. Administration of DL-fenfluramine (20 mg/kg, i.p.) had no effect on the basal levels of ascorbic acid and hydroxyl radical, but significantly blocked ethanol-induced ascorbic acid release and increased hydroxyl radical levels significantly. Exogenous administration of ascorbic acid (20 mg/kg, s.c.) increased the extracellular levels of ascorbic acid in the striatum, and inhibited the increase of 2,3- and 2,5-DHBA in DL-fenfluramine plus ethanol group. These results provide first evidence that release of endogenous ascorbic acid in the striatum plays an important role in preventing oxidative stress by trapping hydroxyl radical in the central nervous system.

  5. Does ethanol inhibit LH secretion in the rat?

    PubMed

    Ellingboe, J; Shaw, D G; Skupny, A S; Sikorski, M A

    1987-01-01

    A prevailing view among those studying neuroendocrine effects of ethanol is that acute doses suppress luteinizing hormone releasing hormone (LHRH) secretion, and consequently inhibit luteinizing hormone (LH) release in the rat. This phenomenon has not been observed in primates, and has been thought to be a species difference. The experimental procedures, however, have involved ethanol administration by oral or intragastric (ig) routes in humans and monkeys, but intraperitoneal (ip) or carotid artery injection in rats. It has also been suggested that inhibition of LH secretion by ethanol in rats is mediated by endogenous opioid peptides (EOP), because the effect can be reversed by the opiate antagonist naloxone. An alternative explanation is that ip ethanol injection might stress rats sufficiently to activate hypothalamic-pituitary-adrenocortical (H-P-A) and EOP systems that are well known to inhibit hormonal activities of the hypothalamic-pituitary-gonadal (H-P-G) axis. Presented here are preliminary results from experiments with male rats. When ethanol is administered ig, under relatively stress-free conditions, it does not inhibit LH secretion in gonadally intact or castrated males. In contrast, ip injection of the same ethanol dose (2.0 g/kg body wt) causes pronounced inhibition of LH secretion and concomitant increases in plasma prolactin (PRL) and corticosterone--indicative of a stress response. Furthermore, when ip ethanol administration is preceded by intracerebroventricular (icv) injection of a corticotropin releasing factor (CRF) antagonist (alpha-helical ovine CRF residues 9 to 41), the effects of ethanol on LH and corticosterone are blocked. These results indicate that it may be stress, rather than ethanol per se, that inhibits LHRH and LH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Effects of ethanol on rat heart and skeletal muscles

    SciTech Connect

    Pagala, M.; Ravindran, K.; Namba, T.; Grob, D. State Univ. of New York, Brooklyn )

    1991-03-11

    Chronic alcoholism causes myopathy of both cardiac and skeletal muscles. In order to evaluate acute effects, the authors infused ethanol intravenously in anesthetized rats, and, 10 min later, monitored the electrocardiogram, and the compound action potential and isometric tension of the anterior tibialis evoked by sciatic nerve stimulation. Ethanol at 0.1, 0.2 and 0.5 g/kg decreased the heart rate by 12%, 22% and 69%, increased the P-R interval by 5%, 25%, and 116%, and reduced the QRS amplitude by 1% , 2% and 10%, respectively. Within 5 min after infusing 0.5 g/kg ethanol, breathing was stopped. Ethanol increased the amplitude of the compound action potential and tension of the anterior tibialis by 25% at 0.1 and 0.2 g/kg, while it decreased the compound action potential by 5% and tension by 35% at 0.5 g/kg. At this dose, ethanol caused 70% decrement in amplitude of the compound action potentials and 50% fade of tetanic tensions evoked by a train of nerve stimulations at 100 Hz for 0.5 sec. When ethanol was injected intraperitoneally, about 10 times greater doses were required to produce effects equivalent to intravenous administration. These results indicate that ethanol reduces cardiac output dose-dependently, and potentiates skeletal muscle function at subintoxication doses and reduces it at higher doses.

  7. Pilot study of the safety of starting administration of low-dose aspirin and cilostazol in acute ischemic stroke.

    PubMed

    Fujita, Keishi; Komatsu, Yoji; Sato, Naoaki; Higuchi, Osamu; Kujiraoka, Yuji; Kamezaki, Takao; Suzuki, Kensuke; Matsumura, Akira

    2011-01-01

    Progressive stroke is a serious problem due to the associated morbidity and mortality. Aspirin is recommended for acute ischemic stroke, but does not reduce the frequency of stroke progression. No standard treatment has been approved for the prevention of stroke progression. Cilostazol, which reduces platelet aggregation about 3 hours after single administration, does not increase the frequency of bleeding events when compared with aspirin or a placebo. Moreover, the combination of 100 mg aspirin and 200 mg cilostazol does not increase the frequency of bleeding events compared with only 100 mg aspirin, and thus is expected to prevent stroke progression with a high degree of safety. The present study investigated the safety of this combination of two drugs administered at the above concentrations in 54 patients with acute ischemic stroke within 48 hours of stroke onset. Modified National Institutes of Health Stroke Scale (NIHSS) measurements were performed at baseline and again on day 4 to 7. Progressive stroke was defined as an increase greater than or equal to 1 point on NIHSS. Patient scores on the modified Rankin Scale (mRS) were evaluated at baseline and 3 months after enrollment. Stroke progression occurred in 11.1% of the patients. The percentages of patients with mRS score from 0 to 2 were 42.6% and 75% at baseline and 3 months, respectively. No symptomatic intracranial hemorrhage or major extracranial hemorrhage occurred. These results suggest that administration of aspirin and cilostazol is safe for acute ischemic stroke.

  8. Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration and withdrawal: evidence that CYP2E1 possesses a rapid phase half-life of 6 hours or less.

    PubMed

    Roberts, B J; Shoaf, S E; Jeong, K S; Song, B J

    1994-12-15

    Controversy exists as to whether the induction of CYP2E1 by ethanol occurs via increased protein synthesis or protein stabilization. To address these issues in vivo, we chronically administered ethanol to rats and determined levels of immunoreactive CYP2E1 in liver, kidney, brain and upper gastro-intestinal tract (GI). Our data shows that chronic ethanol administration induces hepatic (5-6-fold over pair-fed controls) and extra-hepatic CYP2E1, an effect which is strikingly absent 12 hours after ethanol withdrawal. No changes in CYP2E1 mRNA were observed at any time, suggesting these changes are mainly post-translational at a blood ethanol concentration of 0.15% w/v. Our experimental data indicates that CYP2E1 possesses a half-life of 6 hours or less in the liver and is rapidly degraded following the removal of ethanol. This pattern of CYP2E1 turnover was also observed in other tissues, suggestive of a similar mode of regulation.

  9. 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 ...

  10. Differential action for ethanol on baroreceptor reflex control of heart rate and sympathetic efferent discharge in rats

    SciTech Connect

    Xin, Z.; Abdel-Rahman, A.R.A.; Wooles, W.R.

    1988-01-01

    The acute effects of ethanol (0.33, 0.66, or 1 g/kg) on baroreflex control of heart rate (HR) and sympathetic efferent discharge (SED) were investigated in rats. The two higher doses of ethanol caused a progressive and significant increase in baseline SED and a slight increase in HR. The findings suggest that the sensitivity of the reflex control of SED was preserved whereas that of HR was impaired after acute ethanol administration. Since these findings were obtained in the same animals, the data suggest that acute ethanol has a differential action on reflex control of SED and HR. Further, the significant increase in SED after moderate and high doses of ethanol suggests an increased central sympathetic tone as recordings were made from preganglionic nerve fibers (splanchnic nerve). The absence of an increase in baseline MAP, in spite of a significant increase in baseline SED following acute ethanol injection, could be explained, at least in part, by an ethanol-evoked reduction in pressor responsiveness to phenylephrine, an ..cap alpha..-adrenergic agonist.

  11. Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

    PubMed Central

    Mojadadi, Shafi; Jamali, Abbas; Khansarinejad, Behzad; Soleimanjahi, Hoorieh; Bamdad, Taravat

    2009-01-01

    Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-γ production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-γ production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation. PMID:19403060

  12. Acute Carnosine Administration Increases Respiratory Chain Complexes and Citric Acid Cycle Enzyme Activities in Cerebral Cortex of Young Rats.

    PubMed

    Macedo, Levy W; Cararo, José H; Maravai, Soliany G; Gonçalves, Cinara L; Oliveira, Giovanna M T; Kist, Luiza W; Guerra Martinez, Camila; Kurtenbach, Eleonora; Bogo, Maurício R; Hipkiss, Alan R; Streck, Emilio L; Schuck, Patrícia F; Ferreira, Gustavo C

    2016-10-01

    Carnosine (β-alanyl-L-histidine) is an imidazole dipeptide synthesized in excitable tissues of many animals, whose biochemical properties include carbonyl scavenger, anti-oxidant, bivalent metal ion chelator, proton buffer, and immunomodulating agent, although its precise physiological role(s) in skeletal muscle and brain tissues in vivo remain unclear. The aim of the present study was to investigate the in vivo effects of acute carnosine administration on various aspects of brain bioenergetics of young Wistar rats. The activity of mitochondrial enzymes in cerebral cortex was assessed using a spectrophotometer, and it was found that there was an increase in the activities of complexes I-III and II-III and succinate dehydrogenase in carnosine-treated rats, as compared to vehicle-treated animals. However, quantitative real-time RT-PCR (RT-qPCR) data on mRNA levels of mitochondrial biogenesis-related proteins (nuclear respiratory factor 1 (Nrf1), peroxisome proliferator-activated receptor-γ coactivator 1-α (Ppargc1α), and mitochondrial transcription factor A (Tfam)) were not altered significantly and therefore suggest that short-term carnosine administration does not affect mitochondrial biogenesis. It was in agreement with the finding that immunocontent of respiratory chain complexes was not altered in animals receiving carnosine. These observations indicate that acute carnosine administration increases the respiratory chain and citric acid cycle enzyme activities in cerebral cortex of young rats, substantiating, at least in part, a neuroprotector effect assigned to carnosine against oxidative-driven disorders. PMID:26476839

  13. Acute Carnosine Administration Increases Respiratory Chain Complexes and Citric Acid Cycle Enzyme Activities in Cerebral Cortex of Young Rats.

    PubMed

    Macedo, Levy W; Cararo, José H; Maravai, Soliany G; Gonçalves, Cinara L; Oliveira, Giovanna M T; Kist, Luiza W; Guerra Martinez, Camila; Kurtenbach, Eleonora; Bogo, Maurício R; Hipkiss, Alan R; Streck, Emilio L; Schuck, Patrícia F; Ferreira, Gustavo C

    2016-10-01

    Carnosine (β-alanyl-L-histidine) is an imidazole dipeptide synthesized in excitable tissues of many animals, whose biochemical properties include carbonyl scavenger, anti-oxidant, bivalent metal ion chelator, proton buffer, and immunomodulating agent, although its precise physiological role(s) in skeletal muscle and brain tissues in vivo remain unclear. The aim of the present study was to investigate the in vivo effects of acute carnosine administration on various aspects of brain bioenergetics of young Wistar rats. The activity of mitochondrial enzymes in cerebral cortex was assessed using a spectrophotometer, and it was found that there was an increase in the activities of complexes I-III and II-III and succinate dehydrogenase in carnosine-treated rats, as compared to vehicle-treated animals. However, quantitative real-time RT-PCR (RT-qPCR) data on mRNA levels of mitochondrial biogenesis-related proteins (nuclear respiratory factor 1 (Nrf1), peroxisome proliferator-activated receptor-γ coactivator 1-α (Ppargc1α), and mitochondrial transcription factor A (Tfam)) were not altered significantly and therefore suggest that short-term carnosine administration does not affect mitochondrial biogenesis. It was in agreement with the finding that immunocontent of respiratory chain complexes was not altered in animals receiving carnosine. These observations indicate that acute carnosine administration increases the respiratory chain and citric acid cycle enzyme activities in cerebral cortex of young rats, substantiating, at least in part, a neuroprotector effect assigned to carnosine against oxidative-driven disorders.

  14. The validity of ICD codes coupled with imaging procedure codes for identifying acute venous thromboembolism using administrative data.

    PubMed

    Alotaibi, Ghazi S; Wu, Cynthia; Senthilselvan, Ambikaipakan; McMurtry, M Sean

    2015-08-01

    The purpose of this study was to evaluate the accuracy of using a combination of International Classification of Diseases (ICD) diagnostic codes and imaging procedure codes for identifying deep vein thrombosis (DVT) and pulmonary embolism (PE) within administrative databases. Information from the Alberta Health (AH) inpatients and ambulatory care administrative databases in Alberta, Canada was obtained for subjects with a documented imaging study result performed at a large teaching hospital in Alberta to exclude venous thromboembolism (VTE) between 2000 and 2010. In 1361 randomly-selected patients, the proportion of patients correctly classified by AH administrative data, using both ICD diagnostic codes and procedure codes, was determined for DVT and PE using diagnoses documented in patient charts as the gold standard. Of the 1361 patients, 712 had suspected PE and 649 had suspected DVT. The sensitivities for identifying patients with PE or DVT using administrative data were 74.83% (95% confidence interval [CI]: 67.01-81.62) and 75.24% (95% CI: 65.86-83.14), respectively. The specificities for PE or DVT were 91.86% (95% CI: 89.29-93.98) and 95.77% (95% CI: 93.72-97.30), respectively. In conclusion, when coupled with relevant imaging codes, VTE diagnostic codes obtained from administrative data provide a relatively sensitive and very specific method to ascertain acute VTE. PMID:25834115

  15. Nanostructured lipid carriers-based flurbiprofen gel after topical administration: acute skin irritation, pharmacodynamics, and percutaneous absorption mechanism.

    PubMed

    Song, Aihua; Su, Zhen; Li, Sanming; Han, Fei

    2015-01-01

    In order to assess the preliminary safety and effectiveness of nanostructured lipid carriers-based flurbiprofen gel (FP NLC-gel), the acute irritation test, in vivo pharmacodynamics evaluation and pharmacokinetic study were investigated after topical application. No dropsy and erythema were observed after continuous dosing 7 d of FP NLC-gel on the rabbit skin, and the xylene-induced ear drossy could be inhibited by FP NLC-gel at different dosages. The maximum concentration of FP in rats muscle was 2.03 μg/g and 1.55 μg/g after oral and topical administration, respectively. While the peak concentration in untreated muscle after topical administration was only 0.37 μg/mL. And at any time, following topical administration the mean muscle-plasma concentration ratio Cmuscle/CPlasma was obviously higher than that following oral administration. Results indicated that FP could directly penetrate into the subcutaneous muscle tissue from the administration site. Thus, the developed FP NLC-gel could be a safe and effective vehicle for topical delivery of FP.

  16. κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats.

    PubMed

    Nealey, Kathryn A; Smith, Alexander W; Davis, Seth M; Smith, Daniel G; Walker, Brendan M

    2011-01-01

    Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable

  17. Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice.

    PubMed

    Molet, Jenny; Hervé, Denis; Thiébot, Marie-Hélène; Hamon, Michel; Lanfumey, Laurence

    2013-12-01

    Convergent data showed that ethanol exposure during adolescence can alter durably ethanol-related behaviour at adulthood. However, the consequences of juvenile ethanol exposure on the reinforcing effects of other drugs of abuse remain unclear. In the present work, we evaluated in adult male DBA/2J mice the effects of early ethanol exposure on the sensitivity to the incentive effects of cocaine and morphine, and on extracellular signal-regulated kinase (ERK) activation in response to cocaine. Juvenile male mice received intragastric administration of ethanol (2×2.5g/kg/day) or water for 5 days starting on postnatal day 28. When reaching adult age (10 week-old), animals were subjected to an unbiased procedure to assess conditioned place preference (CPP) to cocaine or morphine. In addition, activation of ERK in response to an acute injection of cocaine was investigated using immunoblotting in the striatum and the nucleus accumbens. Mice that have been subjected to early ethanol exposure developed CPP to doses of cocaine (5mg/kg) or morphine (10mg/kg) below the threshold doses to induce CPP in water pre-exposed mice. In addition, early ethanol administration significantly increased striatal ERK phosphorylation normally induced by acute cocaine (10 and 20mg/kg) in adult mice. These results show that, in DBA/2J mice, early exposure to ethanol enhanced the perception of the incentive effects of cocaine and morphine. Ethanol pre-exposure also induced a positive modulation of striatal ERK signalling, in line with the inference that juvenile ethanol intake may contribute to the development of addictive behaviour at adult age. PMID:23619165

  18. Acute and chronic administration of the branched-chain amino acids decreases nerve growth factor in rat hippocampus.

    PubMed

    Scaini, Giselli; Mello-Santos, Lis Mairá; Furlanetto, Camila B; Jeremias, Isabela C; Mina, Francielle; Schuck, Patrícia F; Ferreira, Gustavo C; Kist, Luiza W; Pereira, Talita C B; Bogo, Maurício R; Streck, Emilio L

    2013-12-01

    Maple syrup urine disease (MSUD) is a neurometabolic disorder caused by deficiency of the activity of the mitochondrial enzyme complex branched-chain α-keto acid dehydrogenase leading to accumulation of the branched-chain amino acids (BCAA) and their corresponding branched-chain α-keto acids. In this study, we examined the effects of acute and chronic administration of BCAA on protein levels and mRNA expression of nerve growth factor (NGF) considering that patients with MSUD present neurological dysfunction and cognitive impairment. Considering previous observations, it is suggested that oxidative stress may be involved in the pathophysiology of the neurological dysfunction of MSUD. We also investigated the influence of antioxidant treatment (N-acetylcysteine and deferoxamine) in order to verify the influence of oxidative stress in the modulation of NGF levels. Our results demonstrated decreased protein levels of NGF in the hippocampus after acute and chronic administration of BCAA. In addition, we showed a significant decrease in the expression of ngf in the hippocampus only following acute administration in 10-day-old rats. Interestingly, antioxidant treatment was able to prevent the decrease in NGF levels by increasing ngf expression. In conclusion, the results suggest that BCAA is involved in the regulation of NGF in the developing rat. Thus, it is possible that alteration of neurotrophin levels during brain maturation could be of pivotal importance in the impairment of cognition provoked by BCAA. Moreover, the decrease in NGF levels was prevented by antioxidant treatment, reinforcing that the hypothesis of oxidative stress can be an important pathophysiological mechanism underlying the brain damage observed in MSUD. PMID:23559405

  19. The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation.

    PubMed

    Iravani, Mahmoud M; Leung, Clement C M; Sadeghian, Mona; Haddon, Claire O; Rose, Sarah; Jenner, Peter

    2005-07-01

    Sustained reactive microgliosis may contribute to the progressive degeneration of nigral dopaminergic neurons in Parkinson's disease (PD), in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposed human and in non-human primates. However, the temporal relationship between glial cell activation and nigral cell death is relatively unexplored. Consequently, the effects of acute (24 h) and chronic (30 days) glial cell activation induced by unilateral supranigral lipopolysaccharide (LPS) administration were studied in rats. At 24 h, LPS administration caused a marked reduction in the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra (SN) but striatal TH-ir was unaffected. By 30 days, the loss of TH-positive neurons in the LPS-treated nigra was no greater than at 24 h although a heterogeneous loss of striatal TH-ir was present. The loss of nigrostriatal neurons was of functional significance, as at 30 days, LPS-treated rats exhibited ipsiversive circling in response to (+)-amphetamine administration. At 24 h, there was a moderate increase in glial fibrillary acidic protein (GFAP)-ir astrocytes in the SN but a marked elevation of p47phox positive OX-42-ir microglia, and intense inducible nitric oxide synthase (iNOS)-ir and 3-nitrotyrosine (3-NT)-ir was present. However, by 30 days the morphology of OX-42-ir microglia returned to a resting state, the numbers were greatly reduced and no 3-NT-ir was present. At 30 days, GFAP-ir astrocytes were markedly increased in number and iNOS-ir was present in fibrillar astrocyte-like cells. This study shows that acute glial activation leading to dopaminergic neuron degeneration is an acute short-lasting response that does not itself perpetuate cell death or lead to prolonged microglial activation.

  20. N-Acetylcysteine Administration Prevents Nonthyroidal Illness Syndrome in Patients With Acute Myocardial Infarction: A Randomized Clinical Trial

    PubMed Central

    Vidart, Josi; Wajner, Simone Magagnin; Leite, Rogério Sarmento; Manica, André; Schaan, Beatriz D.; Larsen, P. Reed

    2014-01-01

    Context: The acute phase of the nonthyroidal illness syndrome (NTIS) is characterized by low T3 and high rT3 levels, affecting up to 75% of critically ill patients. Oxidative stress has been implicated as a causative factor of the disturbed peripheral thyroid hormone metabolism. Objective: The objective of the study was to investigate whether N-acetylcysteine (NAC), a potent intracellular antioxidant, can prevent NTIS in patients with acute myocardial infarction. Design: This was a randomized, multicenter clinical trial. Settings: Consecutive patients admitted to the emergency and intensive care units of two tertiary hospitals in southern Brazil were recruited. Patients and intervention included 67 patients were randomized to receive NAC or placebo during 48 hours. Baseline characteristics and blood samples for thyroid hormones and oxidative parameters were collected. Main Outcome: Variation of serum T3 and rT3 levels was measured. Results: Baseline characteristics were similar between groups (all P > .05). T3 levels decreased in the placebo group at 12 hours of follow-up (P = .002) but not in NAC-treated patients (P = .10). Baseline rT3 levels were elevated in both groups and decreased over the initial 48 hours in the NAC-treated patients (P = .003) but not in the control group (P = .75). The free T4 and TSH levels were virtually identical between the groups throughout the study period (P > .05). Measurement of total antioxidant status and total carbonyl content demonstrated that oxidative balance was deranged in acute myocardial infarction patients, whereas NAC corrected these alterations (P < .001). Conclusions: NAC administration prevents the derangement in thyroid hormone concentrations commonly occurring in the acute phase of acute myocardial infarction, indicating that oxidative stress is involved in the NTIS pathophysiology. PMID:25148231

  1. Acute alcohol exposure, acidemia or glutamine administration impacts amino acid homeostasis in ovine maternal and fetal plasma.

    PubMed

    Washburn, Shannon E; Sawant, Onkar B; Lunde, Emilie R; Wu, Guoyao; Cudd, Timothy A

    2013-09-01

    Fetal alcohol syndrome (FAS) is a significant problem in human reproductive medicine. Maternal alcohol administration alters maternal amino acid homeostasis and results in acidemia in both mother and fetus, causing fetal growth restriction. We hypothesized that administration of glutamine, which increases renal ammoniagenesis to regulate acid-base balance, may provide an intervention strategy. This hypothesis was tested using sheep as an animal model. On day 115 of gestation, ewes were anesthetized and aseptic surgery was performed to insert catheters into the fetal abdominal aorta as well as the maternal abdominal aorta and vena cava. On day 128 of gestation, ewes received intravenous administration of saline, alcohol [1.75 g/kg body weight (BW)/h], a bolus of 30 mg glutamine/kg BW, alcohol + a bolus of 30 mg glutamine/kg BW, a bolus of 100 mg glutamine/kg BW, alcohol + a bolus of 100 mg glutamine/kg BW, or received CO2 administration to induce acidemia independent of alcohol. Blood samples were obtained simultaneously from the mother and the fetus at times 0 and 60 min (the time of peak blood alcohol concentration) of the study. Administration of alcohol to pregnant ewes led to a reduction in concentrations of glutamine and related amino acids in plasma by 21-30%. An acute administration of glutamine to ewes, concurrent with alcohol administration, improved the profile of most amino acids (including citrulline and arginine) in maternal and fetal plasma. We suggest that glutamine may have a protective effect against alcohol-induced metabolic disorders and FAS in the ovine model.

  2. Acute and chronic alcohol administration: effects on performance of zebrafish in a latent learning task.

    PubMed

    Luchiari, Ana C; Salajan, Diana C; Gerlai, Robert

    2015-04-01

    Alcohol abuse is a major medical problem. Zebrafish have been proposed to model alcohol related human disorders. Alcohol impairs learning and memory. Here, we analyze the effects of alcohol on performance of zebrafish in a recently developed latent learning paradigm. We employ a 2×3×2 experimental design (chronic×acute alcohol treatment×path blocked). The latent learning task had two phases: one, 30min long exploration trials (16 days, 1 trial/day) with left or right path of a complex maze blocked, and two, a subsequent probe trial with all paths open leading to a goal box that now contained stimulus fish. During the 16 days each fish received one of two chronic treatments: freshwater or 0.50% (v/v%) alcohol. Subsequently, fish were immersed for 1h in one of the following solutions: 0.00 (freshwater), 0.50% or 1.00% alcohol, the acute challenge. Behavior of fish was recorded during the probe trial that commenced immediately after the acute treatment. Path choices, latency to leave the start box and to enter the goal box, time spent in the goal box, distance traveled, and duration of freezing were quantified. We found that acute exposure to 1.00% alcohol after chronic freshwater disrupted learning performance, so did exposure to freshwater after chronic alcohol treatment (withdrawal). We also found exposure to chronic alcohol to diminish the effect of subsequent acute alcohol suggesting development of tolerance. Our results demonstrate that analysis of learning performance of zebrafish allows detection of alcohol-induced functional changes. The simplicity and scalability of the employed task also imply the utility of the zebrafish in high throughput drug screens. PMID:25557800

  3. Acute and Chronic Alcohol Administration: Effects on Performance of Zebrafish in a Latent Learning Task

    PubMed Central

    Luchiari, Ana C; Salajan, Diana C; Gerlai, Robert

    2015-01-01

    Alcohol abuse is a major medical problem. Zebrafish have been proposed to model alcohol related human disorders. Alcohol impairs learning and memory. Here, we analyze the effects of alcohol on performance of zebrafish in a recently developed latent learning paradigm. We employ a 2 × 3 × 2 experimental design (chronic × acute alcohol treatment × path blocked). The latent learning task had two phases: one, 30 min long exploration trials (16 days, 1 trial/day) with left or right path of a complex maze blocked, and two, a subsequent probe trial with all paths open leading to a goal box that now contained stimulus fish. During the 16 days each fish received one of two chronic treatments: freshwater or 0.50% (vol/vol%) alcohol. Subsequently, fish were immersed for 1h in one of the following solutions: 0.00 (freshwater), 0.50 or 1.00% alcohol, the acute challange. Behavior of fish was recorded during the probe trial that commenced immediately after the acute treatment. Path choices, latency to leave the start box and to enter the goal box, time spent in the goal box, distance travelled, and duration of freezing were quantified. We found that acute exposure to 1.00% alcohol after chronic freshwater disrupted learning performance, so did exposure to freshwater after chronic alcohol treatment (withdrawal). We also found exposure to chronic alcohol to diminish the effect of subsequent acute alcohol suggesting development of tolerance. Our results demonstrate that analysis of learning performance of zebrafish allows detection of alcohol-induced functional changes. The simplicity and scalability of the employed task also imply the utility of the zebrafish in high throughput drug screens. PMID:25557800

  4. Prophylactic Administration of Silybin Ameliorates L-Arginine-Induced Acute Pancreatitis

    PubMed Central

    Uçmak, Feyzullah; Ekin, Nazım; İbiloğlu, İbrahim; Arslan, Serkan; Kaplan, İbrahim; Şenateş, Ebubekir

    2016-01-01

    Background Oxidative stress have been shown to play a role in the pathogenesis of acute pancreatitis. The aim of this study was to investigate the potential effect of silybin, a potent antioxidant, on L-arginine-induced acute pancreatitis in an experimental rat model. Material/Methods Forty female Wistar Albino rats were divided into 5 groups as follows: Group 1 (C): control group (n=8), Group 2 (SL): silybin group (n=8), Group 3 (LA): acute pancreatitis group (n=8), Group 4 (SLLA): prophylaxis group (n=8), and Group 5 (LASL): treatment group (n=8). Group C (control) received 2 intraperitoneal (i.p.) injections of physiological saline at an interval of 1 h. Group SL received only a single i.p. injection of silybin. The SLLA group received a single i.p. injection of silybin before the induction of acute pancreatitis with L-arginine, whereas the LASL group received the same injection after the induction of acute pancreatitis with L-arginine. Pancreatic tissues were histopathologically examined. Levels of amylase and oxidative stress markers (total oxidant status and total anti-oxidant status) were determined in the blood samples. Oxidative stress index was calculated. Results In comparison to the LA, the prophylaxis and treatment groups showed significant improvements in serum oxidative stress parameters (p=0.001 and p=0.005, respectively). Histopathological analysis showed that the treatment group had significant improvements in edema scores only (p=0.006), whereas the prophylaxis group had the same improvements in inflammation and necrosis scores as well as in total scores (p=0.004, 0.006, and 0.004, respectively). Conclusions When used for prophylactic rather than therapeutic purposes, silybin ameliorates serum oxidative stress parameters and improves histopathological results via its antioxidant and anti-inflammatory properties. PMID:27725627

  5. Increased Ethanol Consumption and Preference in Mice Lacking Neurotensin Receptor Type 2

    PubMed Central

    Lee, Moonnoh R.; Hinton, David J.; Unal, Sencan S.; Richelson, Elliott; Choi, Doo-Sup

    2010-01-01

    Background Neurotensin receptors (NTS) regulate a variety of the biological functions of neurotensin (NT) in the central nervous system. Although NT and NT receptor type 1 (NTS1) are implicated in some of the behavioral effects of ethanol, the functional roles of NT receptor type 2 (NTS2) in ethanol intoxication and consumption remain unknown. Here we investigated behavioral effects mediated by NTS2 in response to ethanol, which are implicated in ethanol consumption and preference, using NTS2 null mice. Method First, we examined ethanol-induced locomotion, ataxia, hypnosis, and hypothermia in NTS2 null mice. Next, we measured ethanol consumption and preference in NTS2 null mice by giving them free choice between ethanol- and tap water-containing bottles. Then using a brain-permeable neurotensin analog, NT69L, we examined the role of NTS2 in locomotor activity and ataxia. Finally, we examined the effect of NT69L on ethanol consumption and preference in NTS2 null mice. Results We found that NTS2 null mice appear less sensitive to the acute hypnotic effects of ethanol and consumed more ethanol compared to wild-type littermates in a two-bottle choice experiment, even though ethanol-induced locomotion, ataxia, and hypothermia were similar between genotypes. Interestingly, the administration of NT69L for 4 consecutive days significantly reduced alcohol consumption and preference in wild-type littermates as well as in NTS2 null mice. Conclusions Our findings suggest that NTS2 regulates ethanol-induced hypnosis and ethanol consumption. PMID:21039631

  6. Ethanol administration dampens the prolactin response to psychosocial stress exposure in sons of alcohol-dependent fathers.

    PubMed

    Zimmermann, Ulrich S; Buchmann, Arlette F; Spring, Constance; Uhr, Manfred; Holsboer, Florian; Wittchen, Hans-Ulrich

    2009-08-01

    Genetic predisposition and exposure to alcohol and stress increase the risk for alcoholism, possibly by forming a threefold interaction. This is suggested by various aspects of alcohol-induced stress response dampening in offspring of alcoholics. We tested whether such an interaction is also revealed by prolactin secretion, which is predominantly controlled by hypothalamic dopamine. Plasma prolactin was measured during four experimental days in 26 young males with a paternal history of alcoholism (PHA) and in 22 family history negative (FHN) controls. A public speaking stress paradigm was applied on the first 2 days, and a non-stress acoustic startle experiment on the others. Before the tests, subjects drank alcohol (0.6 g/kg) or placebo in a randomized, double-blind crossover design. During placebo experiments, prolactin levels significantly increased after stress, but not after startle, and did not differ between risk groups. Alcohol administration significantly increased prolactin before stress and during startle in both groups, did not alter stress-induced prolactin stimulation in FHN, but significantly attenuated the prolactin stress response in PHA subjects. The alcohol effects on prolactin, cortisol, and adrenocorticotropin stress response were positively interrelated with each other. These data confirm that alcohol specifically dampens the stress response in PHA but not FHN subjects. Since prolactin responses to stress alone and alcohol alone were normal in PHA, we conclude that this genetic effect is not related to altered physiology of the hypothalamic dopaminergic system, but to risk-group specific alcohol effects on hierarchically higher brain areas controlling the stress response in general. PMID:19243891

  7. Long-term ethanol administration enhances age-dependent modulation of redox state in central and peripheral organs of rat: protection by metadoxine.

    PubMed

    Calabrese, V; Randazzo, G; Ragusa, N; Rizza, V

    1998-01-01

    Evidence is accumulating that intermediates of oxygen reduction may be associated with the development of alcoholic disease. In addition, free radical-induced perturbation of the oxidant/antioxidant balance in cells is widely recognized as the main causative factor of age-related disorders. In the present work, we investigated the effects of 25 months of ethanol consumption on the antioxidant defense system in different organs of rat in comparison with normal aging, in the absence and presence of treatment with metadoxine, an ion pair composed of pirrolidone carboxylate and pyridoxine. We demonstrate that aged rats underwent a significant perturbation of the antioxidant defense system, as indicated by depletion of reduced glutathione (GSH) content, and increases in oxidized GSH and free radical-induced luminescence associated with a decrease of GSH reductase and an increase of GSH transferase activities. These modifications, observed particularly in the liver and brain with respect to other organs, were enhanced by long-term alcohol exposure, and interestingly, significantly reduced after metadoxine supplementation. Our results indicate that increased GSH transferase activity and decreased GSH reductase activity, followed by thiol depletion, are important factors sustaining a pathogenic role for oxidative stress in aging and in all situations where age-correlated changes occur. Administration of metadoxine greatly reduces these metabolic abnormalities. This evidence supports the pharmacological potential of metadoxine in the management of alcoholic disturbances. PMID:9675549

  8. Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions.

    PubMed

    Yamamura, Satoshi; Abe, Masao; Nakagawa, Masanori; Ochi, Shinichiro; Ueno, Shu-ichi; Okada, Motohiro

    2011-03-01

    The atypical antidepressant, mirtazapine enhances noradrenergic transmission, but its effects on serotonergic transmission remain to be clarified. The present study determined the effects of acute and chronic administration of mirtazapine on serotonergic transmissions in raphe nuclei and their innervation regions, frontal and entorhinal cortex, using multiple-probes microdialysis with real-time PCR and western blotting. Acute administration of mirtazapine did not affect extracellular serotonin level in raphe nuclei or cortex; however, chronic administration increased extracellular serotonin level in raphe nuclei without affecting that in cortex. Blockade of 5-HT1A receptor, but not that of the 5-HT2A/2C receptor, enhanced the effects of acute administration of mirtazapine on extracellular serotonin level in raphe nuclei. Chronic mirtazapine administration reduced the inhibitory function associated with somatodendritic 5-HT1A receptor in raphe nuclei, but enhanced postsynaptic 5-HT1A receptor in serotonergic innervated cortical regions. Chronic administration reduced the expression of mRNA and protein of serotonin transporter and 5-HT1A receptor in raphe nuclei, but not in the cortices. These results suggested that acute administration of mirtazapine probably activated serotonergic transmission, but its stimulatory action was abolished by activated inhibitory 5-HT1A receptor. Chronic administration of mirtazapine resulted in increased extracellular serotonin level via reduction of serotonin transporter with reduction of somatodendritic 5-HT1A autoreceptor function in raphe nuclei. These pharmacological actions of mirtazapine include its serotonergic profiles as noradrenergic and specific serotonergic antidepressant (NaSSA). PMID:21195096

  9. AMPA receptor potentiation can prevent ethanol-induced intoxication.

    PubMed

    Jones, Nicholas; Messenger, Marcus J; O'Neill, Michael J; Oldershaw, Anna; Gilmour, Gary; Simmons, Rosa M A; Iyengar, Smriti; Libri, Vincenzo; Tricklebank, Mark; Williams, Steve C R

    2008-06-01

    We present a substantial series of behavioral and imaging experiments, which demonstrate, for the first time, that increasing AMPA receptor-mediated neurotransmission via administration of potent and selective biarylsulfonamide AMPA potentiators LY404187 and LY451395 reverses the central effects of an acutely intoxicating dose of ethanol in the rat. Using pharmacological magnetic resonance imaging (phMRI), we observed that LY404187 attenuated ethanol-induced reductions in blood oxygenation level dependent (BOLD) in the anesthetized rat brain. A similar attenuation was apparent when measuring local cerebral glucose utilization (LCGU) via C14-2-deoxyglucose autoradiography in freely moving conscious rats. Both LY404187 and LY451395 significantly and dose-dependently reversed ethanol-induced deficits in both motor coordination and disruptions in an operant task where animals were trained to press a lever for food reward. Both prophylactic and acute intervention treatment with LY404187 reversed ethanol-induced deficits in motor coordination. Given that LY451395 and related AMPA receptor potentiators/ampakines are tolerated in both healthy volunteers and elderly patients, these data suggest that such compounds may form a potential management strategy for acute alcohol intoxication.

  10. Antioxidant Properties and Gastroprotective Effects of 2-(Ethylthio)Benzohydrazones on Ethanol-Induced Acute Gastric Mucosal Lesions in Rats

    PubMed Central

    Ariffin, Azhar; Abdulla, Mahmood A.; Abdullah, Zanariah

    2016-01-01

    A series of new 2-(ethylthio)benzohydrazone derivatives (1–6) were prepared and characterised by IR, 1H NMR, and 13C NMR spectroscopy and mass spectrometry. The newly prepared compounds were screened for their in vitro antioxidant activities using free radical scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Among them, most powerful antioxidant, compound 1 has been selected in order to illustrate anti-ulcer effect on ethanol-induced gastric mucosal lesions in rats. Four groups of Sprague Dawley rats were respectively treated with 10% Tween 20 as ulcer control group, 20 mg/kg omeprazole as reference group, 50 mg/kg and 100 mg/kg compound 1 as experimental animals. Macroscopically, ulcer control group showed extensive hemorrhagic lesions of gastric mucosa compared with omeprazole or compound 1. Rats pre-treated with compound 1 showed increased in gastric pH and gastric mucus. Histologically, ulcer control group showed severe damage to gastric mucosa with edema and leucocytes infiltration of submucosal layer. In immunohistochemical analysis, rats which were pre-treated with compound 1 showed up-regulation of HSP70 and down-regulation of Bax proteins. In conclusion, the gastroprotective effect of compound 1 may be due to its antioxidant activity, and/or due to up-regulation of HSP70 and down-regulation of Bax protein in stained tissue section. PMID:27272221

  11. Effects of acute or chronic administration of novel 3,4-dimethoxyphenylethylamine derivates on anxiety-like behavior

    PubMed Central

    Fedotova, Julia; Barishpolec, Victoria; Zulli, Anthony; Büsselberg, Dietrich; Gaspar, Ludovit; Kruzliak, Peter

    2015-01-01

    Novel anxiolytic medications are necessary to broaden treatment therapy. Thus, the aim of the present study was to compare the clinically effective anxiolytic, diazepam with the novel 3,4-dimethoxyphenylethylamine derivates. The novel 3,4-dimethoxyphenylethylamine derivates (PK, 0.1, 1.0, 10.0 mg/kg, i.p.) and diazepam (1.0 mg/kg) were injected acutely or chronically in animals subjected to the black-white model and the open field test. The acute administration of PK-2122 (0.1 mg/kg, i.p.) exerted anxiogenic-like effect, while in the middle or high doses PK-2122 exerted anxiolytic-like effect compared with the control group (p<0.05). The repeated treatment with PK-2111 was followed by anxiolytic-like effect in doses of 0.1 or 1.0 mg/kg which was more significant compared not only with control group, but with comparison to group treated with diazepam (p<0.05). Chronic treatment with PK-2123 or PK-2122 in all tested doses produced anxiolytic-like effect (p<0.05), compared with control group and diazepam group. These results demonstrate that PK-2126, but not PK-2122, is dose independent and may be effective in experimental model of anxiety in rats when administered acutely or repeatedly. PMID:26807191

  12. [Acute lung injury as a consequence of fresh frozen plasma administration in a patient with factor XII deficiency].

    PubMed

    San Juan-Álvarez, M; Sánchez-Zamora, P; de la Flor-Robledo, M

    2014-10-01

    Along with the complete blood count, the coagulation tests are those most demanded before a surgical procedure. The activated partial thromboplastin time (APPT) quantifies the intrinsic and common coagulation pathways, including factors XII, XI, IX, VIII, X, V and II. Factor XII deficiency is associated with a prolonged APPT and an increase in thromboembolic phenomena, without increasing the intraoperative bleeding risk. A 20 year old man with factor XII deficiency was receiving two units of fresh frozen plasma because of an APPT of 100 seconds, with the intention of normalizing it before an urgent surgery procedure, and the fear of intraoperative bleeding. An hour after starting the transfusion the patient developed an acute lung injury (ALI) compatible with the diagnosis of a transfusion related acute lung injury (TRALI). The surgery continued without complications, and the patient was admitted to the resuscitation unit for 72 h, needing respiratory support. If the APTT is prolonged in the absence of bleeding, the presence of a non-specific circulating anticoagulant, a deficiency of factor XI, XII and VIII (associated to Von Willebrand disease) must be ruled out. Therefore, in the case presented here, the administration of hemoderivatives was unnecessary and can have consequences as serious as the one that the patient presented, a transfusion related acute lung injury.

  13. Differences in the effect of chronic and acute caffeine on self-administration of cocaine in mice.

    PubMed

    Kuzmin, A; Johansson, B; Semenova, S; Fredholm, B B

    2000-08-01

    We have compared the ability of an acute injection of caffeine (3 mg/kg, i.p.) and long-term peroral caffeine consumption for 10 days ( approximately 150 mg/kg/day in tap water) to affect cocaine self-administration in mice. The peak plasma and brain levels of caffeine and its metabolites were similar in the two experimental set-ups. Moreover, the levels reached are close to those obtained in humans upon coffee ingestion. Neither type of caffeine administration affected the reinforcing effect of cocaine, defined as a selective increase in nose-poke responses in mice self-administering cocaine compared to their yoked controls. However, caffeine injection increased the amount of cocaine self-administered whereas caffeine drinking reduced it. A low dose of cocaine, by itself essentially ineffective, produced an increase in c-fos and NGFI-A mRNA in the cerebral cortex in mice that had been drinking caffeine. An acute caffeine injection also enhanced the immediate early gene response to cocaine, but to a lesser degree. Cocaine and caffeine also synergistically increased NGFI-A expression in caudate-putamen. Thus, regular caffeine drinking decreased the cocaine intake without significantly affecting its reinforcing properties, perhaps because it enhanced the activation of the predominantly inhibitory frontal cortical areas produced by low doses of cocaine. PMID:10971643

  14. Acute corticosterone administration during meiotic segregation stimulates females to produce more male offspring.

    PubMed

    Pinson, Sara E; Parr, Christina M; Wilson, Jeanna L; Navara, Kristen J

    2011-01-01

    Birds have demonstrated a remarkable ability to manipulate offspring sex. Previous studies suggest that treatment with hormones can stimulate females to manipulate offspring sex before ovulation. For example, chronic treatments with corticosterone, the primary stress hormone produced by birds, stimulated significant skews toward female offspring. It has been suggested that corticosterone acts by influencing which sex chromosome is donated by the heterogametic female bird into the ovulated ovarian follicle. However, it is difficult to pinpoint when in developmental time corticosterone affects offspring sex, because in previous studies corticosterone treatment was given over a long period of time. We treated laying hens with acute high-dose corticosterone injections 5 h before the predicted time of ovulation and quantified the sexes of the subsequently ovulated eggs to determine whether mechanisms exist by which corticosterone can skew offspring sex ratios just before ovulation. We hypothesized that an injection of corticosterone coincident with segregation of the sex chromosomes would stimulate hens to produce more female than male offspring. Contrary to our predictions, hens injected with corticosterone produced a significant bias toward male offspring, nearly 83%. These results suggest that acute corticosterone treatment during meiosis I can influence primary sex ratios in birds, potentially through nonrandom chromosome segregation. Furthermore, acute corticosterone exposure, compared with chronic exposure, may act through different mechanisms to skew offspring sex.

  15. Differential modulation of antipredator defensive behavior in Swiss-Webster mice following acute or chronic administration of imipramine and fluoxetine.

    PubMed

    Griebel, G; Blanchard, D C; Agnes, R S; Blanchard, R J

    1995-07-01

    The Mouse Defense Test Battery (MDTB) has been designed to assess defensive reactions in Swiss-Webster mice to situations associated with a natural predator, the rat. Primary measures taken before, during and after predator confrontation comprise escape attempts, predator assessment, defensive attack and flight. Previous reports from this laboratory have shown that the panic-promoting drug yohimbine potentiated flight behavior, while long-term treatment with the panicolytic agent alprazolam reduced this response. In order to evaluate further the possibility that the MDTB may represent an effective animal model of panic attacks, the present study investigated the behavioral effect of imipramine and fluoxetine, two serotonin reuptake inhibitors (SRIs) known to alleviate panic symptoms when given on a repeated basis. Both drugs were administered acutely and chronically (one daily IP injection for 21 days) at 5, 10 and 15 mg/kg. Our results showed that a single dose of imipramine or fluoxetine strongly potentiated flight reactions in response to an approaching predator and increased defensive attack toward the rat. This was in contrast to chronic treatment with each drug which dramatically decreased flight responses and defensive attack behaviors. In addition, long-term administration with both SRIs produced a reliable attenuation of predator assessment activities. Taken together, these findings suggest an acute anxiogenic-like effect of imipramine and fluoxetine followed by a fear/anxiety reducing effect after repeated administrations. These results support clinical observations revealing an acute anxiogenic effect of SRIs followed by an anxiolytic and/or panicolytic effect after chronic use, and support previous results suggesting that the MDTB may be useful for the investigation of panic-modulating agents.

  16. Acute Administration of Branched-Chain Amino Acids Increases the Pro-BDNF/Total-BDNF Ratio in the Rat Brain.

    PubMed

    Scaini, Giselli; Morais, Meline O S; Furlanetto, Camila B; Kist, Luiza W; Pereira, Talita C B; Schuck, Patrícia F; Ferreira, Gustavo C; Pasquali, Matheus A B; Gelain, Daniel P; Moreira, José Cláudio F; Bogo, Maurício R; Streck, Emilio L

    2015-05-01

    Maple syrup urine disease (MSUD) is caused by an inborn error in metabolism resulting from a deficiency in the branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine, as well as their corresponding α-keto acids and α-hydroxy acids. High levels of BCAAs are associated with neurological dysfunction and the role of pro- and mature brain-derived neurotrophic factor (BDNF) in the neurological dysfunction of MSUD is still unclear. Thus, in the present study we investigated the effect of an acute BCAA pool administration on BDNF levels and on the pro-BDNF cleavage-related proteins S100A10 and tissue plasminogen activator (tPA) in rat brains. Our results demonstrated that acute Hyper-BCAA (H-BCAA) exposure during the early postnatal period increases pro-BDNF and total-BDNF levels in the hippocampus and striatum. Moreover, tPA levels were significantly decreased, without modifications in the tPA transcript levels in the hippocampus and striatum. On the other hand, the S100A10 mRNA and S100A10 protein levels were not changed in the hippocampus and striatum. In the 30-day-old rats, we observed increased pro-BDNF, total-BDNF and tPA levels only in the striatum, whereas the tPA and S100A10 mRNA expression and the immunocontent of S100A10 were not altered. In conclusion, we demonstrated that acute H-BCAA administration increases the pro-BDNF/total-BDNF ratio and decreases the tPA levels in animals, suggesting that the BCAA effect may depend, at least in part, on changes in BDNF post-translational processing. PMID:25681161

  17. Ethanol extract of Synurus deltoides (Aiton) Nakai suppresses in vitro LPS-induced cytokine production in RAW 264.7 macrophages and in vivo acute inflammatory symptoms

    PubMed Central

    Jiang, Yunyao

    2014-01-01

    Synurus deltoides (Aiton) Nakai, belonging to the Compositae family, is an edible plant widely distributed in Northeast Asia. In this study, we examined the mechanisms underlying the immunomodulative effects of the ethanol extract of S. deltoides (SDE). The SDE extract strongly down-regulated the mRNA expression of the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and tumour necrosis factor (TNF)-α, thereby inhibiting the production of nitric oxide (NO), prostaglandin E2 (PGE2), and TNF-α in the lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Furthermore, SDE also suppressed the nuclear translocation of the activation protein (AP)-1 and the nuclear factor-κB (NF-κB), and simultaneously decreased the phosphorylation of extracellular signal-regulated protein kinases (ERK), p38, and Akt. In agreement with the in vitro observations, the orally administered SDE ameliorated the acute inflammatory symptoms in the arachidonic acid-induced ear edema and the EtOH/HCl-induced gastritis in mice. Therefore, S. deltoides have a potential anti-inflammatory capacity in vitro and in vivo, suggesting the potential therapeutic use in the inflammation-associated disorders. PMID:24611100

  18. Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex.

    PubMed

    Geng, Kai-Wen; He, Ting; Wang, Rui-Rui; Li, Chun-Li; Luo, Wen-Jun; Wu, Fang-Fang; Wang, Yan; Li, Zhen; Lu, Yun-Fei; Guan, Su-Min; Chen, Jun

    2016-10-01

    Ethanol is widely known for its ability to cause dramatic changes in emotion, social cognition, and behavior following systemic administration in humans. Human neuroimaging studies suggest that alcohol dependence and chronic pain may share common mechanisms through amygdala-medial prefrontal cortex (mPFC) interactions. However, whether acute administration of ethanol in the mPFC can modulate pain perception is unknown. Here we showed that bilateral microinjections of ethanol into the prelimbic and infralimbic areas of the mPFC lowered the bilateral mechanical pain threshold for 48 h without influencing thermal pain sensitivity in adult rats. However, bilateral microinjections of artificial cerebrospinal fluid into the mPFC or bilateral microinjections of ethanol into the dorsolateral PFC (also termed as motor cortex area 1 in Paxinos and Watson's atlas of The Rat Brain. Elsevier Academic Press, Amsterdam, 2005) failed to do so, suggesting regional selectivity of the effects of ethanol. Moreover, bilateral microinjections of ethanol did not change the expression of either pro-apoptotic (caspase-3 and Bax) or anti-apoptotic (Bcl-2) proteins, suggesting that the dose was safe and validating the method used in the current study. To determine whether γ-aminobutyric acid A (GABAA) receptors are involved in mediating the ethanol effects, muscimol, a selective GABAA receptor agonist, or bicuculline, a selective GABAA receptor antagonist, was administered alone or co-administered with ethanol through the same route into the bilateral mPFC. The results showed that muscimol mimicked the effects of ethanol while bicuculline completely reversed the effects of ethanol and muscimol. In conclusion, ethanol increases mechanical pain sensitivity through activation of GABAA receptors in the mPFC of rats. PMID:27628528

  19. Effect of acute treatment with cadmium on ethanol anesthesia, body termperature, and synaptosomal Na/sup +/-K/sup +/-ATPase of rat brain

    SciTech Connect

    Magour, S.; Kristof, V.; Baumann, M.; Assmann, G.

    1981-12-01

    The effect of a single intraperitoneal dose of 0.56, 1.12, and 1.68 mg cadmium/kg on the duration of ethanol-induced sleep was investigated in male rats. Cadmium potentiated ethanol sleeping time in a dose dependent manner up to 300% over controls. No significant difference in the elimination rate of ethanol from blood and brain and observed between control and cadmium-pretreated rats. Cadmium slightly inhibited the hepatic alcohol dehydrogenase in vivo and also potentiated ethanol hypothermia but these changes did not play a significant role in the observed prolongation of ethanol sleeping time. However, cadmium and ethanol additively inhibited brain synaptosomal Na/sup +/-K/sup +/-ATPase in a noncompetitive manner. The results so far indicate that cadmium may increase brain responsiveness toward ethanol partly through inhibition of snaptosomal Na/sup +/-K/sup +/-ATPase.

  20. Effects of oral acute administration and subchronic feeding of several levels of D-psicose in rats.

    PubMed

    Matsuo, Tatsuhiro; Tanaka, Tomohiro; Hashiguchi, Mineo; Izumori, Ken; Suzuki, Hiroo

    2002-12-01

    The effects of oral acute administration and subchronic (34 d) feeding of several levels of D-psicose, a C3-epimer of D-fructose, were studied in rats. In the acute administration test, five groups of eight male Wistar rats (3 wk old) were orally given D-psicose in doses of 8, 11, 14, 17, and 20 g/kg. Three rats receiving 14 g/kg, three rats receiving 17 g/kg and eight rats receiving 20 g/kg of D-psicose died within 2 d after administration. The calculated LD50 values were 16.3 g/kg by the Behrens-Karber method and 15.8 g/kg by the Litchfield-Wilcoxon method. In the subcronic feeding test, eight groups of seven male Wistar rats (3 wk old) were fed diets containing 0 (control), 10, 20, 30, and 40% for 34 d. One rat fed 30% D-psicose diet and five rats fed 40% D-psicose diet died during the experimental period. Body weight gain, food intake and food efficiency were more extensively suppressed by the higher D-psicose diets. The weights of heart, spleen and abdominal adipose tissue were smaller in the order of dietary D-psicose concentration. Cecal weight increased with increasing D-psicose concentration in the diets. Cecal hypertrophy was observed in rats fed 10-40% D-psicose diets. These results suggest that D-psicose differs in nutritional characteristics from D-glucose or D-fructose. The feeding of diets extremely high in D-psicose seems to be harmful to the intestinal tract.

  1. Ethanol Blocks Long-Term Potentiation of GABAergic Synapses in the Ventral Tegmental Area Involving μ-Opioid Receptors

    PubMed Central

    Guan, Yan-zhong; Ye, Jiang-Hong

    2010-01-01

    It is well documented that ethanol exposure alters GABA (γ-aminobutyric acid)-releasing synapses, and ethanol addiction is associated with endogenous opioid system. Emerging evidence indicates that opioids block long-term potentiation in the fast inhibitory GABAA receptor synapses (LTPGABA) onto dopamine-containing neurons in the ventral tegmental area (VTA), a brain region essential for reward-seeking behavior. However, how ethanol affects LTPGABA is not known. We report here that in acute midbrain slices from rats, clinically relevant concentrations of ethanol applied both in vitro and in vivo prevents LTPGABA, which is reversed, respectively, by in vitro and in vivo administration of naloxone, a μ-opioid receptor (MOR) antagonist. Furthermore, the blockade of LTPGABA induced by a brief in vitro ethanol treatment is mimicked by DAMGO ([-Ala2, N-MePhe4, Gly-ol]-enkephalin), a MOR agonist. Paired-pulse ratios are similar in slices, 24 h after in vivo injection with either saline or ethanol. Sp-cAMPS, a stable cAMP analog, and pCPT-cGMP, a cGMP analog, potentiates GABAA-mediated inhibitory postsynaptic currents in slices from ethanol-treated rats, indicating that a single in vivo ethanol exposure does not maximally increase GABA release, instead, ethanol produces a long-lasting inability to generate LTPGABA. These neuroadaptations to ethanol might contribute to early stage of addiction. PMID:20393452

  2. Ethanol Metabolism and Osmolarity Modify Behavioral Responses to Ethanol in C. elegans

    PubMed Central

    Alaimo, Joseph T.; Davis, Scott J.; Song, Sam S.; Burnette, Christopher R.; Grotewiel, Mike; Shelton, Keith L.; Pierce-Shimomura, Jonathan T.; Davies, Andrew G.; Bettinger, Jill C.

    2012-01-01

    Background Ethanol is metabolized by a two-step process in which alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase (ALDH). Although variation in ethanol metabolism in humans strongly influences the propensity to chronically abuse alcohol, few data exist on the behavioral effects of altered ethanol metabolism. Here, we used the nematode C. elegans to directly examine how changes in ethanol metabolism alter behavioral responses to alcohol during an acute exposure. Additionally, we investigated ethanol solution osmolarity as a potential explanation for contrasting published data on C. elegans ethanol sensitivity. Methods We developed a gas chromatography assay and validated a spectrophotometric method to measure internal ethanol in ethanol-exposed worms. Further, we tested the effects of mutations in ADH and ALDH genes on ethanol tissue accumulation and behavioral sensitivity to the drug. Finally, we tested the effects of ethanol solution osmolarity on behavioral responses and tissue ethanol accumulation. Results Only a small amount of exogenously applied ethanol accumulated in the tissues of C. elegans and consequently their tissue concentrations were similar to those that intoxicate humans. Independent inactivation of an ADH-encoding gene (sodh-1) or an ALDH-encoding gene (alh-6 or alh-13) increased the ethanol concentration in worms and caused hypersensitivity to the acute sedative effects of ethanol on locomotion. We also found that the sensitivity to the depressive effects of ethanol on locomotion is strongly influenced by the osmolarity of the exogenous ethanol solution. Conclusions Our results indicate that ethanol metabolism via ADH and ALDH has a statistically discernable but surprisingly minor influence on ethanol sedation and internal ethanol accumulation in worms. In contrast, the osmolarity of the medium in which ethanol is delivered to the animals has a more substantial effect on

  3. Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

    PubMed

    Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

    2015-04-01

    Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration.

  4. Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

    PubMed

    Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

    2015-04-01

    Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. PMID:25820086

  5. Ethanol poisoning

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002644.htm Ethanol poisoning To use the sharing features on this page, please enable JavaScript. Ethanol poisoning is caused by drinking too much alcohol. ...

  6. Impairment of Electron Transfer Chain Induced by Acute Carnosine Administration in Skeletal Muscle of Young Rats

    PubMed Central

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I–III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α, and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I–III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α, and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  7. Impairment of electron transfer chain induced by acute carnosine administration in skeletal muscle of young rats.

    PubMed

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I-III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α , and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I-III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α , and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  8. Alterations in attentional mechanisms in response to acute inflammatory pain and morphine administration.

    PubMed

    Boyette-Davis, J A; Thompson, C D; Fuchs, P N

    2008-01-24

    Research indicates that pain negatively impacts attention; however, the extent of this impact and the mechanisms of the effect of pain on normal attentional processing remain unclear. This study 1) examined the impact of acute inflammatory pain on attentional processing, 2) examined the impact of morphine on attentional processing, and 3) determined if an analgesic dose of morphine would return attentional processing to normal levels. Male Sprague-Dawley rats were trained on the 5 choice serial reaction time task (5CSRTT), a test commonly used to assess the attentional mechanisms of rodents. Animals were injected with saline or 1, 3, or 6 mg/kg of morphine. Twenty minutes later, animals received a formalin (or saline) injection into one hind paw to induce an inflammatory condition and were then immediately tested in the 5CSRTT. The results show that the formalin injection significantly impaired performance, as measured by an increase in the number of trials in which the animal failed to attend to the task. Likewise, a high dose of morphine (6 mg/kg) produced similar decrements in task performance. Of primary importance is that 3 mg/kg of morphine produced analgesia with only mild sedation, and performance in the 5CSRTT was improved with this dose. This is the first study to use an animal model of acute pain to demonstrate the negative impact of pain on attention, and provides a novel approach to examine the neural correlates that underlie the disruptive impact of pain on attention.

  9. Acute administration of diosgenin or dioscorea improves hyperglycemia with increases muscular steroidogenesis in STZ-induced type 1 diabetic rats.

    PubMed

    Sato, K; Fujita, S; Iemitsu, M

    2014-09-01

    Acute dehydroepiandrosterone (DHEA) administration improves hyperglycemia in rats with streptozotocin (STZ)-induced type 1 diabetes mellitus. Diosgenin, a steroid structurally similar to DHEA (dehydroepiandrosterone), is contained highly levels in dioscorea; however, it is still unclear whether this natural product improves hyperglycemia in the type 1 diabetes model rats through an increase muscular GLUT4 signaling. After 1 week of STZ injection, fasting glucose level was measured in blood taken from the tail vein every 30 min for 150 min after injection of diosgenin or dioscorea (3mg/kg). On another day, muscle was resected 150 min after diosgenin or dioscorea injections. Serum DHEA level increased significantly 120 min after diosgenin or dioscorea injections; concomitantly, blood glucose level decreased significantly. Moreover, GLUT4 translocation, as well as phosphorylation of Akt and PKC ζ/λ, increased significantly by diosgenin or dioscorea administration. However, these effects of diosgenin and dioscorea were blocked by a 5α-reductase inhibitor that inhibits synthesizing dehydrotestosterone (DHT) from testosterone. Additionally, significant correlations were observed between blood glucose level, GLUT4 translocation level, and muscular sex steroid hormone level 150 min after the administrations. These results suggest that the diosgenin-induced increase in the DHEA level may contribute to the improvement of hyperglycemia by activating the muscular GLUT4 signaling pathway in type 1 diabetes model rats.

  10. Time-course of changes in the social interaction test of anxiety following acute and chronic administration of nicotine.

    PubMed

    Irvine, E E; Cheeta, S; File, S E

    1999-11-01

    The purpose of these experiments was to explore the hypothesis that the effects of nicotine on anxiety depend on the time since administration and the duration of treatment. In the social interaction test of anxiety, acute nicotine administration (0.1 mg/kg, subcutaneously) decreased social interaction when rats were tested 5 min after injection, but increased it when they were tested 30 min after injection. Social interaction was also decreased 1 h post-injection, but levels returned to baseline between 3 and 30 h. As these changes were independent of any changes in locomotor activity, nicotine seemed to be having both anxiogenic and anxiolytic effects at different times after injection. An anxiolytic effect was also observed 30 min after the second nicotine injection, and the anxiogenic effect observed 5 min after injection remained after 4 days of nicotine administration. However, after 7 days of nicotine treatment, tolerance was observed to both these effects. When rats were tested 72 h after the last of 7 or 14 days of nicotine treatment, an anxiogenic withdrawal response was observed. Thus, an oppositional mechanism may underlie tolerance to the anxiolytic effects, whereas there is as yet no evidence for this type of mechanism mediating tolerance to the anxiogenic effects.

  11. Conessine, an H3 receptor antagonist, alters behavioral and neurochemical effects of ethanol in mice.

    PubMed

    Morais-Silva, Gessynger; Ferreira-Santos, Mariane; Marin, Marcelo T

    2016-05-15

    Ethanol abuse potential is mainly due to its reinforcing properties, crucial in the transition from the recreational to pathological use. These properties are mediated by mesocorticolimbic and nigrostriatal dopaminergic pathways and neuroadaptations in these pathways seem to be responsible for addiction. Both pathways are modulated by other neurotransmitters systems, including neuronal histaminergic system. Among the histamine receptors, H3 receptor stands out due to its role in modulation of histamine and other neurotransmitters release. Thus, histaminergic system, through H3 receptors, may have an important role in ethanol addiction development. Aiming to understand these interactions, conessine, an H3 receptor antagonist, was given to mice subjected to the evaluation of ethanol-induced psychostimulation, ethanol CPP and quantification of norepinephrine, dopamine, serotonin and their metabolites in mesocorticolimbic and nigrostriatal pathways following acute ethanol treatment. Systemic conessine administration exacerbated ethanol effects on locomotor activity. Despite of conessine reinforcing effect on CPP, this drug did not alter acquisition of ethanol CPP. Ethanol treatment affects the serotoninergic neurotransmission in the ventral tegmental area, the dopaminergic neurotransmission in the pre-frontal cortex (PFC) and caudate-putamen nucleus (CPu) and the noradrenergic neurotransmission in the CPu. In the PFC, conessine blocked ethanol effects on dopaminergic and noradrenergic neurotransmission. The blockade of H3 receptors and ethanol seem to interact in the modulation of dopaminergic neurotransmission of nigrostriatal pathway, decreasing dopamine metabolites in substantia nigra. In conclusion, conessine was able to change psychostimulant effect of ethanol, without altering its reinforcing properties. This exacerbation of ethanol-induced psychostimulation would be related to alterations in dopaminergic neurotransmission in the nigrostriatal pathway. PMID

  12. The effect of acute ethanol (EtOH) exposure on protein kinase C (PKC) activity in anterior pituitary.

    PubMed

    Steiner, J; Kirsteins, L; LaPaglia, N; Lawrence, A; Williams, D; Emanuele, N; Emanuele, M

    1997-01-01

    Alterations in the protein kinase C (PKC) pathway may interrupt anterior pituitary luteinizing hormone (LH) synthesis and/or secretion, which may impair normal reproductive function. Work by our laboratory and others has shown that EtOH has profound deleterious effects on the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. The present study focuses on PKC translocation from the cytosol to the membrane of anterior pituitary after acute EtOH exposure. Serum levels of LH were measured at three time points (15, 30, and 90 min) after an IP injection of either saline or 3 g/kg EtOH in adult castrated male rats. LH levels dropped significantly (p < 0.03) in EtOH-injected compared to saline-injected control animals. In the same animals, EtOH significantly suppressed PKC localization at its active site at the pituitary cell membrane (p < 0.05). These findings suggest that the mechanism of EtOH's suppression of LH is mediated, at least in part, through a decrease in PKC translocation to the anterior pituitary cell membrane.

  13. Ethanol Basics

    SciTech Connect

    2015-01-30

    Ethanol is a widely-used, domestically-produced renewable fuel made from corn and other plant materials. More than 96% of gasoline sold in the United States contains ethanol. Learn more about this alternative fuel in the Ethanol Basics Fact Sheet, produced by the U.S. Department of Energy's Clean Cities program.

  14. Ethanol Production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This book chapter reviews the current process technologies for fuel ethanol production. In the US, almost all commercial fuel ethanol is produced from corn whereas cane sugar is used almost exclusively in Brazil. In Europe, two major types of feedstock considered for fuel ethanol production are be...

  15. Neuroprotection & mechanism of ethanol in stroke and traumatic brain injury therapy: new prospects for an ancient drug.

    PubMed

    Asmaro, Karam; Fu, Paul; Ding, Yuchuan

    2013-01-01

    Effective efforts to screen for agents that protect against the devastating effects of stroke have not produced viable results thus far. As a result this article reviews the possible role of ethanol as a neuroprotective agent in stroke and traumatic brain injury (TBI). Previous studies have associated ethanol consumption with a decreased risk of ischemic stroke, suggesting a neuroprotective mechanism. The translation of this clinical knowledge into basic science research with the goal of new therapy for acute stroke patients remains in its initial stages. In a recent study involving rats, we have shown that ethanol administration, in the correct dose after stroke onset, protects against ischemia-induced brain injury. The purpose of this paper is to discuss ethanol's neuroprotective properties in stroke when consumed as a preconditioning agent, in TBI with a positive blood alcohol content, and finally in stroke treatment, with the goal of using post-ischemia ethanol (PIE) therapy to ameliorate brain damage in the future.

  16. 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.

  17. Sequential Administration of Methotrexate and Asparaginase in Relapsed or Refractory Pediatric Acute Myeloid Leukemia

    PubMed Central

    Buaboonnam, Jassada; Cao, Xueyuan; Pauley, Jennifer L.; Pui, Ching-Hon; Ribeiro, Raul C.; Rubnitz, Jeffrey E.; Inaba, Hiroto

    2014-01-01

    Background The efficacy of combination chemotherapy with methotrexate (MTX) and asparaginase is not well known in relapsed and refractory acute leukemia after contemporary therapy. Procedure A retrospective study of pediatric patients with relapsed or refractory acute myeloid leukemia (AML) who received MTX and asparaginase as a salvage therapy at St. Jude Children Research Hospital was performed. MTX was given intravenously followed by a dose of asparaginase intramuscularly or intravenously 24 hours later. The chemotherapy cycle was repeated every 7-10 days. Response, survival, and toxicities were evaluated. Results Fifteen patients, median age 10.5 years (range, 1.1-18.5 years), were treated. Median number of previous therapeutic regimens was 3 (range, 1-4). Six patients responded to treatment (3 had morphologic complete remission with incomplete blood count recovery, 2 had partial remission, and 1 had stable disease for 16 months), and 4 are still alive. Three of 6 responders had monoblastic leukemia, and also developed tumor lysis syndrome. The 1- and 2-year overall survival rates are 35.6% and 17.8%, respectively. The most common adverse event was transient elevation of transaminases (9 patients). Two patients developed pancreatitis. Episodes of febrile neutropenia were rare (2 patients), and most courses (75 out of 93 total courses) were given in an outpatient setting. Conclusions Combination chemotherapy with MTX and asparaginase appears to be an effective salvage therapy and well tolerated in patients with relapsed or refractory childhood AML, even in those heavily pretreated with contemporary frontline or salvage therapy. PMID:23335430

  18. Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia

    PubMed Central

    Kraft, Bryan D.; Hess, Dean R.; Harris, R. Scott; Wolf, Monroe A.; Suliman, Hagir B.; Roggli, Victor L.; Davies, John D.; Winkler, Tilo; Stenzler, Alex; Baron, Rebecca M.; Thompson, B. Taylor; Choi, Augustine M.; Welty-Wolf, Karen E.; Piantadosi, Claude A.

    2015-01-01

    Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically relevant baboon model of Streptococcus pneumoniae pneumonia to 1) test a novel, ventilator-compatible CO delivery system; 2) establish a safe and effective CO dosing regimen; and 3) investigate the local and systemic effects of CO therapy on inflammation and acute lung injury (ALI). Animals were inoculated with S. pneumoniae (108-109 CFU) (n = 14) or saline vehicle (n = 5); in a subset with pneumonia (n = 5), we administered low-dose, inhaled CO gas (100–300 ppm × 60–90 min) at 0, 6, 24, and/or 48 h postinoculation and serially measured blood carboxyhemoglobin (COHb) levels. We found that CO inhalation at 200 ppm for 60 min is well tolerated and achieves a COHb of 6–8% with ambient CO levels ≤ 1 ppm. The COHb level measured at 20 min predicted the 60-min COHb level by the Coburn-Forster-Kane equation with high accuracy. Animals given inhaled CO + antibiotics displayed significantly less ALI at 8 days postinoculation compared with antibiotics alone. Inhaled CO was associated with activation of mitochondrial biogenesis in the lung and with augmentation of renal antioxidative programs. These data support the feasibility of safely delivering inhaled CO gas during mechanical ventilation and provide preliminary evidence that CO may accelerate the resolution of ALI in a clinically relevant nonhuman primate pneumonia model. PMID:26320156

  19. Acute and chronic caffeine administration increases physical activity in sedentary adults.

    PubMed

    Schrader, Patrick; Panek, Leah M; Temple, Jennifer L

    2013-06-01

    Caffeine is a commonly used stimulant thought to have ergogenic properties. Most studies on the ergogenic effects of caffeine have been conducted in athletes. The purpose of this study was to test the hypothesis that caffeine reduces ratings of perceived exertion and increases liking of physical activity in sedentary adults. Participants completed treadmill walking at 60% to 70% of their maximal heart rate at baseline and for 6 subsequent visits, during which half of the participants were given caffeine (3 mg/kg) and half given placebo in a sports drink vehicle. To investigate the potential synergistic effects of acute and chronic caffeine on self-determined exercise duration, participants were rerandomized to either the same or different condition for the last visit, creating 4 chronic/acute treatment groups (placebo/placebo, placebo/caffeine, caffeine/placebo, caffeine/caffeine). Participants rated how much they liked the activity and perceived exertion at each visit. There was a main effect of time on liking of physical activity, with liking increasing over time and an interaction of sex and caffeine treatment on liking, with liking of activity increasing in female participants treated with caffeine, but not with placebo. There was no effect of caffeine on ratings of perceived exertion. Individuals who received caffeine on the final test day exercised for significantly longer than those who received placebo. These data suggest that repeated exposure to physical activity significantly increases liking of exercise and reduces ratings of perceived exertion and that caffeine does little to further modify these effects.

  20. Effects of Intracoronary Administration of Autologous Adipose Tissue-Derived Stem Cells on Acute Myocardial Infarction in a Porcine Model

    PubMed Central

    Lee, Hye Won; Park, Jong Ha; Kim, Bo Won; Ahn, Jinhee; Kim, Jin Hee; Park, Jin Sup; Oh, Jun-Hyok; Choi, Jung Hyun; Cha, Kwang Soo; Hong, Taek Jong; Park, Tae Sik; Kim, Sang-Pil; Song, Seunghwan; Kim, Ji Yeon; Park, Mi Hwa; Jung, Jin Sup

    2015-01-01

    Purpose Adipose-derived stem cells (ADSCs) are known to be potentially effective in regeneration of damaged tissue. We aimed to assess the effectiveness of intracoronary administration of ADSCs in reducing the infarction area and improving function after acute transmural myocardial infarction (MI) in a porcine model. Materials and Methods ADSCs were obtained from each pig's abdominal subcutaneous fat tissue by simple liposuction. After 3 passages of 14-days culture, 2 million ADSCs were injected into the coronary artery 30 min after acute transmural MI. At baseline and 4 weeks after the ADSC injection, 99mTc methoxyisobutylisonitrile-single photon emission computed tomography (MIBI-SPECT) was performed to evaluate the left ventricular volume, left ventricular ejection fraction (LVEF; %), and perfusion defects as well as the myocardial salvage (%) and salvage index. At 4 weeks, each pig was sacrificed, and the heart was extracted and dissected. Gross and microscopic analyses with specific immunohistochemistry staining were then performed. Results Analysis showed improvement in the perfusion defect, but not in the LVEF in the ADSC group (n=14), compared with the control group (n=14) (perfusion defect, -13.0±10.0 vs. -2.6±12.0, p=0.019; LVEF, -8.0±15.4 vs. -15.9±14.8, p=0.181). There was a tendency of reducing left ventricular volume in ADSC group. The ADSCs identified by stromal cell-derived factor-1 (SDF-1) staining were well co-localized by von Willebrand factor and Troponin T staining. Conclusion Intracoronary injection of cultured ADSCs improved myocardial perfusion in this porcine acute transmural MI model. PMID:26446632

  1. Ethanol induction of steroidogenesis in rat adrenal and brain is dependent upon pituitary ACTH release and de novo adrenal StAR synthesis

    PubMed Central

    Boyd, Kevin N.; Kumar, Sandeep; O'Buckley, Todd K.; Porcu, Patrizia; Morrow, A. Leslie

    2011-01-01

    The mechanisms of ethanol actions that produce its behavioral sequelae involve the synthesis of potent GABAergic neuroactive steroids, specifically the GABAergic metabolites of progesterone, (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP), and deoxycorticosterone, (3α,5α)-3,21-dihydroxypregnan-20-one. We investigated the mechanisms that underlie the effect of ethanol on adrenal steroidogenesis. We found that ethanol effects on plasma pregnenolone, progesterone, 3α,5α-THP and cortical 3α,5α-THP are highly correlated, exhibit a threshold of 1.5 g/kg, but show no dose dependence. Ethanol increases plasma adrenocorticotropic hormone (ACTH), adrenal steroidogenic acute regulatory protein (StAR), and adrenal StAR phosphorylation, but does not alter levels of other adrenal cholesterol transporters. The inhibition of ACTH release, de novo adrenal StAR synthesis or cytochrome P450 side chain cleavage activity prevents ethanol-induced increases in GABAergic steroids in plasma and brain. ACTH release and de novo StAR synthesis are independently regulated following ethanol administration and both are necessary, but not sufficient, for ethanol-induced elevation of plasma and brain neuroactive steroids. As GABAergic steroids contribute to ethanol actions and ethanol sensitivity, the mechanisms of this effect of ethanol may be important factors that contribute to the behavioral actions of ethanol and risk for alcohol abuse disorders. PMID:20021565

  2. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9.

    PubMed

    Zhang, Lemeng; Deng, Songyun; Zhao, Shuangping; Ai, Yuhang; Zhang, Lina; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong

    2016-01-01

    The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner. PMID:27589725

  3. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9

    PubMed Central

    Zhang, Lemeng; Deng, Songyun; Zhao, Shuangping; Ai, Yuhang; Zhang, Lina; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong

    2016-01-01

    The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner. PMID:27589725

  4. Involvement of ceramide in ethanol-induced apoptotic neurodegeneration in the neonatal mouse brain

    PubMed Central

    Saito, Mariko; Chakraborty, Goutam; Hegde, Medha; Ohsie, Jason; Paik, Sun-Mee; Vadasz, Csaba; Saito, Mitsuo

    2010-01-01

    Acute administration of ethanol to 7-day-old mice is known to cause robust apoptotic neurodegeneration in the brain. Our previous studies have shown that such ethanol-induced neurodegeneration is accompanied by increases in lipids including ceramide, triglyceride, cholesterol ester, and N-acyl phosphatidylethanolamine in the brain. In this study, the effects of ethanol on lipid profiles as well as caspase-3 activation were examined in the cortex, hippocampus, cerebellum, and inferior colliculus of the P7 mouse brain. We found that the cortex, hippocampus, and inferior colliculus, which showed substantial caspase-3 activation by ethanol, manifested significant elevations in ceramide, triglyceride, and N-acylphosphatidylethanolamine. In contrast, the cerebellum, with the least caspase-3 activation, failed to show significant changes in ceramide and triglyceride, and exhibits much smaller increases in N-acyl phosphatidylethanolamine than other brain regions. Ethanol-induced increases in cholesterol ester were observed in all brain regions tested. Inhibitors of serine palmitoyltransferase effectively blocked ethanol-induced caspase-3 activation as well as elevations in ceramide, cholesterol ester, and N-acyl phosphatidylethanolamine. Immunohistochemical studies indicated that the expression of serine palmitoyltransferase was mainly localized in neurons and was enhanced in activated caspase-3-positive neurons generated by ethanol. These results indicate that de novo ceramide synthesis has a vital role in ethanol-induced apoptotic neurodegeneration in the developing brain. PMID:20663015

  5. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice

    PubMed Central

    Wu, Mao-Cheng; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID:27489024

  6. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice.

    PubMed

    Wu, Mao-Cheng; Bing, Yan-Hua; Chu, Chun-Ping; Qiu, De-Lai

    2016-01-01

    Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID:27489024

  7. Pre-exposure to ethanol, but not to caffeine and nicotine, induced place preference and self-administration of the NMDA receptor antagonist-benzodiazepine combination, Zoletil®.

    PubMed

    de la Peña, June Bryan I; dela Peña, Irene Joy I; Lee, Hye Lim; dela Peña, Ike; Shin, Chan Young; Sohn, Aee Ree; Cheong, Jae Hoon

    2013-09-01

    Zoletil® is an equal amount combination of the NMDA receptor antagonist, tiletamine, and the benzodiazepine, zolazepam, usually used as a veterinary anesthetic. Previous studies have shown that pre-exposure to Zoletil® and other psychoactive drugs (e.g. ketamine, diazepam) plays a significant role in the abuse liability of the compound. However, these studies were only focused on illicit psychoactive drugs and not on the more widely used licit psychoactive substances. Thus, the goal of the present work is to investigate whether pre-exposure to the three most commonly used licit psychoactive substances (caffeine, nicotine, and ethanol) affects the rewarding and reinforcing effects of Zoletil®. Rats were pretreated with caffeine (1.25 or 2.5 mg/kg), nicotine (125 or 250 μg/kg), ethanol (0.5, 2, or 4 g/kg), or saline (1 ml/kg) for 14 days, and evaluated for subsequent Zoletil® place preference (2.5 mg/kg) and self-administration (250 μg/kg). Zoletil® produced neither place preference nor self-administration in saline-pretreated rats. Pre-exposure to caffeine or nicotine does not have significant effects on Zoletil®'s abuse potential. However, pretreatment of ethanol significantly produced Zoletil® place preference and self-administration. These results suggest that individuals who are exposed to ethanol may have a high propensity to use/abuse Zoletil®. More importantly, the present result advocates the careful monitoring on the use and dispensation of Zoletil® or related substances. PMID:23916424

  8. Ethanol, growth hormone and testosterone in peripubertal rats.

    PubMed

    Tentler, J J; LaPaglia, N; Steiner, J; Williams, D; Castelli, M; Kelley, M R; Emanuele, N V; Emanuele, M A

    1997-03-01

    The deleterious effects of ethanol on the hypothalamic pituitary growth hormone axis in adult male humans and animals have been well documented. It is also well established that ethanol has toxic effects on testicular function in adult humans and animals. Much less is known, however, about the effects of ethanol on the growth hormone (GH) axis and testicular function in adolescence. Recent studies have established that adolescent problem drinking is a widespread and growing threat to the health of young people in the United States. In the present study, therefore, we investigated if acute ethanol exposure in peripubertal male Sprague-Dawley rats altered normal pituitary and testicular function. Serum levels of GH and testosterone were measured at 1.5, 3, 6, and 24 h after a single i.p. injection of either saline or 3 g/kg body weight ethanol. Histologic analysis as well as serum testosterone levels allowed us to assign animals to either early puberty (35-day-old animals), mid-puberty (41-day-old animals), or young adult (51- and 66-day-old animals) status. Ethanol produced significant decrements in serum testosterone in the 51- and 66-day-old animals, with a trend toward suppression in the 41-day-old group. Furthermore acute ethanol administration significantly decreased serum GH (P < 0.0001 by 3 way ANOVA) demonstrating a significant effect of ethanol on serum GH in all age groups and at all time points studied when compared with saline injected controls (P < 0.01 by Turkey's studentized range test). Despite this significant fall in peripheral GH levels, there was no decrease in either GH mRNA or growth hormone-releasing factor (GRF) mRNA levels nor in hypothalamic concentration of GRF peptide. We conclude that, as in adult animals, acute exposure to ethanol causes a prolonged and severe decrement in serum GH which is possibly mediated at the level of secretion. In addition, there is attenuation in testosterone secretion. These data are all the more important

  9. Fast and delayed locomotor response to acute high-dose nicotine administration in adult male rats.

    PubMed

    Jandová, K; Marešová, D; Pokorný, J

    2013-01-01

    The aim of the present study was to compare the immediate and delayed locomotor response to high-dose nicotine (NIC) administration in rats. The vertical and horizontal activity of behavior in adult male rats exposed to 1 mg/kg NIC or saline (SAL) were tested in a Laboras apparatus for one hour after drug application. Animals were then returned to their cages and housed for another seven days. After this period all animals were placed in Laboras again and their behavioral pattern was retested for another period of one hour (delayed response). Horizontal activity: immediately after nicotine administration animal were less mobile (first 2-minutes interval), when compared with controls. The immobilization effect of nicotine disappeared within 4 minutes and during whole first 10-minutes interval time spent by locomotion did not differ from controls. Locomotion activity of animals treated with nicotine increased robustly in following 10 minutes and remained significantly higher in 2nd, 3rd and 5th 10-minutes interval. Vertical activity: Rearing frequency was significantly lowered by NIC administration in first two minutes of the experiment and the same was found when the duration of rearing was analyzed. Lower rearing intensity of NIC treated animals disappeared in 4 minutes and was finally higher during whole test session as compared with controls. When duration of rearing was analyzed it was significantly longer in NIC treated animals. In majority of observed behavioral aspects there were no differences between NIC treated rats and controls seven days after NIC or SAL treatment. Our results reflect effect of NIC and we conclude that NIC significantly influences behavior of experimental animals.

  10. Acute effects of oxygen administration on transmural pulmonary artery pressure in obstructive sleep apnea.

    PubMed

    Marrone, O; Bellia, V; Pieri, D; Salvaggio, A; Bonsignore, G

    1992-04-01

    In order to investigate the role of hypoxia on the cyclic oscillation of transmural pulmonary artery pressure (PAP) in obstructive sleep apnea, oxygen was administered during one half of the night to six patients affected by obstructive sleep apnea syndrome during a nocturnal polysomnographic study. In each patient, transmural PAP measurements were performed on 15 randomly selected apneas recorded while breathing room air, and on 15 during O2 administration. During O2 administration in all patients, apneas were associated with a higher oxyhemoglobin saturation (SaO2), a smaller SaO2 swing, and a higher transcutaneous PCO2. The mean highest level of transmural PAP in the apneic episodes, commonly reached at their end, was significantly lower than while breathing room air in only two patients; however, due to a decrease in the mean lowest PAP level (at the beginning of apneas), the extent of the PAP increase within apneas did not differ between air and O2 breathing; these patients showed the smallest increase in transcutaneous PCO2 in our sample. End-apneic transmural PAP during O2 administration was significantly higher in one subject (for systolic values) and was not significantly different in the remaining three subjects. The extent of the increase in transmural PAP within apneas was greater in one patient; it was smaller in another one, but only for the diastolic values; and it did not differ significantly with respect to the value observed while breathing room air in all of the other subjects. The results suggest that hypoxia in obstructive apneas, at least in some patients, may lead to a steady increase in PAP, detectable both at the beginning and at the end of the episodes; conversely, the increase in PAP within apneas does not seem to be influenced by the simultaneous decrease in SaO2. PMID:1555416

  11. Persistent penile prolapse associated with acute blood loss and acepromazine maleate administration in a horse.

    PubMed

    Nie, G J; Pope, K C

    1997-09-01

    Prolonged penile prolapse in horses has been reported in association with administration of phenothiazine tranquilizers, trauma, neuropathies, severe general debilitation or exhaustion, starvation, rabies, herpes myeloencephalitis, equine infectious anemia, and purpura hemorrhagica. A 5-year-old gelding was admitted for treatment of prolonged penile prolapse of 12 days' duration that developed after acepromazine maleate was administered to allow examination of a laceration that had resulted in severe blood loss. The horse was sedated, and the penis was replaced in the preputial cavity by use of a combination of massage and bandaging. Treatment was successful, and recovery was complete.

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

    PubMed

    Raivio, Noora; Miettinen, Pekka; Kiianmaa, Kalervo

    2014-09-01

    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.

  13. Immobilization-induced increases of systolic blood pressure and dysregulation of electrolyte balance in ethanol-treated rats.

    PubMed

    Yasmin, Farzana; Haque, Zeba; Ikram, Huma; Haleem, Darakhshan Jabeen

    2015-07-01

    Clinical and experimental studies revealed that alcohol drinking and life event stresses are predisposing factors to hypertension. Intra and extra cellular levels of electrolytes may play important role in the pathogenesis and treatment of hypertension. Dietary intake of sodium, potassium, calcium and magnesium is suggested to have a role in the regulation of blood pressure. The present study was designed to monitor the effects of acute exposure to 2h immobilization stress and ethanol administration at a dose of 2.5 g/kg body weight (i.p.) and combined effect of acute administration of ethanol and immobilization stress on systolic blood pressure (SBP), intraerythrocyte, serum and tissue electrolytes in rats. Results showed that acute exposure to 2h immobilization increased SBP, intraerythrocyte sodium and decreased intraerythrocyte potassium in water as well as in ethanol injected rats. The concentration of Na⁺ and Ca²⁺ increased while that of K⁺ and Mg²⁺ decreased in the heart and kidney tissue. Ethanol administration also increased Na⁺ and Ca²⁺ levels and decreased K⁺ and Mg²⁺ levels in the heart and kidney tissue. Restraint stress decreased serum levels of Na⁺, K⁺, Ca²⁺, P, and Cl⁻ and increased serum Mg²⁺, glucose and haematocrit. Ethanol administration also decreased serum levels of Na⁺, K⁺, Ca²⁺, P, and Cl⁻ and increased serum Mg²⁺, glucose and haematocrit. The effects of ethanol and stress on the changes of blood and tissues electrolytes were additive and may be involved in the greater occurrence of hypertension in alcoholics. Our results suggested an important role of intra and extra cellular electrolytes in both stress and ethanol-induced hypertension. The findings may help to develop strategies for the treatment of hypertension in alcoholics.

  14. Chronic glial activation, neurodegeneration, and APP immunoreactive deposits following acute administration of double-stranded RNA.

    PubMed

    Melton, Lisa M; Keith, Alexander B; Davis, Sue; Oakley, Arthur E; Edwardson, James A; Morris, Christopher M

    2003-10-01

    Several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are associated with immunocompetent microglia, leading to the suggestion that chronic glial-mediated inflammation contributes to the neurodegeneration seen in these diseases. Little direct evidence supports this hypothesis, and no suitable rodent models exist that do not involve the use of blunt trauma or ischaemia, events that are infrequently encountered in the human disease state. In the present study, we report that administration of double-stranded RNA, a classical inducer of interferon-gamma (IFN-gamma), causes rapid and persistent activation of microglia and astrocytes, as well as induction of interleukin-1beta (IL-beta) and nitric oxide synthase. In close temporal succession to glial activation, there is neurodegeneration, with neuron loss involving apoptosis in selected brain regions including the septal nucleus, hippocampus, cortex and thalamus, along with hippocampal atrophy. This neuronal loss is accompanied by punctate deposits of material that are immunoreactive for amyloid precursor protein, beta-amyloid peptide (Abeta), and apolipoprotein E. The findings may have clinical relevance, since the administration of the nonsteroidal antiinflammatory agent (NSAID) ibuprofen markedly reduces the neurodegeneration observed in the absence of significant glial inhibition. These findings may be relevant to the pathogenesis of Alzheimer's disease in particular, and to other neurodegenerative diseases involving inflammation.

  15. Effects of acute administration of caffeine on local cerebral glucose utilization in the rat.

    PubMed

    Nehlig, A; Lucignani, G; Kadekaro, M; Porrino, L J; Sokoloff, L

    1984-05-18

    The quantitative 2-[14C]deoxyglucose autoradiographic method was used to study the effects of acute intravenous injections (15 min prior to study) of caffeine on brain energy metabolism. With doses of 0.1 mg/kg the effects of caffeine on cerebral glucose utilization were limited to the habenula, spinal trigeminal and paraventricular nuclei. After the 1.0 mg/kg dose significant increases were additionally seen in the caudate, ventral tegmental area and medial septum. After the injection of 10 mg/kg of caffeine, average glucose utilization of the brain as a whole was increased by 15%, and of 71 structures examined 31 structures were statistically significantly affected. Among these were all brainstem monoaminergic cell groupings, components of the extrapyramidal motor system, anterior cingulate, and medial prefrontal cortex. In the hypothalamus glucose utilization increased only in the paraventricular nucleus, arcuate nucleus, and median eminence. This study demonstrates that there is a correlation between the known stimulant effects of caffeine on behavior and widespread increases in glucose utilization throughout the brain.

  16. Differential effects of acute morphine administrations on polymorphonuclear cell metabolism in various mouse strains.

    PubMed

    Di Francesco, P; Tavazzi, B; Gaziano, R; Lazzarino, G; Casalinuovo, I A; Di Pierro, D; Garaci, E

    1998-01-01

    This paper shows that an acute morphine treatment dose-dependently alters the energetic and oxidative metabolism of polymorphonuclear leukocytes obtained from BALB/c and DBA/2 mice, while phagocytic cells from C57BL/6 were not affected. In sensitive mouse strains, i.e. BALB/c and DBA/2, morphine decreased both ATP concentration and energy charge potential. At the same time, ATP catabolic products, i.e. nucleosides (inosine+adenosine) and oxypurines (hypoxanthine+xanthine+uric acid), significantly increased, indicating an imbalance between energy production and consumption. Morphine treatment also induced malondialdehyde and superoxide anions production in leukocyte cells from sensitive mice. The opiate antagonist naloxone blocked morphine-induced modifications by the lower morphine dose. The same parameters in cells from C57BL/6 mice were not affected. These findings confirm that: i) the phagocytic cells are an important target for the in vivo effects of morphine, and ii) the genotype-dependent variation influences the immunological responsiveness to opiates.

  17. Paradoxical glucose-sensitizing yet proinflammatory effects of acute ASP administration in mice.

    PubMed

    Fisette, Alexandre; Poursharifi, Pegah; Oikonomopoulou, Katerina; Munkonda, Mercedes N; Lapointe, Marc; Cianflone, Katherine

    2013-01-01

    Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system, which stimulates fat storage and is typically increased in obesity, type 2 diabetes, and cardiovascular disease. Using a diet-induced obesity (DIO) mouse model, the acute effects of ASP on energy metabolism and inflammatory processes in vivo were evaluated. We hypothesized that ASP would specifically exert proinflammatory effects. C57Bl/6 wild-type mice were put on a high-fat-high-sucrose diet for 12 weeks. Mice were then subjected to both glucose and insulin tolerance tests, each manipulation being preceded by recombinant ASP or vehicle (control) bolus injection. ASP supplementation increased whole-body glucose excursion, and this was accomplished with reduced concomitant insulin levels. However, ASP did not directly alter insulin sensitivity. ASP supplementation induced a proinflammatory phenotype, with higher levels of cytokines including IL-6 and TNF-α in plasma and in adipose tissue, liver, and skeletal muscle mRNA. Additionally, ASP increased M1 macrophage content of these tissues. ASP exerted a direct concentration-dependent role in the migration and M1 activation of cultured macrophages. Altogether, the in vivo and in vitro experiments demonstrate that ASP plays a role in both energy metabolism and inflammation, with paradoxical whole-body glucose-sensitizing yet proinflammatory effects.

  18. [Ethanol metabolism and pathobiochemistry of organ damage--1992. IV. Ethanol in relation to the cardiovascular system. Hematologic, immunologic, endocrine disorders and muscle and bone damage caused by ethanol. Fetal alcohol syndrome].

    PubMed

    Zima, T

    1993-01-01

    Peripheral vasodilatation with increased cardiac output, tachycardia and increased blood pressure are described after alcohol administration. An increased HDL-cholesterol is found in moderate drinkers (both HDL-2 and HDL-3 fractions), with diminishing risk of coronary heart diseases. Acute ethanol intake causes an increased the level of triglycerides without changes in HDL-cholesterol level. This may be put into correlation with higher incidence of cardiovascular diseases in so-called "week-end" drinkers. Alcohol abuse may result in central diabetes insipidus. An increased elimination of lactate diminishes tubular secretion of uric acid with subsequent secondary hyperuricemia. Ethanol reduced the number of lymphocytes, reduces phagocytosis by macrophages and diminishes the activity of NK-cells. Bone marrow cellulity diminishes with the subsequent reduction in erythropoiesis, trombopoiesis and leukopoiesis. Alcohol may cause sideropenic and megaloblastic anemia. There are two forms of alcohol muscle injury: the acute one, with myonecrosis and inflammatory reaction, and chronic one, with muscle weakness and atrophy. Alcohol is one of etiologic factors of osteoporosis. An acute intoxication result in transitory hypoparatthyreoidism, while chronic ethanol intake make grow the PTH level and decreases the level of D vitamin metabolises. Stimulation of cortisol secretion, decrease of testosterone level and a reversible decrease of T3 and T4 levels have been described following ethanol administration. Hypothalamic-pituitary-adrenal axis suffers alteration in alcoholics, and secondary amenorrhea is observed in female alcoholics. Ethanol behaves as an agonist on GABA receptor. Fetal alcohol syndrome together with Down's syndrome and spina bifida are the most frequent reasons of mental retardation in developed countries. Toxicity of ethanol affects the whole pregnancy period.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. National Veterans Health Administration inpatient risk stratification models for hospital-acquired acute kidney injury

    PubMed Central

    Cronin, Robert M; VanHouten, Jacob P; Siew, Edward D; Eden, Svetlana K; Fihn, Stephan D; Nielson, Christopher D; Peterson, Josh F; Baker, Clifton R; Ikizler, T Alp; Speroff, Theodore

    2015-01-01

    Objective Hospital-acquired acute kidney injury (HA-AKI) is a potentially preventable cause of morbidity and mortality. Identifying high-risk patients prior to the onset of kidney injury is a key step towards AKI prevention. Materials and Methods A national retrospective cohort of 1,620,898 patient hospitalizations from 116 Veterans Affairs hospitals was assembled from electronic health record (EHR) data collected from 2003 to 2012. HA-AKI was defined at stage 1+, stage 2+, and dialysis. EHR-based predictors were identified through logistic regression, least absolute shrinkage and selection operator (lasso) regression, and random forests, and pair-wise comparisons between each were made. Calibration and discrimination metrics were calculated using 50 bootstrap iterations. In the final models, we report odds ratios, 95% confidence intervals, and importance rankings for predictor variables to evaluate their significance. Results The area under the receiver operating characteristic curve (AUC) for the different model outcomes ranged from 0.746 to 0.758 in stage 1+, 0.714 to 0.720 in stage 2+, and 0.823 to 0.825 in dialysis. Logistic regression had the best AUC in stage 1+ and dialysis. Random forests had the best AUC in stage 2+ but the least favorable calibration plots. Multiple risk factors were significant in our models, including some nonsteroidal anti-inflammatory drugs, blood pressure medications, antibiotics, and intravenous fluids given during the first 48 h of admission. Conclusions This study demonstrated that, although all the models tested had good discrimination, performance characteristics varied between methods, and the random forests models did not calibrate as well as the lasso or logistic regression models. In addition, novel modifiable risk factors were explored and found to be significant. PMID:26104740

  20. Acute liver failure in a term neonate after repeated paracetamol administration

    PubMed Central

    Bucaretchi, Fábio; Fernandes, Carla Borrasca; Branco, Maíra Migliari; Capitani, Eduardo Mello De; Hyslop, Stephen; Caldas, Jamil Pedro S.; Moreno, Carolina Araújo; Porta, Gilda

    2014-01-01

    Objective: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. Case description: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1mEq/L), hypoglycemia (18mg/dL), increased serum aminotransferase activity (AST=4,039IU/L; ALT=1,087IU/L) and hyperbilirubinemia (total: 9.57mg/dL; direct: 6.18mg/dL) after receiving oral paracetamol (10mg/kg/dose every 4 hours) for three consecutive days (total dose around 180mg/kg; serum concentration 36-48 hours after the last dose of 77µg/ mL). Apart from supportive measures, the patient was successfully treated with intravenous N-acetylcysteine infusion during 11 consecutive days, and was discharged on day 34. The follow-up revealed full recovery of clinical and of laboratory findings of hepatic function. Comments: The paracetamol pharmacokinetics and pharmacodynamics in neonates and infants differ substantially from those in older children and adults. Despite the reduced rates of metabolism by the P-450 CYP2E1 enzyme system and the increased ability to synthesize glutathione - which provides greater resistance after overdoses -, it is possible to produce hepatotoxic metabolites (N-acetyl-p-benzoquinone) that cause hepatocellular damage, if glutathione sources are depleted. Paracetamol clearance is reduced and the half-life of elimination is prolonged. Therefore, a particular dosing regimen should be followed due to the toxicity risk of cumulative doses. This report highlights the risk for severe hepatotoxicity in neonates after paracetamol multiple doses for more than two to three days. PMID:24676202

  1. Adrenal mediation of ethanol's inhibition of benzo(a)pyrene metabolism. [Rats

    SciTech Connect

    Bogdanffy, M.S.; Schatz, R.A.; Brown, D.R.

    1984-01-01

    Previous studies in rats have demonstrated that acute ethanol (1 h) at high doses inhibits xenobiotic metabolism and that the effect is modulated by the adrenals. In this paper, a similar phenomenon is reported for benzo(a)pyrene (BaP) metabolism but the inhibitory effect is restricted to detoxification without effect on activation routes. Rats were administered ethanol (5 g/kg) orally and sacrificed 1 h later. Microsomes were isolated and assayed for capacity to metabolize BaP to activated and detoxified products. Ethanol treatment inhibited detoxification, as evidenced by approximately 50% decrease in 3-hydroxy-BaP formation. There was little effect on metabolic routes forming activated products, as indicated by no change in the rate of dihydrodiol formation. To determine the role of the adrenals in ethanol's inhibitory effect towards detoxication, a similar experiment was performed in adrenalectomized (ADX) rats. ADX alone slightly decreased 3-hydroxy-BaP formation, but treatment with ethanol resulted in no significant differences from ADX controls. Corticosterone administration to ADX rats resulted in an inhibition of the formation of all metabolites. The data suggest that acute ethanol inhibits the detoxication of BaP without effecting activation and that this effect is mediated by the adrenals. This would be expected to increase the proporation of carcinogenic metabolites. 38 references, 2 figures, 3 tables.

  2. Acute and carryover effects in mice of MDMA ("ecstasy") administration during periadolescence.

    PubMed

    Morley-Fletcher, Sara; Bianchi, Mauro; Gerra, Gilberto; Laviola, Giovanni

    2002-07-12

    In spite of the increasing evidence concerning its neurotoxicity, young human individuals are often involved in the recreational use of amphetamine-type stimulants such as 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). A study aimed to investigate short- and long-term consequences of a repeated and intermittent MDMA administration (0, 5 or 10 mg/kg i.p., 3 days treatment history) was conducted in mice. Mice were injected at different phases in development, namely at early (28 days old), middle (38 days old) or late (52 days old) adolescence. When assessed for nociceptive response, a dose-dependent analgesia was found in middle and late adolescent mice. Carryover consequences of previous MDMA treatment were then investigated at adulthood (80 days old). In a social interaction test, levels of environment exploration and social behaviour resulted markedly increased in drug-free state as a function of drug exposure during development, whereas others behaviours were reduced. MDMA challenge (5-mg/kg dose) produced the expected hyperactivity, as well as a marked increment of hypothalamic serotonin (5-hydroxyhyptamine, 5-HT) levels. Mice treated chronically with MDMA during middle and late adolescence were associated with important reductions of the indoleamine. As a whole, these results indicate a differential long-term vulnerability to behavioural and neurotoxicant effects of MDMA as a function of the developmental stage of exposure.

  3. Anti-ulcer activity of Ficus religiosa leaf ethanolic extract

    PubMed Central

    Gregory, Marslin; Divya, B.; Mary, Revina Ann; Viji, M. M. Hipolith; Kalaichelvan, V. K.; Palanivel, V.

    2013-01-01

    Objective To evaluate the anti-ulcer activity and acute toxicity of Ficus religiosa (F. religiosa) leaf ethanolic extract in animal models. Methods Anti-ulcer activity of F. religiosa ethanolic extract (250 and 500 mg/kg body weight) was studied on stress induced ulcer animal models. Ranitidine was used as standard. The anti-ulcer activity of F. religiosa was evaluated with the help of ulcer area and histopatholgical examination. Preliminary phyto-chemical screening and acute toxicity studies of F. religiosa also carried out. Results Results showed that the extract treatments prevented ulcer area and gastric secretion in a dose-dependent manner. Administration of 2 000 mg/kg extract did not show any acute toxicity in albino mice. Preliminary phytochemical analysis identified the presence of flavonoids in the