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Sample records for potentiates locomotor sensitization

  1. Tea component, epigallocatechin gallate, potentiates anticataleptic and locomotor-sensitizing effects of caffeine in mice.

    PubMed

    Kasture, Sanjay B; Gaikar, Mayur; Kasture, Veena; Arote, Sanjay; Salve, Balu; Rosas, Michela; Cotti, Elisabetta; Acquas, Elio

    2015-02-01

    Tea is the most popular beverage worldwide. Caffeine, the psychoactive principle of tea, pharmacologically interacts with several drugs and bioactive molecules. Epigallocatechin gallate (EGCG) is a major component of tea and its known interactions with caffeine make it worthwhile to further study them by investigating the influence of EGCG on the anticataleptic and locomotor-sensitizing effects of caffeine. In the present investigation, we observed that (a) administration of caffeine or EGCG alone inhibited haloperidol-induced catalepsy, a widely used animal model to study parkinsonism, and (b) a combination of caffeine and EGCG produced greater inhibition of haloperidol-induced catalepsy. Furthermore, after repeated administration of caffeine and EGCG, either alone or in combination, we observed that (c) caffeine and EGCG contrasted the sensitization of catalepsy observed after repeated haloperidol administration by significantly reducing the duration of catalepsy. Furthermore, as haloperidol-induced catalepsy was also associated with increased lipid peroxidation, we observed that (d) EGCG administration reduced striatal lipid peroxide levels in a dose-dependent manner and that (e) the combination of caffeine with EGCG was most effective in reducing haloperidol-increased striatal lipid peroxide. Finally, we observed that (f) chronic caffeine and EGCG significantly elicited locomotor sensitization and that (g) their combination resulted in significantly greater effects. In conclusion, EGCG potentiated the effects of caffeine on haloperidol-induced catalepsy and of caffeine-elicited locomotor sensitization. Overall, these observations indicate critical interactions between caffeine and EGCG in an animal model of parkinsonism and locomotor activity and suggest that tea consumption might reduce antipsychotic-induced side effects.

  2. The potential anti-addictive agent, 18-methoxycoronaridine, blocks the sensitized locomotor and dopamine responses produced by repeated morphine treatment.

    PubMed

    Szumlinski, K K; Maisonneuve, I M; Glick, S D

    2000-05-02

    18-Methoxycoronaridine (18-MC), a novel synthetic iboga congener, attenuates the reinforcing efficacy of morphine, disrupts some signs of morphine withdrawal in physically dependent rats and attenuates the dopamine response in the nucleus accumbens to acute morphine. The present study further investigated the interactions between 18-MC and morphine by examining the effects of 18-MC (40 mg/kg, i.p., 19 h earlier) on the expression of dopamine sensitization in the nucleus accumbens in response to morphine (20 mg/kg, i.p.) and on the dose-effect curves for morphine-induced locomotion (0-30 mg/kg, i.p.) in rats treated either acutely or repeatedly (five, once daily, injections of 20 mg/kg, i.p.) with morphine. Compared to vehicle pretreated controls, 18-MC increased the potency of morphine, shifting the dose-response curve to the left, in acute morphine treated rats; however, 18-MC did not alter the potency of morphine in rats treated repeatedly with morphine. Repeated morphine administration induced locomotor sensitization in approximately 50% of the rats tested; in vehicle pretreated rats, the morphine dose-response curve was shifted to the left in sensitized as compared to non-sensitized rats. In 18-MC pretreated rats, sensitized and non-sensitized rats responded similarly to morphine, revealing a blockade of sensitization by 18-MC. Consistent with this behavioural finding, 18-MC pretreatment completely abolished the sensitized dopamine response in the nucleus accumbens expressed by rats repeatedly treated with morphine. It is suggested that the potential anti-addictive efficacy of 18-MC might be related to an ability to restore normal functioning to a hypersensitive mesolimbic dopamine system produced by previous repeated morphine administration.

  3. ΔFosB induction in orbitofrontal cortex potentiates locomotor sensitization despite attenuating the cognitive dysfunction caused by cocaine

    PubMed Central

    Winstanley, Catharine A.; Green, Thomas A.; Theobald, David E.H.; Renthal, William; LaPlant, Quincey; DiLeone, Ralph J.; Chakravarty, Sumana; Nestler, Eric J.

    2010-01-01

    The effects of addictive drugs change with repeated use: many individuals become tolerant of their pleasurable effects but also more sensitive to negative sequelae (e.g., anxiety, paranoia, and drug craving). Understanding the mechanisms underlying such tolerance and sensitization may provide valuable insight into the basis of drug dependency and addiction. We have recently shown that chronic cocaine administration reduces the ability of an acute injection of cocaine to affect impulsivity in rats. However, animals become more impulsive during withdrawal from cocaine self-administration. We have also shown that chronic administration of cocaine increases expression of the transcription factor ΔFosB in the orbitofrontal cortex (OFC). Mimicking this drug-induced elevation in OFC ΔFosB through viral-mediated gene transfer mimics these behavioural changes: ΔFosB over-expression in OFC induces tolerance to the effects of an acute cocaine challenge but sensitizes rats to the cognitive sequelae of withdrawal. Here we report novel data demonstrating that increasing ΔFosB in the OFC also sensitizes animals to the locomotor-stimulant properties of cocaine. Analysis of nucleus accumbens tissue taken from rats over-expressing ΔFosB in the OFC and treated chronically with saline or cocaine does not provide support for the hypothesis that increasing OFC ΔFosB potentiates sensitization via the nucleus accumbens. These data suggest that both tolerance and sensitization to cocaine’s many effects, although seemingly opposing processes, can be induced in parallel via the same biological mechanism within the same brain region, and that drug-induced changes in gene expression within the OFC play an important role in multiple aspects of addiction. PMID:19135469

  4. Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice.

    PubMed

    Saito, Luis P; Fukushiro, Daniela F; Hollais, André W; Mári-Kawamoto, Elisa; Costa, Jacqueline M; Berro, Laís F; Aramini, Tatiana C F; Wuo-Silva, Raphael; Andersen, Monica L; Tufik, Sergio; Frussa-Filho, Roberto

    2014-02-01

    It has been demonstrated that a prolonged period (48 h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. In the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6 h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1-gentle handling method) or PSD (experiment 2-multiple platforms method) for 6 h. Immediately after the sleep deprivation period, mice were tested in the open field for 10 min under the effects of saline or 2.0 mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0 mg/kg AMP and were tested in the open field for 10 min. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. The data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-h PSD had no effects on AMP-induced hyperlocomotion or sensitization, our data suggest that the deprivation of slow wave sleep plays a critical role in the mechanisms that underlie the potentiating effects of TSD on both the acute and sensitized addiction-related responses to AMP.

  5. Caffeine and amphetamine produce cross-sensitization to nicotine-induced locomotor activity in mice.

    PubMed

    Celik, Eylem; Uzbay, I Tayfun; Karakas, Sirel

    2006-01-01

    Sensitization development is linked to the addictive potential of the drugs. The same mechanisms might play a role in sensitization development to the different addictive drugs. The aim of the study was to investigate the development of cross-sensitization to caffeine and amphetamine in nicotine-induced locomotor sensitization in mice. Caffeine (2.5-20 mg/kg), amphetamine (1-16 mg/kg) or saline were injected to Swiss-Webster mice and locomotor activity was recorded for 30 min. Nicotine (0.5-2 mg/kg) or saline were injected to mice and locomotor activity was recorded for 30 min. Process was applied for 19 days, every other day (10 sessions). Caffeine (5 mg/kg), amphetamine (4 mg/kg) or saline were challenged to the different groups of nicotine-sensitized mice 2 days later on the last nicotine injection, and locomotor activity was recorded. Repetitive injections of nicotine (0.5-2 mg) produced locomotor sensitization in mice. After caffeine and amphetamine challenge injections, locomotor activity of the nicotine-sensitized mice was found to be significantly higher than saline-pretreated mice. Saline challenge did not produce any significant effect in nicotine- or saline-pretreated mice. Our results suggest that a cross-sensitization developed to both caffeine and amphetamine in nicotine-sensitized mice. In conclusion, similar central mechanisms may be responsible for the development of addiction to these substances.

  6. Effects of Sodium Butyrate on Methamphetamine-Sensitized Locomotor Activity

    PubMed Central

    Harkness, John H.; Hitzemann, Robert J.; Edmunds, Stephanie; Phillips, Tamara J.

    2012-01-01

    Neuroadaptations associated with behavioral sensitization induced by repeated exposure to methamphetamine (MA) appear to be involved in compulsive drug pursuit and use. Increased histone acetylation, an epigenetic effect resulting in altered gene expression, may promote sensitized responses to psychostimulants. The role of histone acetylation in the expression and acquisition of MA-induced locomotor sensitization was examined by measuring the effect of histone deacetylase inhibition by sodium butyrate (NaB). For the effect on expression, vehicle or NaB (630 mg/kg, intraperitoneally) was administered 30 min prior to MA challenge in mice treated repeatedly with MA (10 days of 2 mg/kg MA) or saline (10 days), and then locomotor response to MA challenge was measured. NaB treatment increased the locomotor response to MA in both acutely MA treated and sensitized animals. For acquisition, NaB was administered 30 min prior to each MA exposure (10 days of 1 or 2 mg/kg), but not prior to the MA challenge test. Treatment with NaB during the sensitization acquisition period significantly increased locomotor activation by MA in sensitized mice only. NaB alone did not significantly alter locomotor activity. Acute NaB or MA, but not the combination, appeared to increase striatal acetylation at histone H4. Repeated treatment with MA, but not NaB or MA plus NaB, increased striatal acetylation at histone H3. Although increased histone acetylation may alter the expression of genes involved in acute locomotor response to MA and in the acquisition of MA-induced sensitization, results for acetylation at H3 and H4 showed little correspondence with behavior. PMID:23137698

  7. Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole.

    PubMed

    Beerepoot, Pieter; Lam, Vincent; Luu, Alice; Tsoi, Bernice; Siebert, Daniel; Szechtman, Henry

    2008-12-03

    Locomotor sensitization induced by the dopamine agonist quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to quinpirole. Rats were co-treated with 0.5 mg/kg quinpirole and either salvinorin A (0.04, 0.4 or 2.0 mg/kg) or U69593 (0.3 mg/kg). Control groups were co-treated with vehicle and saline, vehicle and quinpirole (0.5 mg/kg), or saline and salvinorin A (0.4 mg/kg). Rats were injected biweekly for a total of 10 injections and locomotor activity measured after each treatment. Results showed that the highest dose of salvinorin A potentiated sensitization to quinpirole as did U69593, the middle salvinorin A dose had no effect on quinpirole sensitization, and the lowest dose of salvinorin A attenuated sensitization to quinpirole. These findings indicate that structural differences between salvinorin A and U69593 do not affect the potentiation of quinpirole sensitization. Moreover, the opposite effects of high and low salvinorin A doses suggest that salvinorin A can produce bidirectional modulation of sensitization to dopamine agonists.

  8. Effects of nicotine on ethanol-induced locomotor sensitization: A model of neuroadaptation.

    PubMed

    Gubner, Noah R; Phillips, Tamara J

    2015-07-15

    Co-morbid use of nicotine-containing tobacco products and alcohol (ethanol) is prevalent in young adults initiating use and in alcohol dependent adults, suggesting that these drugs in combination may increase risk to develop dependence on one or both drugs. Neuroadaptations caused by repeated drug exposure are related to the development of drug dependence and vulnerability to relapse. Locomotor sensitization has been used as a behavioral measure used to detect changes in neural drug sensitivity that are thought to contribute to drug dependence and relapse. Locomotor sensitization was measured in the current studies to examine potential differences in the effects of nicotine and ethanol given alone and in combination. Baseline activity levels of DBA/2J mice were assessed on 2 days, then mice were treated for 10 days with saline, nicotine (1 or 2mg/kg of nicotine tartrate), ethanol (1 or 2g/kg), or nicotine plus ethanol and locomotor activity was assessed every third day. On the following day, all mice were challenged with ethanol to measure the expression of sensitization. Mice treated with both nicotine and ethanol exhibited greater stimulation than predicted from the combined independent effects of these drugs, consistent with our previously published results. The combined effects of nicotine and ethanol on locomotor sensitization were dependent on the dose of ethanol and whether testing was performed after the drugs were given together, or after challenge with ethanol alone. These results suggest that nicotine and ethanol in combination can have neuroadaptive effects that differ from the independent effects of these drugs.

  9. Effects of Nicotine on Ethanol-Induced Locomotor Sensitization: A Model of Neuroadaptation

    PubMed Central

    Gubner, Noah R.; Phillips, Tamara J.

    2015-01-01

    Co-morbid use of nicotine-containing tobacco products and alcohol (ethanol) is prevalent in young adults initiating use and in alcohol dependent adults, suggesting that these drugs in combination may increase risk to develop dependence on one or both drugs. Neuroadaptations caused by repeated drug exposure are related to the development of drug dependence and vulnerability to relapse. Locomotor sensitization has been used as a behavioral measure used to detect changes in neural drug sensitivity that are thought to contribute to drug dependence and relapse. Locomotor sensitization was measured in the current studies to examine potential differences in the effects of nicotine and ethanol given alone and in combination. Baseline activity levels of DBA/2J mice were assessed on 2 days, then mice were treated for ten days with saline, nicotine (1 or 2 mg/kg of nicotine tartrate), ethanol (1 or 2 g/kg), or nicotine plus ethanol and locomotor activity was assessed every third day. On the following day, all mice were challenged with ethanol to measure the expression of sensitization. Mice treated with both nicotine and ethanol exhibited greater stimulation than predicted from the combined independent effects of these drugs, consistent with our previously published results. The combined effects of nicotine and ethanol on locomotor sensitization were dependent on the dose of ethanol and whether testing was performed after the drugs were given together, or after challenge with ethanol alone. These results suggest that nicotine and ethanol in combination can have neuroadaptive effects that differ from the independent effects of these drugs. PMID:25857831

  10. Zebrafish Locomotor Responses Predict Irritant Potential of ...

    EPA Pesticide Factsheets

    Over the past few decades, the drying and warming trends of global climate change have increased wildland fire (WF) season length, as well as geographic area impacted. Consequently, exposures to WF fine particulate matter (PM2.5; aerodynamic diameter <2.5 µm) are likely to increase in frequency and duration, contributing to a growing public health burden. Given the influence of fuel type and combustion conditions on WFPM2.5 composition, there is pressing need to identify the biomass fuel sources and emission constituents that drive toxicity. Previously, we reported the utility of 6-day post-fertilization (dpf) zebrafish larvae in evaluating diesel exhaust PM-induced irritation, demonstrating responses analogous to those in mammals. In the present study, combustions, separated by smoldering or flaming conditions, of pine needles, red oak, pine, eucalyptus, and peat were achieved using an automated tube furnace paired with a cryo-trapping apparatus to collect condensates of emissions. The condensates were extracted and prepared for use in zebrafish assays. We hypothesized that 1) the extractable organic fractions of biomass smoke PM will elicit dose-dependent irritant responses in 6-dpf zebrafish larvae, and 2) the relative potencies will vary across biomass emissions, potentially driven by varying chemical composition of fuel sources. Six-dpf zebrafish (n= 28-32/group) were exposed acutely to PM extracts (5 concentrations; 0.3-30 µg/ml; half-log intervals) and

  11. Ibogaine enhances the expression of locomotor sensitization in rats chronically treated with cocaine.

    PubMed

    Szumlinski, K K; Maisonneuve, I M; Glick, S D

    1999-07-01

    Pretreatment (19 h) with the putative antiaddictive agent, ibogaine, has been shown previously to potentiate cocaine-induced locomotion in rats. The present study demonstrates that the magnitude of this effect of ibogaine is dependent on the previous cocaine history of the animal, on the time following ibogaine treatment, and on the number of ibogaine treatments. Compared to rats with no previous cocaine experience, ibogaine pretreatment (40 mg/kg, IP, 19 h earlier) markedly enhanced the expression of locomotor sensitization in response to a cocaine challenge injection (7.5 mg/kg) in rats that were chronically treated with cocaine (15 mg/ kg, IP, daily for 5 days). Tolerance to cocaine-induced locomotor sensitization appeared to occur in vehicle-pretreated chronic cocaine controls. Following a second series of identical treatments (beginning 3-4 days after the initial treatment series), locomotor responding to the cocaine challenge was further enhanced by a second ibogaine injection in chronically cocaine-treated animals. Twenty-four hours later, when animals were challenged again with cocaine in the absence of any further ibogaine pretreatment, the effect of ibogaine had dissipated. Consistent with previous studies from this laboratory, these data demonstrate that ibogaine can enhance sensitivity to the psychomotor stimulant effect of cocaine. The results of the present study further indicate that the extent of this effect depends on the animal's history of exposure to both ibogaine and cocaine.

  12. Differential housing and novelty response: Protection and risk from locomotor sensitization.

    PubMed

    Garcia, Erik J; Haddon, Tara N; Saucier, Donald A; Cain, Mary E

    2017-03-01

    High novelty seeking increases the risk for drug experimentation and locomotor sensitization. Locomotor sensitization to psychostimulants is thought to reflect neurological adaptations that promote the transition to compulsive drug taking. Rats reared in enrichment (EC) show less locomotor sensitization when compared to rats reared in isolation (IC) or standard conditions (SC). The current research study was designed to test if novelty response contributed locomotor sensitization and more importantly, if the different housing environments could change the novelty response to protect against the development of locomotor sensitization in both adolescence and adulthood. Experiment 1: rats were tested for their response to novelty using the inescapable novelty test (IEN) and pseudorandomly assigned to enriched (EC), isolated (IC), or standard (SC) housing conditions for 30days. After housing, they were tested with IEN. Rats were then administered amphetamine (0.5mg/kg) or saline and locomotor activity was measured followed by a sensitization test 14days later. Experiment 2: rats were tested in the IEN test early adulthood and given five administrations of amphetamine (0.3mg/kg) or saline and then either stayed in or switched housing environments for 30days. Rats were then re-tested in the IEN test in late adulthood and administered five more injections of their respective treatments and tested for locomotor sensitization. Results indicate that IC and SC increased the response to novelty. EC housing decreased locomotor response to amphetamine and saline, and SC housing increased the locomotor response to amphetamine. Mediation results indicated that the late adult novelty response fully mediates the locomotor response to amphetamine and saline, while the early adulthood novelty response did not. Differential housing changes novelty and amphetamine locomotor response. Novelty response is altered into adulthood and provides evidence that enrichment can be used to reduce

  13. Mirtazapine attenuates the expression of nicotine-induced locomotor sensitization in rats.

    PubMed

    Barbosa-Méndez, Susana; Jurado, Noé; Matus-Ortega, Maura; Martiñon, Susana; Heinze, Gerardo; Salazar-Juárez, Alberto

    2017-10-05

    Nicotine is the primary psychoactive component of tobacco. Many addictive nicotinic actions are mediated by an increase in the activity of the serotonin (5-HT) system. Some studies show that the 5-HT2A, 5-HT2C, and 5-HT3 receptors have a central role in the induction and expression of nicotine-induced locomotor sensitization. Mirtazapine, an antagonist of the α2-adrenergic receptors, the 5-HT2A/C, and the 5-HT3 receptors, has proven effective in reducing behavioral effects induced by drugs like cocaine and methamphetamines in human and animal. In this study, we evaluated the effect of mirtazapine on the locomotor activity and on the expression of nicotine-induced locomotor sensitization. We used the nicotine locomotor sensitization paradigm to assess the effects of mirtazapine on nicotine-induced locomotor activity and locomotor sensitization. Mirtazapine (30mg/kg, i.p.) was administered during extinction. Our study found that mirtazapine attenuated the expression of locomotor sensitization induced by different nicotine doses, decreased the duration of locomotor effects and locomotor activity induced by binge administration of nicotine. In addition, our study revealed that treatment with mirtazapine for 60 days produced an enhanced attenuation of nicotine-induced locomotor activity during the expression phase of behavioral sensitization, compared to that obtained when mirtazapine was administered for 30 days. This suggests that use of mirtazapine in controlled clinical trials may be a useful therapy to maintain abstinence for long periods. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: implications for addiction.

    PubMed

    Shuman, Tristan; Cai, Denise J; Sage, Jennifer R; Anagnostaras, Stephan G

    2012-12-01

    Modafinil is a wake-promoting drug effective at enhancing alertness and attention with a variety of approved and off-label applications. The mechanism of modafinil is not well understood but initial studies indicated a limited abuse potential. A number of recent publications, however, have shown that modafinil can be rewarding under certain conditions. The present study assessed the reinforcing properties of modafinil using conditioned place preference and locomotor sensitization in mice. Experiment 1 examined a high dose of modafinil (75 mg/kg) as well as its interactions with cocaine (15 mg/kg). Cocaine alone and modafinil co-administered with cocaine induced sensitization of locomotor activity; modafinil alone showed little or no locomotor sensitization. Animals given modafinil alone, cocaine alone, and modafinil plus cocaine exhibited a strong and roughly equivalent place preference. When tested for sensitization using a low challenge dose of modafinil, cross-sensitization was observed in all cocaine-pretreated mice. Experiment 2 examined a low dose of modafinil that is similar to the dose administered to humans and has been shown to produce cognitive enhancements in mice. Low dose modafinil (0.75 mg/kg) did not produce conditioned place preference or locomotor sensitization. Together, these results suggest that modafinil has the potential to produce reward, particularly in cocaine addicts, and should be used with caution. However, the typical low dose administered likely moderates these effects and may account for lack of addiction seen in humans.

  15. Baclofen blocks the development of sensitization to the locomotor stimulant effect of amphetamine.

    PubMed

    Bartoletti, M; Gubellini, C; Ricci, F; Gaiardi, M

    2005-11-01

    The GABAB agonist baclofen (BCF) has recently been reported to block the expression of sensitization to the locomotor effect of amphetamine (AMPH), and to reverse it after repeated administration. The present study was undertaken to investigate whether baclofen could also prevent the development of sensitization to the psychostimulant. Chronic AMPH treatment (1.5 mg/kg i.p. for 10 days) led to an increased locomotor response to AMPH (1.5 mg/kg) when the animals were challenged 3 and 30 days after the end of repeated treatment. Chronic co-administration of BCF (2 mg/kg, i.p.) and AMPH blocked the development of sensitization to the stimulant effect of AMPH. An ancillary experiment excluded that a 'state-dependency' hypothesis could account for the effect of baclofen. Furthermore, a previous repeated treatment with baclofen alone had no influence either on the acute AMPH effect or on the subsequent development of sensitization to AMPH. In conclusion, the results confirm that GABAB receptors play an important role in the acquisition of AMPH behavioural sensitization and further support a potential use of GABAB agonists in the treatment of psychostimulant addiction.

  16. Differential effects of propranolol on conditioned hyperactivity and locomotor sensitization induced by morphine in rats

    PubMed Central

    Wei, Shuguang; Li, Xinwang

    2014-01-01

    According to memory reconsolidation theory, when long-term memory is reactivated by relevant clues, the memory traces become labile, which can be altered by pharmacological manipulations. Accumulating evidence reveals that memory related to drug abuse can be erased by disrupting reconsolidation process. We used an animal model that could simultaneously measure conditioned hyperactivity and locomotor sensitization induced by morphine. β-adrenoceptor antagonist propranolol or saline were administered following conditioned stimuli (CS) or a small dose of morphine reactivation. The results showed that the conditioned hyperactivity could be disrupted by propranolol treatment following CS reactivation. However, the expression of locomotor sensitization could not be disrupted by propranolol administration following CS or morphine reactivation. Furthermore, morphine injection and propranolol intervention enhanced the locomotor sensitization effect. These data suggest that blocking the reconsolidation process can disrupt the conditioned hyperactivity induced by environmental cues associated with morphine treatment, but not morphine-induced locomotor sensitization. PMID:24445603

  17. Differential effects of propranolol on conditioned hyperactivity and locomotor sensitization induced by morphine in rats.

    PubMed

    Wei, Shuguang; Li, Xinwang

    2014-01-21

    According to memory reconsolidation theory, when long-term memory is reactivated by relevant clues, the memory traces become labile, which can be altered by pharmacological manipulations. Accumulating evidence reveals that memory related to drug abuse can be erased by disrupting reconsolidation process. We used an animal model that could simultaneously measure conditioned hyperactivity and locomotor sensitization induced by morphine. β-Adrenoceptor antagonist propranolol or saline were administered following conditioned stimuli (CS) or a small dose of morphine reactivation. The results showed that the conditioned hyperactivity could be disrupted by propranolol treatment following CS reactivation. However, the expression of locomotor sensitization could not be disrupted by propranolol administration following CS or morphine reactivation. Furthermore, morphine injection and propranolol intervention enhanced the locomotor sensitization effect. These data suggest that blocking the reconsolidation process can disrupt the conditioned hyperactivity induced by environmental cues associated with morphine treatment, but not morphine-induced locomotor sensitization.

  18. Nicotine-induced locomotor sensitization: pharmacological analyses with candidate smoking cessation aids.

    PubMed

    Goutier, Wouter; Kloeze, Margreet; McCreary, Andrew C

    2016-03-01

    There are a number of approved therapeutics for the management of alcohol dependence, which might also convey the potential as smoking cessation aids. The present study investigated the effect of a few of these therapeutics and potential candidates (non-peptide vasopressin V1b antagonists) on the expression of nicotine-induced behavioral sensitization in Wistar rats. The following compounds were included in this evaluation: rimonabant, bupropion, topiramate, acamprosate, naltrexone, mecamylamine, nelivaptan (SSR-149415, V1b antagonist) and two novel V1b antagonists. Following the development of nicotine-induced locomotor sensitization and a withdrawal period, the expression of sensitization was assessed in the presence of one of the examined agents given 30 minutes prior to the nicotine challenge injection. Acamprosate, naltrexone, rimonabant, mecamylamine, nelivaptan and V1b antagonist 'compound 2' significantly antagonized the expression of nicotine-induced sensitization. Whereas topiramate showed a trend for effects, the V1b antagonist 'compound 1' did not show any significant effects. Bupropion failed to block sensitization but increased activity alone and was therefore tested in development and cross-sensitization studies. Taken together, these findings provide pre-clinical evidence that these molecules attenuated the expression of nicotine-induced sensitization and should be further investigated as putative treatments for nicotine addiction. Moreover, V1b antagonists should be further investigated as a potential novel smoking cessation aid. © 2014 Society for the Study of Addiction.

  19. Inhibitory Role of Inducible cAMP Early Repressor (ICER) in Methamphetamine-Induced Locomotor Sensitization

    PubMed Central

    Han, Wenhua; Takamatsu, Yukio; Yamamoto, Hideko; Kasai, Shinya; Endo, Shogo; Shirao, Tomoaki; Kojima, Nobuhiko; Ikeda, Kazutaka

    2011-01-01

    Background The inducible cyclic adenosine monophosphate (cAMP) early repressor (ICER) is highly expressed in the central nervous system and functions as a repressor of cAMP response element-binding protein (CREB) transcription. The present study sought to clarify the role of ICER in the effects of methamphetamine (METH). Methods and Findings We tested METH-induced locomotor sensitization in wildtype mice, ICER knockout mice, and ICER I-overexpressing mice. Both ICER wildtype mice and knockout mice displayed increased locomotor activity after continuous injections of METH. However, ICER knockout mice displayed a tendency toward higher locomotor activity compared with wildtype mice, although no significant difference was observed between the two genotypes. Moreover, compared with wildtype mice, ICER I-overexpressing mice displayed a significant decrease in METH-induced locomotor sensitization. Furthermore, Western blot analysis and quantitative real-time reverse transcription polymerase chain reaction demonstrated that ICER overexpression abolished the METH-induced increase in CREB expression and repressed cocaine- and amphetamine-regulated transcript (CART) and prodynorphin (Pdyn) expression in mice. The decreased CART and Pdyn mRNA expression levels in vivo may underlie the inhibitory role of ICER in METH-induced locomotor sensitization. Conclusions Our data suggest that ICER plays an inhibitory role in METH-induced locomotor sensitization. PMID:21738744

  20. Evidence of memory generalization in contextual locomotor sensitization induced by amphetamine.

    PubMed

    Engelke, Douglas Senna; Filev, Renato; Mello, Luiz E; Santos-Junior, Jair Guilherme

    2017-01-15

    Addiction is a multifactorial disease that comprises physiological mechanisms of learning and memory. Addict subjects have intense plasticity in cortical and limbic circuits during intoxication, abstinence or even in drug seeking behavior. Locomotor sensitization is a classic animal model of drug addiction that mimics the changes that occur in the transition from drug use to drug addiction. Several studies have demonstrated the importance of contextual associative processes in this task. However, whether the mechanisms of sensitization are maintained and precise over the time remain an open question. Thus, the aim of this study was to investigate the importance of context in the maintenance and precision of locomotor sensitization across time. For this, male c57bl/6 mice were submitted to different contexts during the acquisition phase of amphetamine-induced locomotor sensitization. We found that after 3days of withdrawal, the expression of locomotor sensitization was context dependent, as characterized by an increased locomotion in the acquisition context (A), but not in the novel context (B). Surprisingly, when the expression of locomotor sensitization was tested after 28days of withdrawal, mice that acquired sensitization in the context A exhibited increased locomotion in both contexts (A and B), suggesting that memories associated with amphetamine drugs generalize following long periods of abstinence. The same generalization did not occur in mice sensitized in a well-known context (home cage). These results demonstrate, for the first time, the influence of memory generalization in amphetamine-induced locomotor sensitization. The evidence that memory generalization also occurs in sensitization provides new advances in the comprehension of the mechanisms underlying memory role in addiction process. Elucidating the mechanisms of amphetamine sensitization may shed some light on understanding the transition from drug use to addiction. Copyright © 2016 Elsevier B

  1. Rapid Sensitization of Physiological, Neuronal, and Locomotor Effects of Nicotine: Critical Role of Peripheral Drug Actions

    PubMed Central

    Lenoir, Magalie; Tang, Jeremy S.; Woods, Amina S.

    2013-01-01

    Repeated exposure to nicotine and other psychostimulant drugs produces persistent increases in their psychomotor and physiological effects (sensitization), a phenomenon related to the drugs' reinforcing properties and abuse potential. Here we examined the role of peripheral actions of nicotine in nicotine-induced sensitization of centrally mediated physiological parameters (brain, muscle, and skin temperatures), cortical and VTA EEG, neck EMG activity, and locomotion in freely moving rats. Repeated injections of intravenous nicotine (30 μg/kg) induced sensitization of the drug's effects on all these measures. In contrast, repeated injections of the peripherally acting analog of nicotine, nicotine pyrrolidine methiodide (nicotinePM, 30 μg/kg, i.v.) resulted in habituation (tolerance) of the same physiological, neuronal, and behavioral measures. However, after repeated nicotine exposure, acute nicotinePM injections induced nicotine-like physiological responses: powerful cortical and VTA EEG desynchronization, EMG activation, a large brain temperature increase, but weaker hyperlocomotion. Additionally, both the acute locomotor response to nicotine and nicotine-induced locomotor sensitization were attenuated by blockade of peripheral nicotinic receptors by hexamethonium (3 mg/kg, i.v.). These data suggest that the peripheral actions of nicotine, which precede its direct central actions, serve as a conditioned interoceptive cue capable of eliciting nicotine-like physiological and neural responses after repeated nicotine exposure. Thus, by providing a neural signal to the CNS that is repeatedly paired with the direct central effects of nicotine, the drug's peripheral actions play a critical role in the development of nicotine-induced physiological, neural, and behavioral sensitization. PMID:23761889

  2. Prefrontal microRNA-221 Mediates Environmental Enrichment-Induced Increase of Locomotor Sensitivity to Nicotine

    PubMed Central

    Gomez, Adrian M.; Altomare, Diego; Sun, Wei-Lun; Midde, Narasimha M.; Ji, Hao; Shtutman, Michael; Turner, Jill R.; Creek, Kim E.

    2016-01-01

    phosphorylated cAMP-response element-binding protein in the medial prefrontal cortex of impoverished condition but not enriched condition rats. Conclusion: These findings suggest that environmental enrichment, via upregulation of prefrontal microRNA-221 expression, suppresses the nicotine-induced activation of extracellular signal-regulated kinase and cAMP-response element-binding protein, which provides a potential mechanism underlying enhanced locomotor sensitivity to nicotine. PMID:26232787

  3. Assessment of substance abuse liability in rodents: self-administration, drug discrimination, and locomotor sensitization.

    PubMed

    Paterson, Neil E

    2012-09-01

    Assessing abuse liability is a crucial step in the development of a novel chemical entity (NCE) with central nervous system (CNS) activity or with chemical or pharmacological properties in common with known abused substances. Rodent assessment of abuse liability is highly attractive due to its relatively low cost and high predictive validity. Described in this unit are three rodent assays commonly used to provide data on the potential for abuse liability based on the acute effects of NCEs: specifically, self-administration, drug discrimination, and locomotor sensitization. As these assays provide insight into the potential abuse liability of NCEs as well as in vivo pharmacological mechanism(s) of action, they should form a key part of the development process for novel therapeutics aimed at treating CNS disorders.

  4. Oxycodone-induced conditioned place preference and sensitization of locomotor activity in adolescent and adult mice

    PubMed Central

    Niikura, Keiichi; Ho, Ann; Kreek, Mary Jeanne; Zhang, Yong

    2013-01-01

    Nonmedical use of the prescription opioid oxycodone has become a major public health problem in the United States, with special concern for adolescents. Although adults and adolescents have different sensitivities for drugs, little is known about the rewarding effects of oxycodone in adolescents compared to adults, even in rodent models. Here, we investigate sensitivity to oxycodone by the conditioned place preference assay of conditioned reward, and effect on the locomotor activity in adolescent (4 weeks old) and adult (10 weeks old) C57BL/6J mice. Mice of both ages were trained with multiple doses of oxycodone (0, 0.3, 1, and 3 mg/kg) and showed conditioned preference in a dose-dependent manner. The adult mice developed conditioned preference to the lowest dose tested (0.3 mg/kg), but adolescent mice did not. Dose-dependent oxycodone-induced increases in locomotor activity were observed across the conditioning session. Interestingly, adolescent mice developed greater sensitization to the locomotor-activating effects of oxycodone than adult mice. Thus differences in sensitivity to oxycodone, such as the lower initial sensitivity for conditioned preference but greater locomotor sensitization in adolescent mice, may indicate contributing factors in oxycodone abuse and later addiction in human adolescents. PMID:23827650

  5. Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitizes locomotor responding to the drug

    PubMed Central

    Baker, Lorinda K; Mao, Danyan; Chi, Henry; Govind, Anitha P; Vallejo, Yolanda F; Iacoviello, Michael; Herrera, Stacy; Cortright, James J; Green, William N; McGehee, Daniel S; Vezina, Paul

    2012-01-01

    Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) mediate the behavioral and motivational effects of many drugs of abuse, including nicotine. Repeated intermittent administration of these drugs, a pattern often associated with initial drug exposure, sensitizes the reactivity of dopamine (DA) neurons in this pathway, enhances the locomotor behaviors the drugs emit, and promotes their pursuit and self-administration. Here we show that activation of nicotinic acetylcholine receptors (nAChRs) in the VTA, but not the NAcc, is essential for the induction of locomotor sensitization by nicotine. Repeated intermittent nicotine exposure (4 × 0.4 mg/kg, base, i.p., administered over 7 days), a regimen leading to long-lasting locomotor sensitization, also produced upregulation of nAChRs in the VTA, but not the NAcc, in the hours following the last exposure injection. Functional nAChR upregulation was observed selectively in DA but not GABA neurons in the VTA. These effects were followed by long-term potentiation of excitatory inputs to these cells and increased nicotine-evoked DA overflow in the NAcc. Withdrawal symptoms were not observed following this exposure regimen. Thus, intermittent activation and upregulation by nicotine of nAChRs in DA neurons in the VTA may contribute to the development of behavioral sensitization and increased liability for nicotine addiction. PMID:23331514

  6. The development and expression of locomotor sensitization to nicotine in the presence of ibogaine.

    PubMed

    Zubaran, C; Shoaib, M; Stolerman, I P

    2000-08-01

    Ibogaine is a naturally occurring psychoactive alkaloid with claimed efficacy in the treatment of certain drug addictions, including nicotine. It has been reported to be a non-competitive blocker of nicotinic receptors, with a potent inhibitory action on nicotinic acetylcholine receptor-mediated catecholamine release. We have investigated the effect of different doses of ibogaine on the development and expression of sensitization to the locomotor stimulant effect of nicotine in rats, a facilitatory process in which a history of exposure to nicotine results in enhanced locomotor activity when the same dose of nicotine is administered repeatedly. The effects were determined of co-administering ibogaine (0.0, 5.0 or 10 mg/kg i.p.) with nicotine (0.0 or 0.4 mg/kg s.c.) daily for 21 days. Dose-response curves for nicotine (0.04-0.8 mg/kg s.c.) were then determined in groups of 10 rats. There was clear sensitization of the locomotor activity produced by nicotine in photocell activity cages but co-administration of ibogaine with nicotine had no effect on the degree of sensitization. Ibogaine (5-20 mg/kg) itself did not influence locomotor activity and was also without effect on the expression of the sensitized response to 0.4 mg/kg of nicotine (n = 10). Thus, there was no evidence that ibogaine may retard or suppress sensitization to nicotine.

  7. A silent synapse-based mechanism for cocaine-induced locomotor sensitization.

    PubMed

    Brown, Travis E; Lee, Brian R; Mu, Ping; Ferguson, Deveroux; Dietz, David; Ohnishi, Yoshinori N; Lin, Ying; Suska, Anna; Ishikawa, Masago; Huang, Yanhua H; Shen, Haowei; Kalivas, Peter W; Sorg, Barbara A; Zukin, R Suzanne; Nestler, Eric J; Dong, Yan; Schlüter, Oliver M

    2011-06-01

    Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

  8. A Silent Synapse-based Mechanism for Cocaine-induced Locomotor Sensitization

    PubMed Central

    Brown, Travis E.; Lee, Brian R.; Mu, Ping; Ferguson, Deveroux; Dietz, David; Ohnishi, Yoshinori N.; Lin, Ying; Suska, Anna; Ishikawa, Masago; Huang, Yanhua H.; Shen, Haowei; Kalivas, Peter W; Sorg, Barbara A.; Zukin, R. Suzanne; Nestler, Eric; Dong, Yan; Schlüter, Oliver M.

    2011-01-01

    Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry and electrophysiology in a locomotor sensitization paradigm with repeated, daily noncontingent cocaine (15 mg/kg) injections, we show that dominant negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDAR) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations. PMID:21632938

  9. The Effects of 4-Methylethcathinone on Conditioned Place Preference, Locomotor Sensitization, and Anxiety-Like Behavior: A Comparison with Methamphetamine.

    PubMed

    Xu, Peng; Qiu, Yi; Zhang, Yizhi; Βai, Yanping; Xu, Pengfei; Liu, Yuan; Kim, Jee Hyun; Shen, Hao-wei

    2016-04-01

    4-Methylethcathinone is a drug that belongs to the second generation of synthetic cathinones, and recently it has been ranked among the most popular "legal highs". Although it has similar in vitro neurochemical actions to other drugs such as cocaine, the behavioral effects of 4-methylethcathinone remain to be determined. The addictive potential and locomotor potentiation by 4-methylethcathinone were investigated in rats using the conditioned place preference and sensitization paradigm. Methamphetamine was used as a positive control. Because synthetic cathinones can have psychological effects, we also examined anxiety-like behavior using the elevated plus maze. A conditioning dose of 10 mg/kg 4-methylethcathinone was able to induce conditioned place preference and reinstatement (following 2 weeks of withdrawal). Acute or repeated injections of 4-methylethcathinone at 3 or 10mg/kg failed to alter locomotor activity. At 30 mg/kg, however, acute 4-methylethcathinone increased locomotor activity compared with saline, while chronic 4-methylethcathinone induced a delayed and attenuated sensitization compared with methamphetamine. Additionally, repeated daily injections of 4-methylethcathinone (30 mg/kg) reduced, whereas methamphetamine increased time spent by rats in the open arm of an elevated plus maze compared with saline injections. Interestingly, a 2-week withdrawal period following chronic injections of 4-methylethcathinone or methamphetamine increased time spent in the open arm in all rats. The rewarding properties of 4-methylethcathinone were found to be dissociated from its effects on locomotor activity. Additionally, chronic 4-methylethcathinone use may trigger abnormal anxious behaviors. These behavioral effects caused by 4-methylethcathinone appear to last even after a withdrawal period. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  10. The Effects of 4-Methylethcathinone on Conditioned Place Preference, Locomotor Sensitization, and Anxiety-Like Behavior: A Comparison with Methamphetamine

    PubMed Central

    Xu, Peng; Qiu, Yi; Zhang, Yizhi; Βai, Yanping; Xu, Pengfei; Liu, Yuan; Kim, Jee Hyun

    2016-01-01

    Background: 4-Methylethcathinone is a drug that belongs to the second generation of synthetic cathinones, and recently it has been ranked among the most popular “legal highs”. Although it has similar in vitro neurochemical actions to other drugs such as cocaine, the behavioral effects of 4-methylethcathinone remain to be determined. Methods: The addictive potential and locomotor potentiation by 4-methylethcathinone were investigated in rats using the conditioned place preference and sensitization paradigm. Methamphetamine was used as a positive control. Because synthetic cathinones can have psychological effects, we also examined anxiety-like behavior using the elevated plus maze. Results: A conditioning dose of 10mg/kg 4-methylethcathinone was able to induce conditioned place preference and reinstatement (following 2 weeks of withdrawal). Acute or repeated injections of 4-methylethcathinone at 3 or 10mg/kg failed to alter locomotor activity. At 30mg/kg, however, acute 4-methylethcathinone increased locomotor activity compared with saline, while chronic 4-methylethcathinone induced a delayed and attenuated sensitization compared with methamphetamine. Additionally, repeated daily injections of 4-methylethcathinone (30mg/kg) reduced, whereas methamphetamine increased time spent by rats in the open arm of an elevated plus maze compared with saline injections. Interestingly, a 2-week withdrawal period following chronic injections of 4-methylethcathinone or methamphetamine increased time spent in the open arm in all rats. Conclusions: The rewarding properties of 4-methylethcathinone were found to be dissociated from its effects on locomotor activity. Additionally, chronic 4-methylethcathinone use may trigger abnormal anxious behaviors. These behavioral effects caused by 4-methylethcathinone appear to last even after a withdrawal period. PMID:26612552

  11. Meal schedule influences food restriction-induced locomotor sensitization to methamphetamine

    PubMed Central

    Sharpe, Amanda L.; Klaus, Joshua D.

    2015-01-01

    Rationale Traditional protocols for inducing sensitization to psychostimulants use an intermittent or “binge”-like drug administration, and binge eating behavior is comorbid with drug abuse in humans. Food restriction increases the reinforcing properties and self-administration of many drugs of abuse. Objective The present study tested the hypotheses that (1) food restriction induces sensitization to the locomotor stimulation observed in response to methamphetamine and (2) a binge-like feeding schedule during food restriction produces increased sensitization compared to equally restricted mice fed in three daily meals. Methods Male DBA/2J mice were fed ad libitum or were food restricted to either an 8% or 16% loss of body weight. Additionally, the food-restricted mice were divided into two groups that were fed in either one meal (binge) or three equal-sized meals (meal). After the reduced body weight was stable, mice were tested for locomotor activity following saline and methamphetamine (1 mg/kg) injections. Results Both 16% body weight loss groups exhibited sensitization to methamphetamine. Opposite to our hypothesis, the 8% meal but not the 8% binge food-restricted group demonstrated locomotor sensitization. Serum corticosterone levels were significantly higher in the meal-fed groups when compared to the binge- and ad libitum-fed groups. Conclusions These results support a role for feeding schedule and plasma corticosterone levels in food restriction-induced enhancement of the effects of methamphetamine. PMID:21750897

  12. Acute sensitivity of FAST and SLOW mice to the effects of abused drugs on locomotor activity.

    PubMed

    Phillips, T J; Burkhart-Kasch, S; Gwiazdon, C C; Crabbe, J C

    1992-05-01

    The universal nature of the stimulant or euphoric effect of addictive drugs suggests that it may be an important predictor of a drug's addiction potential. Furthermore, assessment of stimulant sensitivity could be useful for predicting the liability of individuals to drug abuse. The stimulant actions of abused drugs from different pharmacological classes may share a common biological mechanism. We investigated this notion by assessing the drug responses relative to base-line locomotor activity of mice selectively bred for increased (FAST) and reduced (SLOW) sensitivity to ethanol-induced stimulation. FAST mice were more sensitive than SLOW mice to the stimulant effects of methanol (1.5-3.0 g/kg), t-butanol (0.2-0.6 g/kg), n-propanol (0.15-1.2 g/kg), pentobarbital (10-40 mg/kg) and phenobarbital (15-120 mg/kg). FAST and SLOW mice were similarly stimulated by d-amphetamine (1.25-10 mg/kg) and caffeine (2.5-20 mg/kg). The activity of FAST and SLOW mice was equally depressed by nicotine (0.5-2.0 mg/kg) and morphine (4-75 mg/kg). Finally, FAST mice were unaffected, whereas SLOW mice were depressed by diazepam (1-8 mg/kg). Selection for relative sensitivity to stimulation by ethanol has generalized to other alcohols and to barbiturates, but not to several other abused drugs, including amphetamine. The data presented here support a hypothesized common mechanism of stimulant action for alcohols and barbiturates, and suggest that differences in sensitivity to drug stimulant effects can be seen in the absence of dopamine system differences.

  13. Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference.

    PubMed

    Felszeghy, Klara; Espinosa, José Manuel; Scarna, Hélène; Bérod, Anne; Rostène, William; Pélaprat, Didier

    2007-12-01

    Chronic use of psychostimulants induces enduringly increased responsiveness to a subsequent psychostimulant injection and sensitivity to drug-associated cues, contributing to drug craving and relapse. Neurotensin (NT), a neuropeptide functionally linked to dopaminergic neurons, was suggested to participate in these phenomena. We and others have reported that SR 48692, an NT receptor antagonist, given in pre- or co-treatments with cocaine or amphetamine, alters some behavioral effects of these drugs in rats. However, its efficacy when applied following repeated cocaine administration remains unknown. We, therefore, evaluated the ability of SR 48692, administered after a cocaine regimen, to interfere with the expression of locomotor sensitization and conditioned place preference (CPP) in rats. We demonstrated that the expression of locomotor sensitization, induced by four cocaine injections (15 mg/kg, i.p.) every other day and a cocaine challenge 1 week later, was attenuated by a subsequent 2-week daily administration of SR 48692 (1 mg/kg, i.p.). Furthermore, the expression of cocaine-induced CPP was suppressed by a 10-day SR 48692 treatment started after the conditioning period (four 15 mg/kg cocaine injections every other day). Taken together, our data show that a chronic SR 48692 treatment given after a cocaine regimen partly reverses the expression of locomotor sensitization and CPP in the rat, suggesting that NT participates in the maintenance of these behaviors. Our results support the hypothesis that targeting neuromodulatory systems, such as the NT systems may offer new strategies in the treatment of drug addiction.

  14. Behavioral cross-sensitization between DOCA-induced sodium appetite and cocaine-induced locomotor behavior

    PubMed Central

    Acerbo, Martin J.; Johnson, Alan Kim

    2011-01-01

    Behavioral sensitization involves increases in the magnitude of a response to a stimulus after repeated exposures to the same response initiator. Administration of psychomotor stimulants and the induction of appetitive motivational states associated with natural reinforcers like sugar and salt are among experimental manipulations producing behavioral sensitization. In rats, repeated administration of the mineralocorticoid agonist deoxycorticosterone acetate (DOCA) initially induces incremental increases in daily hypertonic saline consumption (i.e., sensitization of sodium appetite) in spite of the retention of sodium. The present studies investigated whether sodium appetite sensitization induced by DOCA shares mechanisms similar to those of psychomotor stimulant-induced sensitization, and whether there is evidence for reciprocal cross-sensitization. In Experiments 1 and 3, rats received control or cocaine treatments to induce locomotor sensitization. A week later DOCA (or vehicle) was administered to generate a sodium appetite. Animals pretreated with cocaine showed a greater sodium appetite. In Experiment 2, the order of the putative sensitizing treatments was reversed. Rats first received either a series of DOCA or vehicle treatments either with or without access to saline and were later tested for sensitization of the locomotor response to cocaine. Animals pretreated with DOCA without access to saline showed greater locomotor responses to cocaine than animals receiving vehicle treatments. Together these experiments indicate that treatments generating a sustained salt appetite and producing cocaine-induced psychomotor responses show reciprocal behavioral cross-sensitization. The underlying mechanisms accounting for this relationship may be the fact that psychostimulants and an unresolved craving for sodium can act as potent stressors. PMID:21352848

  15. Behavioral cross-sensitization between DOCA-induced sodium appetite and cocaine-induced locomotor behavior.

    PubMed

    Acerbo, Martin J; Johnson, Alan Kim

    2011-05-01

    Behavioral sensitization involves increases in the magnitude of a response to a stimulus after repeated exposures to the same response initiator. Administration of psychomotor stimulants and the induction of appetitive motivational states associated with natural reinforcers like sugar and salt are among experimental manipulations producing behavioral sensitization. In rats, repeated administration of the mineralocorticoid agonist deoxycorticosterone acetate (DOCA) initially induces incremental increases in daily hypertonic saline consumption (i.e., sensitization of sodium appetite) in spite of the retention of sodium. The present studies investigated whether sodium appetite sensitization induced by DOCA shares mechanisms similar to those of psychomotor stimulant-induced sensitization, and whether there is evidence for reciprocal cross-sensitization. In Experiments 1 and 3, rats received control or cocaine treatments to induce locomotor sensitization. A week later DOCA (or vehicle) was administered to generate a sodium appetite. Animals pretreated with cocaine showed a greater sodium appetite. In Experiment 2, the order of the putative sensitizing treatments was reversed. Rats first received either a series of DOCA or vehicle treatments either with or without access to saline and were later tested for sensitization of the locomotor response to cocaine. Animals pretreated with DOCA without access to saline showed greater locomotor responses to cocaine than animals receiving vehicle treatments. Together these experiments indicate that treatments generating a sustained salt appetite and producing cocaine-induced psychomotor responses show reciprocal behavioral cross-sensitization. The underlying mechanisms accounting for this relationship may be the fact that psychostimulants and an unresolved craving for sodium can act as potent stressors.

  16. Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens

    PubMed Central

    David, H N; Dhilly, M; Degoulet, M; Poisnel, G; Meckler, C; Vallée, N; Blatteau, J-É; Risso, J-J; Lemaire, M; Debruyne, D; Abraini, J H

    2015-01-01

    We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence. PMID:26151922

  17. Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens.

    PubMed

    David, H N; Dhilly, M; Degoulet, M; Poisnel, G; Meckler, C; Vallée, N; Blatteau, J-É; Risso, J-J; Lemaire, M; Debruyne, D; Abraini, J H

    2015-07-07

    We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.

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

    PubMed Central

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

    2014-01-01

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

  19. Insulin-Dependent Activation of MCH Neurons Impairs Locomotor Activity and Insulin Sensitivity in Obesity.

    PubMed

    Hausen, A Christine; Ruud, Johan; Jiang, Hong; Hess, Simon; Varbanov, Hristo; Kloppenburg, Peter; Brüning, Jens C

    2016-12-06

    Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IR(ΔMCH)) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IR(ΔMCH) mice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance.

  20. Ethanol-induced Locomotor Sensitization in DBA/2J Mice is Associated with Alterations in GABAA Subunit Gene Expression and Behavioral Sensitivity to GABAA Acting Drugs

    PubMed Central

    Linsenbardt, David N.; Boehm, Stephen L.

    2013-01-01

    Repeated exposure to ethanol may produce increased sensitivity to its acute locomotor stimulant actions, a process referred to as locomotor sensitization. Neuroadaptation within certain brain circuits, including those possessing GABAA receptors, may underlie locomotor sensitization to ethanol. Indeed, GABAA receptors are documented mediators of ethanol's cellular and behavioral actions. Moreover, because subunit composition of this receptor is predictive of its pharmacology, it is possible that alterations in subunit composition contribute to the expression of locomotor sensitization to ethanol. The goal of the present study was to determine if alterations in GABAA subunit composition are associated with the expression of locomotor sensitization in DBA/2J mice, a strain known to be particularly susceptible to the development of this behavioral phenomenon. Following a modified 14 day sensitization procedure (Phillips et al., 1994) relative changes in GABAA subunit gene expression were assessed in discrete mesolimbic brain regions. To determine if the observed changes in gene expression produced functional changes in the locomotor responses to drugs known to either preferentially or generally activate GABAA receptors normally possessing the significantly altered subunits, separate cohorts of animals were challenged with one of several low doses of zolpidem (α1-selective), etomidate (β2/3-selective), or flurazepam (γ2-directed) and assessed for locomotor alterations. Sensitized animals displayed increased expression of the α1, β2, and γ2 (v1) subunits in the Nucleus Accumbens (NAc) but not Ventral Tegmental Area (VTA). Additionally, sensitized animals displayed altered sensitivity to the locomotor actions of etomidate and flurazepam. These results support the hypothesis that neuroadaptive changes in GABAA subunit composition participate in the expression of locomotor sensitization. PMID:20219525

  1. Melatonin treatment during the incubation of sensitization attenuates methamphetamine-induced locomotor sensitization and MeCP2 expression.

    PubMed

    Wu, Jintao; Zhu, Dexiao; Zhang, Jing; Li, Guibao; Liu, Zengxun; Sun, Jinhao

    2016-02-04

    Behavior sensitization is a long-lasting enhancement of locomotor activity after exposure to psychostimulants. Incubation of sensitization is a phenomenon of remarkable augmentation of locomotor response after withdrawal and reflects certain aspects of compulsive drug craving. However, the mechanisms underlying these phenomena remain elusive. Here we pay special attention to the incubation of sensitization and suppose that the intervention of this procedure will finally decrease the expression of sensitization. Melatonin is an endogenous hormone secreted mainly by the pineal gland. It is effective in treating sleep disorder, which turns out to be one of the major withdrawal symptoms of methamphetamine (MA) addiction. Furthermore, melatonin can also protect neuronal cells against MA-induced neurotoxicity. In the present experiment, we treated mice with low dose (10mg/kg) of melatonin for 14 consecutive days during the incubation of sensitization. We found that melatonin significantly attenuated the expression of sensitization. In contrast, the vehicle treated mice showed prominent enhancement of locomotor activity after incubation. MeCP2 expression was also elevated in the vehicle treated mice and melatonin attenuated its expression. Surprisingly, correlation analysis suggested significant correlation between MeCP2 expression in the nucleus accumbens (NAc) and locomotion in both saline control and vehicle treated mice, but not in melatonin treated ones. MA also induced MeCP2 over-expression in PC12 cells. However, melatonin failed to reduce MeCP2 expression in vitro. Our results suggest that melatonin treatment during the incubation of sensitization attenuates MA-induced expression of sensitization and decreases MeCP2 expression in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Concurrent Risperidone Administration Attenuates the Development of Locomotor Sensitization Following Sub-Chronic Phencyclidine in Rats.

    PubMed

    McKibben, C E; Reynolds, G P; Jenkins, T A

    2016-03-01

    In schizophrenia early treatment may prevent disorder onset, or at least minimize its impact, suggesting possible neuroprotective properties of antipsychotics. The present study investigates the effects of chronic treatment with the atypical antipsychotic, risperidone, on locomotor sensitization in the subchronic phencyclidine-treated rat. Rats were treated with phencyclidine sub-chronically (2 mg/kg bi-daily for one week followed by a one-week wash-out period) or vehicle. Half of the phencyclidine group was concurrently treated with risperidone (0.5 mg/kg IP) twice daily for 15 days, beginning 3 days before the start of phencyclidine administration. 6 weeks after treatment all rats were injected with a phencyclidine-challenge (3.2 mg/kg) and immediately after their locomotor activity measured for 20 min. Co-administration of risperidone at the time of phencyclidine administration significantly reduced the phencyclidine-challenge locomotor effect administered 6 weeks later. These results demonstrate that concurrent risperidone is neuroprotective, and clearly suggests its functionality can be translated to a clinical setting for treating the so-called prodrome. © Georg Thieme Verlag KG Stuttgart · New York.

  3. Effects of spatial memory on morphine CPP and locomotor sensitization in mice.

    PubMed

    Zhu, Xiaolin; Sun, Wei; Li, Xinwang; Tan, Shuping; Zhang, Xiangyang

    2015-10-01

    Drug addiction is associated with memory processes. We simultaneously measured conditioned place preference (CPP) and locomotor sensitization to investigate the influence of spatial memory retrieval on morphine reward and psychomotor excitement. According to their performance in space probe trial involving the Morris water maze mice were assigned to high (including morphine and saline subgroups, H-Mor and H-Sal) and low spatial memory retrieval ability groups (L-Mor and L-Sal). Morphine (10mg/kg) produced significant CPP in L-Mor and H-Mor mice, although, L-Mor mice showed a significantly greater response to morphine. During the development period of behavior sensitization, no significant group-by-day interaction was found. However, locomotor activities of L-Mor mice were also significantly higher than H-Mor mice during the expression period of behavior sensitization. Our findings suggested that the spatial memory retrieval ability of mice influences morphine CPP, as well as behavioral sensitization. Thus, spatial memory might be implicated in drug addiction.

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

    PubMed

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

    2013-06-01

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

  5. Levo-tetrahydropalmatine attenuates the development and expression of methamphetamine-induced locomotor sensitization and the accompanying activation of ERK in the nucleus accumbens and caudate putamen in mice.

    PubMed

    Zhao, N; Chen, Y; Zhu, J; Wang, L; Cao, G; Dang, Y; Yan, C; Wang, J; Chen, T

    2014-01-31

    Levo-tetrahydropalmatine (l-THP) is an alkaloid purified from corydalis and has been used in many traditional Chinese herbal preparations for its analgesic, sedative, and hypnotic properties. Previous studies indicated that l-THP has modest antagonist activity against dopamine receptors and thus it might have potential therapeutic effects on drug addiction. However, whether and how l-THP contributes to methamphetamine (METH)-induced locomotor sensitization remains unclear. Therefore, the current study aims to examine the roles of l-THP in the development and expression of METH-induced locomotor sensitization as well as the accompanying extracellular-regulated kinase (ERK) activation in the nucleus accumbens (NAc), caudate putamen (CPu) and prefrontal cortex (PFc) in mice. We found that moderate doses of METH (0.5 and 2 mg/kg) induced hyper-locomotor activity in mice on all METH injection days whereas high dose of METH (5 mg/kg)-treated mice displayed only acute locomotor response to METH and severe stereotyped behaviors on the first day after drug injection. Interestingly, only 2 mg/kg dose of METH-induced locomotor sensitization which was accompanied by the activation of ERK1/2 in the NAc and CPu in mice. Although l-THP (5 and 10 mg/kg) per se did not induce obvious changes in locomotor activities in mice, its co-administration with METH could significantly attenuate acute METH-induced hyper-locomotor activity, the development and expression of METH-induced locomotor sensitization, and the accompanying ERK1/2 activation in the NAc and CPu. These results suggest that l-THP has potential therapeutic effect on METH-induced locomotor sensitization, and the underlying molecular mechanism might be related to its inhibitory effect on ERK1/2 phosphorylation in the NAc and CPu.

  6. CRFR1 in the ventromedial caudate putamen modulates acute stress-enhanced expression of cocaine locomotor sensitization.

    PubMed

    Liu, Shuli; Wang, Zhiyan; Li, Yijing; Sun, Xiaowei; Ge, Feifei; Yang, Mingda; Wang, Xinjuan; Wang, Na; Wang, Junkai; Cui, Cailian

    2017-07-15

    Repeated exposure to psychostimulants induces a long-lasting enhancement of locomotor activity called behavioral sensitization, which is often reinforced by stress after drug withdrawal. The mechanisms underlying these phenomena remain elusive. Here we explored the effects of acute stress 3 or 14 days after the cessation of chronic cocaine treatment on the expression of locomotor sensitization induced by a cocaine challenge in rats and the key brain region and molecular mechanism underlying the phenomenon. A single session of forced swimming, as an acute stress (administered 2 days after the cessation of cocaine), significantly enhanced the expression of cocaine locomotor sensitization 14 days after the final cocaine injection (challenge at 12 days after acute stress) but not 3 days after the cessation of cocaine (challenge at 1 day after acute stress). The result indicated that acute stress enhanced the expression of cocaine locomotor sensitization after incubation for 12 days rather than 1 day after the last cocaine injection. Moreover, the enhancement in locomotor sensitization was paralleled by a selective increase in the number of the c-Fos(+) cells, the level of CRFR1 mRNA in the ventromedial caudate putamen (vmCPu). Furthermore, the enhancement was significantly attenuated by CRFR1 antagonist NBI-27914 into the vmCPu, implying that the up-regulation of CRFR1 in the vmCPu seems to be critical in the acute stress-enhanced expression of cocaine locomotor sensitization. The findings demonstrate that the long-term effect of acute stress on the expression of cocaine locomotor sensitization is partially mediated by CRFR1 in the vmCPu. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Conditioned place preference and locomotor sensitization after repeated administration of cocaine or methamphetamine in rats treated with epidermal growth factor during the neonatal period.

    PubMed

    Mizuno, Makoto; Malta, Romulo S; Nagano, Tadasato; Nawa, Hiroyuki

    2004-10-01

    Epidermal growth factor (EGF) and its structurally related proteins are involved in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. We recently reported EGF and EGF-receptor abnormalities in both the brain tissues and blood of schizophrenic patients. Administration of EGF to neonatal rats transiently increases tyrosine hydroxylase expression and subsequently results in behavioral abnormalities in prepulse inhibition of acoustic startle, locomotor activity, and social interaction after development. The enhanced locomotor and stereotypic responses of the neonatally EGF-treated rats are considered to be an animal model for positive schizophrenia symptoms. In the present study, we investigated psychostimulant sensitivity of neonatally EGF-treated rats. At the adult stage, EGF-treated rats were challenged with cocaine (15 mg/kg) or methamphetamine (1 mg/kg), and conditioned place preference and locomotor activity were examined. The rats that received EGF during the neonatal period had significantly higher conditioned place preference for where cocaine or methamphetamine was administered than controls. The neonatal EGF treatment enhanced behavioral response to methamphetamine and behavioral sensitization to cocaine at the adult stage. Drug-naive controls gradually increased locomotor responses to cocaine during their daily injections, whereas EGF-treated rats exhibited a larger increase in cocaine responses. These results indicate that overactivation of the EGF receptors (ErbB1) during the neonatal period influences future sensitivity to psychostimulants. Our findings indicate a potential link between EGF-receptor activation and drug addiction.

  8. Morphine-induced sensitization of locomotor activity in mice: effect of social isolation on plasma corticosterone levels.

    PubMed

    Francès, H; Graulet, A; Debray, M; Coudereau, J P; Guéris, J; Bourre, J M

    2000-03-31

    This study examined the influence of social isolation on behavioural sensitization to the locomotor effect of morphine and the link between this behaviour and plasma corticosterone concentrations. Four weeks isolation induced an increase in the locomotor effect of morphine. In social and isolated mice, repeated administrations (6) of morphine (one injection every 3 or 4 days) followed by 3 h in an actimeter induced behavioural sensitization to the locomotor effect of morphine. No interaction was observed between social isolation and behavioural sensitization to morphine. Resocializing previously isolated mice for 3 weeks reduced the morphine-induced locomotor effect without altering the behavioural sensitization. Corticosterone plasma levels were more increased (416%) in mice isolated 5 weeks than in mice isolated for 2 weeks (243%) and they return to the control levels following 3 weeks of resocialization. Since there was no interaction between the increase in morphine locomotor effect induced by social isolation and the morphine-induced behavioural sensitization, it is suggested that each of these two events acts independently. Whether or not a common mechanism (plasma corticosterone levels?) partly underlies both effects, the result resembles a simple additive effect.

  9. Attenuated methamphetamine-induced locomotor sensitization in serotonin transporter knockout mice is restored by serotonin 1B receptor antagonist treatment.

    PubMed

    Igari, Moe; Shen, Hao-Wei; Hagino, Yoko; Fukushima, Setsu; Kasahara, Yoshiyuki; Lesch, Klaus-Peter; Murphy, Dennis L; Hall, Frank Scott; Uhl, George R; Ikeda, Kazutaka; Yaegashi, Nobuo; Sora, Ichiro

    2015-02-01

    Repeated administration of methamphetamine (METH) enhances acute locomotor responses to METH administered in the same context, a phenomenon termed as 'locomotor sensitization'. Although many of the acute effects of METH are mediated by its influences on the compartmentalization of dopamine, serotonin systems have also been suggested to influence the behavioral effects of METH in ways that are not fully understood. The present experiments examined serotonergic roles in METH-induced locomotor sensitization by assessing: (a) the effect of serotonin transporter (SERT; Slc6A4) knockout (KO) on METH-induced locomotor sensitization; (b) extracellular monoamine levels in METH-treated animals as determined by in-vivo microdialysis; and (c) effects of serotonin (5-HT) receptor antagonists on METH-induced behavioral sensitization, with focus on effects of the 5-HT1B receptor antagonist SB 216641 and a comparison with the 5-HT2 receptor antagonist ketanserin. Repeated METH administration failed to induce behavioral sensitization in homozygous SERT KO (SERT-/-) mice under conditions that produced substantial sensitization in wild-type or heterozygous SERT KO (SERT+/-) mice. The selective 5-HT1B antagonist receptor SB 216641 restored METH-induced locomotor sensitization in SERT-/- mice, whereas ketanserin was ineffective. METH-induced increases in extracellular 5-HT (5-HTex) levels were substantially reduced in SERT-/- mice, although SERT genotype had no effect on METH-induced increases in extracellular dopamine. These experiments demonstrate that 5-HT actions, including those at 5-HT1B receptors, contribute to METH-induced locomotor sensitization. Modulation of 5-HT1B receptors might aid therapeutic approaches to the sequelae of chronic METH use.

  10. Dissociation of corticotropin-releasing factor receptor subtype involvement in sensitivity to locomotor effects of methamphetamine and cocaine

    PubMed Central

    Giardino, William J.; Mark, Gregory P.; Stenzel-Poore, Mary P.

    2011-01-01

    Rationale Enhanced sensitivity to the euphoric and locomotor-activating effects of psychostimulants may influence an individual's predisposition to drug abuse and addiction. While drug-induced behaviors are mediated by the actions of several neurotransmitter systems, past research revealed that the corticotropin-releasing factor (CRF) system is important in driving the acute locomotor response to psychostimulants. Objectives We previously reported that genetic deletion of the CRF type-2 receptor (CRF-R2), but not the CRF type-1 receptor (CRF-R1) dampened the acute locomotor stimulant response to methamphetamine (1 mg/kg). These results contrasted with previous studies implicating CRF-R1 in the locomotor effects of psychostimulants. Since the majority of previous studies focused on cocaine, rather than methamphetamine, we set out to test the hypothesis that these drugs differentially engage CRF-R1 and CRF-R2. Methods We expanded our earlier findings by first replicating our previous experiments at a higher dose of methamphetamine (2 mg/kg), and by assessing the effects of the CRF-R1-selective antagonist CP-376,395 (10 mg/kg) on methamphetamine-induced locomotor activity. Next, we used both genetic and pharmacological tools to examine the specific components of the CRF system underlying the acute locomotor response to cocaine (5–10 mg/kg). Results While genetic deletion of CRF-R2 dampened the locomotor response to methamphetamine (but not cocaine), genetic deletion and pharmacological blockade of CRF-R1 dampened the locomotor response to cocaine (but not methamphetamine). Conclusions These findings highlight the differential involvement of CRF receptors in acute sensitivity to two different stimulant drugs of abuse, providing an intriguing basis for the development of more targeted therapeutics for psychostimulant addiction. PMID:21833501

  11. Individual Differences in Ethanol Locomotor Sensitization Are Associated with Dopamine D1 Receptor Intra-Cellular Signaling of DARPP-32 in the Nucleus Accumbens

    PubMed Central

    Abrahao, Karina Possa; Oliveira Goeldner, Francine; Souza-Formigoni, Maria Lucia Oliveira

    2014-01-01

    In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as “sensitized” and the 33% with the lowest levels as "non-sensitized”. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor

  12. Exploring the role of locomotor sensitization in the circadian food entrainment pathway

    PubMed Central

    Opiol, Hanna; de Zavalia, Nuria; Delorme, Tara; Solis, Pavel; Rutherford, Spencer; Shalev, Uri; Amir, Shimon

    2017-01-01

    Food entrainment is the internal mechanism whereby the phase and period of circadian clock genes comes under the control of daily scheduled food availability. Food entrainment allows the body to efficiently realign the internal timing of behavioral and physiological functions such that they anticipate food intake. Food entrainment can occur with or without caloric restriction, as seen with daily schedules of restricted feeding (RF) or restricted treat (RT) that restrict food or treat intake to a single feeding time. However, the extent of clock gene control is more pronounced with caloric restriction, highlighting the role of energy balance in regulating clock genes. Recent studies have implicated dopamine (DA) to be involved in food entrainment and caloric restriction is known to affect dopaminergic pathways to enhance locomotor activity. Since food entrainment results in the development of a distinct behavioral component, called food anticipatory activity (FAA), we examined the role of locomotor sensitization (LS) in food entrainment by 1) observing whether amphetamine (AMPH) sensitization results in enhanced locomotor output of FAA and 2) measuring LS of circadian and non-circadian feeding paradigms to an acute injection of AMPH (AMPH cross-sensitization). Unexpectedly, AMPH sensitization did not show enhancement of FAA. On the contrary, LS did develop with sufficient exposure to RF. LS was present after 2 weeks of RF, but not after 1, 3 or 7 days into RF. When food was returned and rats regain their original body weight at 10–15 days post-RF, LS remained present. LS did not develop to RT, nor to feedings of a non-circadian schedule, e.g. variable restricted feeding (VRF) or variable RT (VRT). Further, when RF was timed to the dark period, LS was observed only when tested at night; RF timed to the light period resulted in LS that was present during day and night. Taken together our results show that LS develops with food entrainment to RF, an effect that is

  13. Exploring the role of locomotor sensitization in the circadian food entrainment pathway.

    PubMed

    Opiol, Hanna; de Zavalia, Nuria; Delorme, Tara; Solis, Pavel; Rutherford, Spencer; Shalev, Uri; Amir, Shimon

    2017-01-01

    Food entrainment is the internal mechanism whereby the phase and period of circadian clock genes comes under the control of daily scheduled food availability. Food entrainment allows the body to efficiently realign the internal timing of behavioral and physiological functions such that they anticipate food intake. Food entrainment can occur with or without caloric restriction, as seen with daily schedules of restricted feeding (RF) or restricted treat (RT) that restrict food or treat intake to a single feeding time. However, the extent of clock gene control is more pronounced with caloric restriction, highlighting the role of energy balance in regulating clock genes. Recent studies have implicated dopamine (DA) to be involved in food entrainment and caloric restriction is known to affect dopaminergic pathways to enhance locomotor activity. Since food entrainment results in the development of a distinct behavioral component, called food anticipatory activity (FAA), we examined the role of locomotor sensitization (LS) in food entrainment by 1) observing whether amphetamine (AMPH) sensitization results in enhanced locomotor output of FAA and 2) measuring LS of circadian and non-circadian feeding paradigms to an acute injection of AMPH (AMPH cross-sensitization). Unexpectedly, AMPH sensitization did not show enhancement of FAA. On the contrary, LS did develop with sufficient exposure to RF. LS was present after 2 weeks of RF, but not after 1, 3 or 7 days into RF. When food was returned and rats regain their original body weight at 10-15 days post-RF, LS remained present. LS did not develop to RT, nor to feedings of a non-circadian schedule, e.g. variable restricted feeding (VRF) or variable RT (VRT). Further, when RF was timed to the dark period, LS was observed only when tested at night; RF timed to the light period resulted in LS that was present during day and night. Taken together our results show that LS develops with food entrainment to RF, an effect that is

  14. Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats.

    PubMed

    Strong, C E; Schoepfer, K J; Dossat, A M; Saland, S K; Wright, K N; Kabbaj, M

    2017-07-15

    Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction. Copyright © 2017. Published by Elsevier Ltd.

  15. The 5-HT3 receptor antagonist, ondansetron, blocks the development and expression of ethanol-induced locomotor sensitization in mice.

    PubMed

    Umathe, Sudhir N; Bhutada, Pravinkumar S; Raut, Vivek S; Jain, Nishant S; Mundhada, Yogita R

    2009-02-01

    Manipulation of the serotonergic system has been shown to alter ethanol sensitization. Ondansetron is a 5-HT3 receptor antagonist, reported to attenuate cocaine and methamphetamine-induced behavioral sensitization, but no reports are available on its role in ethanol-induced behavioral sensitization. Therefore, an attempt has been made to assess this issue by using an earlier used animal model of ethanol-induced locomotor sensitization. Results indicated that ondansetron (0.25-1.0 mg/kg, subcutaneously) given before the challenge dose of ethanol (2.4 g/kg, intraperitoneally) injection, significantly and dose dependently attenuated the expression of sensitization. In addition, ondansetron (1.0 mg/kg, subcutaneously) given before ethanol injection on days 1, 4, 7, and 10 significantly blocked the development (days 1, 4, 7, and 10), and expression (day 15) of sensitization to the locomotor stimulant effect of ethanol injection. Ondansetron had no effect per se on locomotor activity and did not affect blood ethanol levels. Therefore, the results raise the possibility that ondansetron blocked the development and expression of ethanol-induced locomotor sensitization by acting on 5-HT3 receptors.

  16. Different locomotor sensitization responses to repeated cocaine injections are associated with differential phosphorylation of GluA1 in the dorsomedial striatum of adult rats.

    PubMed

    Kim, Myonghwan; Kim, Wonju; Baik, Ja-Hyun; Yoon, Bong-June

    2013-11-15

    Behavioral sensitization to psychostimulants reflects neural adaptation, which might share a common mechanism with drug addiction. Outbred male rats show different locomotor sensitization responses to cocaine, and cocaine also produces varied addictive progress in humans. We investigated whether differences in the induction of sensitization would affect the long-term persistence of sensitized locomotor activity, and we sought to determine the molecular basis for the variability in sensitization. Male Sprague-Dawley rats that showed sensitized locomotor responses over 5 consecutive daily cocaine injections (SENS) had significantly lower initial locomotor responses to the 1st cocaine exposure than did rats that did not show locomotor sensitization (NONS). Furthermore, rats that underwent 1 month of cocaine withdrawal after 5 repeated cocaine injections also exhibited sensitized or non-sensitized locomotor responses to a challenge injection of cocaine (SENS-C or NONS-C, respectively). This variability was also related to the initial responsiveness to cocaine. We examined the level of phosphorylation of the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropioniate receptor (AMPAR) in the dorsal striatum and found that there were significant differences between the sensitized rats and the non-sensitized rats. pGluA1-Ser831 was increased in the SENS rats during the induction of locomotor sensitization, and pGluA1-Ser845 was increased in the SENS-C rats during the expression of locomotor sensitization. These phosphorylation changes were observed in the dorsomedial striatum (DMS) of adult rats but not in the dorsolateral striatum (DLS) of adults. Our findings suggest that differential phosphorylation of AMPAR might be an important mechanism that contributes to the development of locomotor sensitization to cocaine in adult rats.

  17. Chronic treatment with curcumin enhances methamphetamine locomotor sensitization and cue-induced reinstatement of methamphetamine self-administration.

    PubMed

    Zhao, Chun; Lou, Zhongze; Zimmer, Benjamin; Yu, Zhewei; Li, Pengping; Ma, Baomiao; Sun, Yan; Huang, Kunyu; Zhou, Wenhua; Liu, Yu

    2012-10-01

    Curcumin, a major active component of Curcuma longa, possesses antidepressant effects that are mediated by the 5-HT system. However, little is known about the effect of curcumin on the behavioral consequences of methamphetamine (METH). The subjects were male, adult Sprague-Dawley rats. In Experiment 1, the effects of 20 and 40 mg/kg curcumin (i.p.) on response rates and breakpoints of 0.06 mg/kg/infusion METH were evaluated. In Experiment 2, rats were self-administering METH for 10 days followed by a 14-day abstinence period. During the abstinence period, the animals were treated with DMSO, 20 or 40 mg/kg curcumin. All rats were then tested for extinction responding and cue-induced reinstatement. In Experiment 3, rats were treated with DMSO, 20, or 40 mg/kg curcumin 15 min before a METH-induced locomotor activity test for 14 consecutive days. In Experiment 4, rats were pretreated with DMSO or curcumin (20 mg/kg or 40 mg/kg) for 13 days and were subsequently tested for METH-induced locomotor activity on the 14th day. In Experiment 5, three groups were tested for locomotor activity after an injection of DMSO, 20, or 40 mg/kg curcumin. The test was repeated for 14 days. Curcumin produced little effect on response rates and breakpoints maintained by METH. Chronic treatment of only 40 mg/kg curcumin during the abstinence phase enhanced cue-induced reinstatement of METH self-administration. Chronic administration of curcumin increased METH-induced sensitization of locomotor activity at the lower (20 mg/kg) but not higher (40 mg/kg) dose. However pretreatment of curcumin alone showed no significant effect on acute locomotor responses to METH and locomotor responses per se. Curcumin enhanced, rather than inhibited the behavioral effects of METH. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Temporal and behavioral variability in cannabinoid receptor expression in outbred mice submitted to ethanol-induced locomotor sensitization paradigm.

    PubMed

    Coelhoso, Cássia C; Engelke, Douglas S; Filev, Renato; Silveira, Dartiu X; Mello, Luiz E; Santos-Junior, Jair G

    2013-09-01

    There is a close relationship between the endocannabinoid system and alcoholism. This study investigated possible differential expression of cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) in an outbred mice strain displaying behavioral variability to ethanol (EtOH)-induced locomotor sensitization. Male adult Swiss mice treated chronically with EtOH (2 g/kg, i.p., daily for 21 days) were classified as "EtOH_High" or "EtOH_Low" according to their locomotor activity after the 21st EtOH injection. A control group was similarly injected with saline. Temporal analysis of CB1R and CB2R immunoreactivity was performed in 3 different occasions: (i) at the end of chronic EtOH treatment, (ii) on the fifth day of EtOH withdrawal, and (iii) after EtOH challenge. Overall, no differences were seen between experimental groups regarding the CB1R at the end of acquisition. However, there were decreases in CB2R in the prefrontal cortex and the hippocampus in EtOH_Low mice. On the fifth day of withdrawal, only EtOH_High mice presented increase in CB1R. Nonetheless, CB2R up-regulation was observed in both EtOH_High and EtOH_Low mice. EtOH challenge counteracted CB1R and CBR2 up-regulation, mainly in the EtOH_High, in structures related to emotionality, such as prefrontal cortex, ventral tegmental area, amygdala, striatum, and hippocampus. There are different patterns of cannabinoid receptor expression during locomotor sensitization paradigm, at both temporal and behavioral perspectives. We hypothesize that CB2R down-regulation might be related to resilience to develop locomotor sensitization, while CB1R up-regulation relates to withdrawal aspects in sensitized mice. Copyright © 2013 by the Research Society on Alcoholism.

  19. Role of MT1 Melatonin Receptors in Methamphetamine-induced Locomotor Sensitization in C57BL/6 Mice

    PubMed Central

    Hutchinson, Anthony J.; Ma, Jason; Liu, Jiabei; Hudson, Randall L.; Dubocovich, Margarita L.

    2015-01-01

    RATIONALE Melatonin modifies physiological and behavioral responses to psychostimulants, with the MT1 and MT2 melatonin receptors specifically implicated in facilitating methamphetamine-induced sensitization in melatonin-proficient mice. OBJECTIVE To assess differences in locomotor sensitization after a single dose of methamphetamine in low melatonin-expressing C57BL/6 wild-type and MT1KO mice, and comparing with melatonin-expressing C3H/HeN mice. METHODS Mice received a vehicle or methamphetamine (1.2 mg/kg, i.p.) pretreatment (Day 1) during the light (ZT5–9) or dark (ZT 19–21) periods in novel test arenas. Locomotor sensitization was assessed by methamphetamine challenge after an eight-day (Day 9) abstinence. TH protein expression was evaluated by immunofluorescence and Western blot analysis. RESULTS Methamphetamine pretreatment induced statistically significant locomotor sensitization upon challenge after eight-day abstinence in C3H and C57 wild-type mice during the light period. The magnitude of sensitization in C57 mice was diminished in the dark period and completely abrogated in MT1 receptor knockout (MT1KO) mice. No differences were observed in tyrosine hydroxylase immunoreactivity in the mesolimbic dopamine system. Additional exposures to the test arenas after methamphetamine pretreatment (Nights 2–6) enhanced sensitization. CONCLUSIONS Deletion of the MT1 melatonin receptor abolishes sensitization induced by a single METH pretreatment. The magnitude of sensitization is also altered by time of day and contextual cues. We conclude that the MT1 melatonin receptor is emerging as a novel target of therapeutic intervention for drug abuse disorders. PMID:23934259

  20. mPer1 promotes morphine-induced locomotor sensitization and conditioned place preference via histone deacetylase activity.

    PubMed

    Perreau-Lenz, Stéphanie; Hoelters, Laura-Sophie; Leixner, Sarah; Sanchis-Segura, Carla; Hansson, Anita; Bilbao, Ainhoa; Spanagel, Rainer

    2017-06-01

    Previous studies have shown that repeated exposure to drugs of abuse is associated with changes in clock genes expression and that mice strains with various mutations in clock genes show alterations in drug-induced behaviors. The objective of this study is to characterize the role of the clock gene mPer1 in the development of morphine-induced behaviors and a possible link to histone deacetylase (HDAC) activity. In Per1 (Brdm1) null mutant mice and wild-type (WT) littermates, we examined whether there were any differences in the development of morphine antinociception, tolerance to antinociception, withdrawal, sensitization to locomotion, and conditioned place preference (CPP). Per1 (Brdm1) mutant mice did not show any difference in morphine antinociception, tolerance development, nor in physical withdrawal signs precipitated by naloxone administration compared to WT. However, morphine-induced locomotor sensitization and CPP were significantly impaired in Per1 (Brdm1) mutant mice. Because a very similar dissociation between tolerance and dependence vs. sensitization and CPP was recently observed after the co-administration of morphine and the HDAC inhibitor sodium butyrate (NaBut), we studied a possible link between mPer1 and HDAC activity. As opposed to WT controls, Per1 (Brdm1) mutant mice showed significantly enhanced striatal global HDAC activity within the striatum when exposed to a locomotor-sensitizing morphine administration regimen. Furthermore, the administration of the HDAC inhibitor NaBut restored the ability of morphine to promote locomotor sensitization and reward in Per1 (Brdm1) mutant mice. Our results reveal that although the mPer1 gene does not alter morphine-induced antinociception nor withdrawal, it plays a prominent role in the development of morphine-induced behavioral sensitization and reward via inhibitory modulation of striatal HDAC activity. These data suggest that PER1 inhibits deacetylation to promote drug-induced neuroplastic changes.

  1. Local field potentials in the ventral tegmental area during cocaine-induced locomotor activation: Measurements in freely moving rats.

    PubMed

    Harris Bozer, Amber L; Li, Ai-Ling; Sibi, Jiny E; Bobzean, Samara A M; Peng, Yuan B; Perrotti, Linda I

    2016-03-01

    The ventral tegmental area (VTA) has been established as a critical nucleus for processing behavioral changes that occur during psychostimulant use. Although it is known that cocaine induced locomotor activity is initiated in the VTA, not much is known about the electrical activity in real time. The use of our custom-designed wireless module for recording local field potential (LFP) activity provides an opportunity to confirm and identify changes in neuronal activity within the VTA of freely moving rats. The purpose of this study was to investigate the changes in VTA LFP activity in real time that underlie cocaine induced changes in locomotor behavior. Recording electrodes were implanted in the VTA of rats. Locomotor behavior and LFP activity were simultaneously recorded at baseline, and after saline and cocaine injections. Results indicate that cocaine treatment caused increases in both locomotor behavior and LFP activity in the VTA. Specifically, LFP activity was highest during the first 30 min following the cocaine injection and was most robust in Delta and Theta frequency bands; indicating the role of low frequency VTA activity in the initiation of acute stimulant-induced locomotor behavior. Our results suggest that LFP recording in freely moving animals can be used in the future to provide valuable information pertaining to drug induced changes in neural activity.

  2. Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

    PubMed

    Perrine, Shane A; Ghoddoussi, Farhad; Desai, Kirtan; Kohler, Robert J; Eapen, Ajay T; Lisieski, Michael J; Angoa-Perez, Mariana; Kuhn, Donald M; Bosse, Kelly E; Conti, Alana C; Bissig, David; Berkowitz, Bruce A

    2015-11-01

    A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence.

  3. Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not adolescent rats susceptible to diet-induced obesity

    PubMed Central

    Oginsky, Max F.; Maust, Joel D.; Corthell, John T.; Ferrario, Carrie R.

    2015-01-01

    Rationale Basal and diet-induced differences in mesolimbic function, particularly within the nucleus accumbens (NAc), may contribute to human obesity; these differences may be more pronounced in susceptible populations. Objectives We determined whether there are differences in cocaine-induced behavioral plasticity in rats that are susceptible vs. resistant to diet-induced obesity, and basal differences in the striatal neuron function in adult and adolescent obesity-prone and obesity-resistant rats. Methods Susceptible and resistant outbred rats were identified based on “junk-food” diet-induced obesity. Then, the induction and expression of cocaine-induced locomotor sensitization, which is mediated by enhanced striatal function and is associated with increased motivation for rewards and reward-paired cues, were evaluated. Basal differences in mesolimbic function were examined in selectively bred obesity-prone and obesity-resistant rats (P70-80 and P30-40) using both cocaine induced locomotion and whole-cell patch clamping approaches in NAc core medium spiny neurons (MSNs). Results In rats that became obese after eating “junk-food”, the expression of locomotor sensitization was enhanced compared to non-obese rats, with similarly strong responses to 7.5 and 15 mg/kg cocaine. Without diet manipulation, obesity-prone rats were hyper-responsive to the acute locomotor-activating effects of cocaine, and the intrinsic excitability of NAc core MSNs was enhanced by ~60% at positive and negative potentials. These differences were present in adult, but not adolescent rats. Post-synaptic glutamatergic transmission was similar between groups. Conclusions Mesolimbic systems, particularly NAc MSNs, are hyper-responsive in obesity-prone individuals; and interactions between predisposition and experience influence neurobehavioral plasticity in ways that may promote weight gain and hamper weight loss in susceptible rats. PMID:26612617

  4. Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not in adolescent rats susceptible to diet-induced obesity.

    PubMed

    Oginsky, Max F; Maust, Joel D; Corthell, John T; Ferrario, Carrie R

    2016-03-01

    Basal and diet-induced differences in mesolimbic function, particularly within the nucleus accumbens (NAc), may contribute to human obesity; these differences may be more pronounced in susceptible populations. We examined differences in cocaine-induced behavioral plasticity in rats that are susceptible vs. resistant to diet-induced obesity and basal differences in striatal neuron function in adult and in adolescent obesity-prone and obesity-resistant rats. Susceptible and resistant outbred rats were identified based on "junk-food" diet-induced obesity. Then, the induction and expression of cocaine-induced locomotor sensitization, which is mediated by enhanced striatal function and is associated with increased motivation for rewards and reward-paired cues, were evaluated. Basal differences in mesolimbic function were examined in selectively bred obesity-prone and obesity-resistant rats (P70-80 and P30-40) using both cocaine-induced locomotion and whole-cell patch clamping approaches in NAc core medium spiny neurons (MSNs). In rats that became obese after eating junk-food, the expression of locomotor sensitization was enhanced compared to non-obese rats, with similarly strong responses to 7.5 and 15 mg/kg cocaine. Without diet manipulation, obesity-prone rats were hyper-responsive to the acute locomotor-activating effects of cocaine, and the intrinsic excitability of NAc core MSNs was enhanced by ∼60 % at positive and negative potentials. These differences were present in adult, but not adolescent rats. Post-synaptic glutamatergic transmission was similar between groups. Mesolimbic systems, particularly NAc MSNs, are hyper-responsive in obesity-prone individuals, and interactions between predisposition and experience influence neurobehavioral plasticity in ways that may promote weight gain and hamper weight loss in susceptible rats.

  5. The glial cell modulators, ibudilast and its amino analog, AV1013, attenuate methamphetamine locomotor activity and its sensitization in mice

    PubMed Central

    SNIDER, SARAH E.; VUNCK, SARAH A.; VAN DEN OORD, EDWIN J.C.G.; ADKINS, DANIEL E.; MCCLAY, JOSEPH L.; BEARDSLEY, PATRICK M.

    2014-01-01

    Over 800,000 Americans abuse the psychomotor stimulant, methamphetamine, yet its abuse is without an approved medication. Methamphetamine induces hypermotor activity, and sensitization to this effect is suggested to represent aspects of the addiction process. Methamphetamine’s regulation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels may be partially responsible for its behavioral effects, and compounds that inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP, can alter methamphetamine-induced behaviors. Methamphetamine also activates glial cells and causes a subsequent increase in pro-inflammatory cytokine levels. Modulation of glial cell activation is associated with changes in behavioral responses, and substances that oppose inflammatory activity can attenuate drug-induced behaviors. Ibudilast (aka AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine), inhibits both PDE and glial pro-inflammatory activity. Ibudilast’s amino analogue, AV1013, modulates similar glial targets but negligibly inhibits PDE. The present study determined whether ibudilast and AV1013 would attenuate methamphetamine-induced locomotor activity and its sensitization in C57BL/6J mice. Mice were treated b.i.d. with ibudilast (1.8-13 mg/kg), AV1013 (10-56mg/kg) or their vehicles intraperitoneally for 7 days, beginning 48 h before 5 days of daily 1-h locomotor activity tests. Each test was initiated by either a methamphetamine (3 mg/kg) or a saline injection. Ibudilast significantly (P<0.05) reduced the acute, chronic, and sensitization effects of methamphetamine's locomotor activity without significantly affecting activity by itself. AV1013 had similar anti-methamphetamine effects, suggesting that glial cell activity, by itself, can modulate methamphetamine's effects and perhaps serve as a medication target for its abuse. PMID:22306241

  6. Decreased Sensitivity in Adolescent versus Adult Rats to the Locomotor Activating Effects of Toluene

    PubMed Central

    Bowen, Scott E.; Charlesworth, Jonathan D.; Tokarz, Mary E.; Jerry Wright, M.; Wiley, Jenny L.

    2007-01-01

    Volatile organic solvent (inhalant) abuse continues to be a major health concern throughout the world. Of particular concern is the abuse of inhalants by adolescents because of its toxicity and link to illicit drug use. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. While studies have assessed outcomes of exposure to inhalants in adult male animals, there is little research on the neurobehavioral effects of inhalants in female or younger animals. In attempt to address these shortcomings, we exposed male and female Long-Evans rats to 20 min of 0, 2,000, 4,000, or 8,000 parts per million (ppm) inhaled toluene for 10 days in rats aged postnatal (PN) day 28-39 (adolescent), PN44-PN55, or >PN70 (adult). Animals were observed individually in 29-l transparent glass cylindrical jars equipped with standard photocells that were used to measure locomotor activity. Toluene significantly increased activity as compared to air exposure in all groups of male and female rats with the magnitude of locomotor stimulation produced by 4000 ppm toluene being significantly greater for female adults than during any age of adolescence. The results demonstrate that exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous locomotor behavior in rats and that the expression of these effects appears to depend upon the postnatal age of testing and sex of the animal. PMID:17869480

  7. The effect of early environmental manipulation on locomotor sensitivity and methamphetamine conditioned place preference reward.

    PubMed

    Hensleigh, E; Pritchard, L M

    2014-07-15

    Early life stress leads to several effects on neurological development, affecting health and well-being later in life. Instances of child abuse and neglect are associated with higher rates of depression, risk taking behavior, and an increased risk of drug abuse later in life. This study used repeated neonatal separation of rat pups as a model of early life stress. Rat pups were either handled and weighed as controls or separated for 180 min per day during postnatal days 2-8. In adulthood, male and female rats were tested for methamphetamine conditioned place preference reward and methamphetamine induced locomotor activity. Tissue samples were collected and mRNA was quantified for the norepinephrine transporter in the prefrontal cortex and the dopamine transporter in the nucleus accumbens. Results indicated rats given methamphetamine formed a conditioned place preference, but there was no effect of early separation or sex. Separated males showed heightened methamphetamine-induced locomotor activity, but there was no effect of early separation for females. Overall females were more active than males in response to both saline and methamphetamine. No differences in mRNA levels were observed across any conditions. These results suggest early neonatal separation affects methamphetamine-induced locomotor activity in a sex-dependent manner but has no effects on methamphetamine conditioned place preference.

  8. Parvalbumin Interneurons of the Mouse Nucleus Accumbens are Required For Amphetamine-Induced Locomotor Sensitization and Conditioned Place Preference.

    PubMed

    Wang, Xiaoting; Gallegos, David A; Pogorelov, Vladimir M; O'Hare, Justin K; Calakos, Nicole; Wetsel, William C; West, Anne E

    2017-08-25

    To determine the requirement for parvalbumin (PV) expressing GABAergic interneurons of the nucleus accumbens (NAc) in the behavioral adaptations induced by amphetamine (AMPH), we blocked synaptic vesicle release from these neurons using Cre-inducible viral expression of the tetanus toxin light chain in male and female PV-Cre mice. Silencing PV+ interneurons of the NAc selectively inhibited the expression of locomotor sensitization following repeated injections of AMPH and blocked AMPH-induced conditioned place preference (CPP). AMPH induced significantly more expression of the activity-dependent gene Fos in both D1 and D2 dopamine receptor-expressing medium spiny neurons (MSNs) of the NAc of PV+ interneuron silenced mice, suggesting a function for PV+ interneuron-mediated MSN inhibition in the expression of AMPH-induced locomotor sensitization and CPP. These data show a requirement for PV+ interneurons of the NAc in behavioral responses to AMPH, and they raise the possibility that modulation of PV+ interneuron function may alter the development or expression of psychostimulant-induced behavioral adaptations.Neuropsychopharmacology advance online publication, 27 September 2017; doi:10.1038/npp.2017.178.

  9. Chronic intermittent heroin produces locomotor sensitization and long-lasting enhancement of conditioned reinforcement.

    PubMed

    Morrison, J; Thornton, V; Ranaldi, R

    2011-09-01

    In a previous study we showed that chronic intermittent heroin in rats enhanced responding with conditioned reinforcement and reversal learning of a conditioned magazine approach task when tested three days after the heroin treatment. Whether or not this enhanced appetitive learning persists after a protracted withdrawal period remains unknown and constitutes the aim of the present study. Forty-eight male Long Evans rats were each exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, two groups of rats received saline and two groups received heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. This was followed by testing in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another no stimulus. For one saline and one heroin group this testing occurred after 2 days of withdrawal while for the other saline and heroin groups it occurred after 30 days of withdrawal. The results indicate that animals treated with heroin displayed progressively and significantly greater locomotor activity across sessions while animals treated with saline displayed locomotor activity that remained low and stable across sessions. In addition, the heroin groups in each withdrawal condition displayed significantly enhanced responding with conditioned reinforcement compared to their respective saline control groups. These results demonstrate that chronic intermittent heroin enhances appetitive learning for natural reinforcers and motivational processes and that this effect persists even after 30-days of withdrawal.

  10. Genetic deletion of MT1 and MT2 melatonin receptors differentially abrogates the development and expression of methamphetamine-induced locomotor sensitization during the day and the night in C3H/HeN mice

    PubMed Central

    Hutchinson, Anthony J.; Hudson, Randall L.; Dubocovich, Margarita L.

    2013-01-01

    This study explored the role of the melatonin receptors in methamphetamine (METH)-induced locomotor sensitization during the light and dark phases in C3H/HeN mice with genetic deletion of theMT1 and/or MT2 melatonin receptors. Six daily treatments with METH (1.2 mg/kg, i.p.) in a novel environment during the light phase led to the development of locomotor sensitization in wild-type (WT), MT1KO and MT2KO mice. Following four full days of abstinence, METH challenge (1.2 mg/kg, i.p.) triggered the expression of locomotor sensitization in METH-pretreated but not in vehicle (VEH)-pretreated mice. In MT1/MT2KO mice, the development of sensitization during the light phase was significantly reduced and the expression of sensitization was completely abrogated upon METH challenge. During the dark phase the development of locomotor sensitization in METH-pretreated WT, MT1KO and MT2KO mice was statistically different from VEH-treated controls. However, WT and MT2KO, but not MT1KO mice receiving repeated VEH pretreatments during the dark phase expressed a sensitized response to METH challenge that is of an identical magnitude to that observed upon 6 days of METH pretreatment. We conclude that exposure to a novel environment during the dark phase, but not during the light phase, facilitated the expression of sensitization to a METH challenge in a manner dependent on MT1 melatonin receptor activation by endogenous melatonin. We suggest that MT1 and MT2 melatonin receptors are potential targets for pharmacotherapeutic intervention in METH abusers. PMID:22672659

  11. GABAA overactivation potentiates the effects of NMDA blockade during the brain growth spurt in eliciting locomotor hyperactivity in juvenile mice.

    PubMed

    Oliveira-Pinto, Juliana; Paes-Branco, Danielle; Cristina-Rodrigues, Fabiana; Krahe, Thomas E; Manhães, Alex C; Abreu-Villaça, Yael; Filgueiras, Cláudio C

    2015-01-01

    Both NMDA receptor blockade and GABAA receptor overactivation during the brain growth spurt may contribute to the hyperactivity phenotype reminiscent of attention-deficit/hyperactivity disorder. Here, we evaluated the effects of exposure to MK801 (a NMDA antagonist) and/or to muscimol (a GABAA agonist) during the brain growth spurt on locomotor activity of juvenile Swiss mice. This study was carried out in two separate experiments. In the first experiment, pups received a single i.p. injection of either saline solution (SAL), MK801 (MK, 0.1, 0.3 or 0.5 mg/kg) or muscimol (MU, 0.02, 0.1 or 0.5 mg/kg) at the second postnatal day (PND2), and PNDs 4, 6 and 8. In the second experiment, we investigated the effects of a combined injection of MK (0.1 mg/kg) and MU (doses: 0.02, 0.1 or 0.5 mg/kg) following the same injection schedule of the first experiment. In both experiments, locomotor activity was assessed for 15 min at PND25. While MK promoted a dose-dependent increase in locomotor activity, exposure to MU failed to elicit significant effects. The combined exposure to the highest dose of MU and the lowest dose of MK induced marked hyperactivity. Moreover, the combination of the low dose of MK and the high dose of MU resulted in a reduced activity in the center of the open field, suggesting an increased anxiety-like behavior. These findings suggest that, during the brain growth spurt, the blockade of NMDA receptors induces juvenile locomotor hyperactivity whereas hyperactivation of GABAA receptors does not. However, GABAA overactivation during this period potentiates the effects of NMDA blockade in inducing locomotor hyperactivity.

  12. Attenuated effects of experimenter-administered heroin in adolescent vs. adult male rats: physical withdrawal and locomotor sensitization

    PubMed Central

    Doherty, James M.; Frantz, Kyle J.

    2012-01-01

    Objectives Early onset of heroin use during adolescence might increase chances of later drug addiction. Prior work from our laboratory suggests, however, that adolescent male rats are actually less sensitive than adults to some enduring effects of heroin self-administration. In the present study, we tested two likely correlates of sensitivity to behavioral reinforcement in rats: physical withdrawal and locomotor sensitization. Methods Adolescent (35 days old at start) and adult (79 days old) male Sprague-Dawley rats were administered escalating doses of heroin, increasing from 1.0 to 8.0 mg/kg (i.p.) every 12 hr, across 13 days. Somatic signs of spontaneous withdrawal were scored 12 and 24 hr after the last injection, then every 24 hr for 5 days; locomotion was recorded concurrently. Challenge injections of heroin (1 mg/kg i.p.) were given at 4 points: as the first of the escalating doses (day 1), at days 7 and 13 during the escalating regimen, and after 12 days of forced abstinence. Body mass and food intake were measured throughout experimentation. Results A heroin withdrawal syndrome was not observed among adolescents as it was among adults, including somatic signs as well as reduced locomotion, body mass, and food intake. On the other hand, heroin-induced locomotor sensitization did not differ across ages. Conclusion Reduced withdrawal is consistent with the attenuated reinforcing effects of heroin among adolescent male rats that we reported previously. Thus, it is possible that adolescent rats could reveal important neuroprotective factors for use in treatment of heroin dependence. PMID:22941050

  13. Attenuated effects of experimenter-administered heroin in adolescent vs. adult male rats: physical withdrawal and locomotor sensitization.

    PubMed

    Doherty, James M; Frantz, Kyle J

    2013-02-01

    Early onset of heroin use during adolescence might increase chances of later drug addiction. Prior work from our laboratory suggests, however, that adolescent male rats are actually less sensitive than adults to some enduring effects of heroin self-administration. In the present study, we tested two likely correlates of sensitivity to behavioral reinforcement in rats: physical withdrawal and locomotor sensitization. Adolescent (35 days old at start) and adult (79 days old) male Sprague-Dawley rats were administered escalating doses of heroin, increasing from 1.0 to 8.0 mg/kg (i.p.) every 12 h, across 13 days. Somatic signs of spontaneous withdrawal were scored 12 and 24 h after the last injection, and then every 24 h for 5 days; locomotion was recorded concurrently. Challenge injections of heroin (1 mg/kg i.p.) were given at four points: as the first of the escalating doses (day 1), at days 7 and 13 during the escalating regimen, and after 12 days of forced abstinence. Body mass and food intake were measured throughout experimentation. A heroin withdrawal syndrome was not observed among adolescents as it was among adults, including somatic signs as well as reduced locomotion, body mass, and food intake. On the other hand, heroin-induced locomotor sensitization did not differ across ages. Reduced withdrawal is consistent with the attenuated reinforcing effects of heroin among adolescent male rats that we reported previously. Thus, it is possible that adolescent rats could reveal important neuroprotective factors for use in treatment of heroin dependence.

  14. Argon prevents the development of locomotor sensitization to amphetamine and amphetamine-induced changes in mu opioid receptor in the nucleus accumbens.

    PubMed

    David, Hélène N; Dhilly, Martine; Poisnel, Géraldine; Degoulet, Mickael; Meckler, Cédric; Vallée, Nicolas; Blatteau, Jean-Éric; Risso, Jean-Jacques; Lemaire, Marc; Debruyne, Danièle; Abraini, Jacques H

    2014-01-01

    Systemic administration of γ-amino-butyric acid type A (GABA-A) and benzodiazepine receptor agonists has been reported to block the development of locomotor sensitization to amphetamine. Here, we investigated whether the non-anesthetic noble gas argon, shown to possess agonistic properties at these receptors, may block the acquisition of amphetamine-induced locomotor sensitization and mu opioid receptor activation in the nucleus accumbens. Rats were pretreated with saline solution or amphetamine (1 mg/kg) from day 1 to day 3 and then exposed, immediately after injection of amphetamine, to medicinal air or argon at 75 vol% (with the remainder being oxygen). After a 3-day period of withdrawal, rats were challenged with amphetamine on day 7. Rats pretreated with amphetamine and argon had lower locomotor activity (U = 5, P < 0.005) and mu opioid receptor activity in the nucleus accumbens (U = 0, P < 0.001) than rats pretreated with amphetamine and air. In contrast, argon had effect on locomotor and mu receptor activity neither in rats pretreated with saline and challenged with amphetamine (acute amphetamine) nor in rats pretreated and challenged with saline solution (controls). These results indicate that argon inhibits the development of both locomotor sensitization and mu opioid receptor activation induced by repeated administration of amphetamine.

  15. AMN082, a metabotropic glutamate receptor 7 allosteric agonist, attenuates locomotor sensitization and cross-sensitization induced by cocaine and morphine in mice.

    PubMed

    Jenda, M; Gawel, K; Marszalek, M; Komsta, L; Kotlinska, J H

    2015-03-03

    Previous studies have indicated that metabotropic glutamate receptors 7 (mGluR7s) are involved in drug addiction. However, the role of these receptors in drug-induced behavioral sensitization is unknown. The aim of the present study was to determine whether systemic injection of AMN082, a selective mGluR7 allosteric agonist, reduces the cocaine- and morphine-induced hyperactivity and the development and expression of locomotor sensitization, and also affects the reciprocal cross-sensitization to the stimulant effect of cocaine and morphine in mice. AMN082 (1.25-10.0 mg/kg, i.p.) did not have an impact on locomotion of naive mice and did not affect the acute cocaine- or morphine-induced hyperactivity, except the dose of 10 mg/kg that suppressed the locomotor effect of both drugs. Repeated exposure to cocaine or morphine (10 mg/kg, 5× every 3 days) gradually increased locomotion during induction of sensitization and after 4 (cocaine) or 7 day (morphine) withdrawal phase when challenged with cocaine (10 mg/kg, i.p.) or morphine (10 mg/kg, i.p.) on day 17 or 20, respectively. Pretreatment of animals with the lower doses of AMN082 (1.25-5.0 mg/kg, i.p.), 30 min before every cocaine or morphine injection during repeated drug administration or before cocaine or morphine challenge, dose-dependently attenuated the development, as well as the expression of cocaine or morphine locomotor sensitization. AMN082 also inhibited the reciprocal cross-sensitization between these drugs. Prior to administration of MMPIP (10 mg/kg, i.p.), a selective mGluR7 antagonist reversed the inhibitory effect of AMN082 on the development or expression of cocaine or morphine sensitization. These data indicate that AMN082 attenuated the development and expression of cocaine and morphine sensitization, and the reciprocal cross-sensitization via a mechanism that involves mGluR7s. Thus, AMN082 might have therapeutic implications not only in the treatment of cocaine or opioid addiction but also in the

  16. The expression of methiopropamine-induced locomotor sensitization requires dopamine D2, but not D1, receptor activation in the rat.

    PubMed

    Yoon, Hyung Shin; Cai, Wen Ting; Lee, Young Hun; Park, Kyung Tae; Lee, Yong Sup; Kim, Jeong-Hoon

    2016-09-15

    Methiopropamine (MPA) is a structural analog to methamphetamine and is categorized as a novel psychoactive substance that needs to be controlled. However, no study has been performed to determine whether MPA actually develops an addiction-like behavior similar to those arising from other psychomotor stimulants. Thus, we attempted to determine whether MPA produces locomotor sensitization in a manner similar to amphetamine. In the first experiment, rats were pre-exposed to either saline or one of three different doses of MPA (0.2, 1.0, or 5.0mg/kg, IP) with a total of four injections, respectively. After a 2-week withdrawal period, when they were challenged with the same dose of MPA, only the group that was pre-exposed to high dose of MPA (5.0mg/kg) showed sensitized locomotor activity. In the second experiment, all rats were pre-exposed to MPA (5.0mg/kg) only. Interestingly, the expression of MPA-induced locomotor sensitization was inhibited by a pre-injection of a dopamine D2 receptor antagonist, eticlopride (0.05mg/kg, IP), though not by a dopamine D1 receptor antagonist, SCH23390 (0.01mg/kg, IP). These results suggest that repeated injection of MPA in the rat provokes certain neuronal changes involving specific, likely D2, dopamine receptor-mediated pathways that contribute to the expression of MPA-induced locomotor sensitization.

  17. NR2B-deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol.

    PubMed

    Badanich, K A; Doremus-Fitzwater, T L; Mulholland, P J; Randall, P K; Delpire, E; Becker, H C

    2011-10-01

    The NR2B subunit of N-methyl d-aspartate glutamate receptors influences pharmacological properties and confers greater sensitivity to the modulatory effects of ethanol. This study examined behavioral responses to acute ethanol in a conditional knockout mouse model that allowed for a delayed genetic deletion of the NR2B subunit to avoid mouse lethality. Mice lacking the NR2B gene (knockout) were produced by mating NR2B[f/f] mice with CAMKIIa-driven tTA transgenic mice and the tetO-CRE transgenic mice. Adult male and female offspring representing each of the resultant genotypes (knockout, CAM, CRE and wildtype mice) were tested for open-field locomotor activity following acute low- and high-dose ethanol challenge as well as loss of righting reflex. Findings indicate that male and female mice lacking the NR2B subunit exhibited greater overall activity in comparison to other genotypes during the baseline locomotor activity test. NR2B knockout mice exhibited an exaggerated stimulant response to 1.5 g/kg (i.p.) and an exaggerated depressant response to 3.0 g/kg (i.p.) ethanol challenge. In addition, NR2B knockout mice slept longer following a high dose of ethanol (4.0 g/kg, i.p.). To evaluate pharmacokinetics, clearance rates of ethanol (1.5, 4.0 g/kg, i.p.) were measured and showed that female NR2B knockouts had a faster rate of metabolism only at the higher ethanol dose. Western blot analyses confirmed significant reduction in NR2B expression in the forebrain of knockout mice. Collectively, these data indicate that the NR2B subunit of the N-methyl d-aspartate glutamate receptor is involved in regulating low-dose stimulant effects of ethanol and the depressant/hypnotic effects of ethanol.

  18. NR2B-Deficient Mice are More Sensitive to the Locomotor Stimulant and Depressant Effects of Ethanol

    PubMed Central

    Mulholland, Patrick J.; Randall, Patrick K.; Delpire, Eric; Becker, Howard C.

    2014-01-01

    The NR2B subunit of N-methyl D-aspartate glutamate receptors influences pharmacological properties and confers greater sensitivity to the modulatory effects of ethanol. This study examined behavioral responses to acute ethanol in a conditional knockout mouse model that allowed for a delayed genetic deletion of the NR2B subunit to avoid mouse lethality. Mice lacking the NR2B gene (knockout) were produced by mating NR2B[f/f] mice with CAMKIIa-drive tTA transgenic mice and the tetO-CRE transgenic mice. Adult male and female offspring representing each of the resultant genotypes (knockout, CAM, CRE, and wild-type mice) were tested for open field locomotor activity following acute low and high dose ethanol challenge as well as loss of righting reflex. Findings indicate that male and female mice lacking the NR2B subunit exhibited greater overall activity in comparison to other genotypes during the baseline locomotor activity test. NR2B knockout mice exhibited an exaggerated stimulant response to 1.5 g/kg (ip) and an exaggerated depressant response to 3.0 g/kg (ip) ethanol challenge. Additionally, NR2B knockout mice slept longer following a high dose of ethanol (4.0 g/kg, ip). To evaluate pharmacokinetics, clearance rates of ethanol (1.5, 4.0 g/kg, ip) were measured and showed female NR2B knockouts had a faster rate of metabolism only at the higher ethanol dose. Western blot analyses confirmed significant reduction in NR2B expression in the forebrain of knockout mice. Collectively, these data indicate the NR2B subunit of the N-methyl D-aspartate glutamate receptor is involved in regulating low-dose stimulant effects of ethanol and the depressant/hypnotic effects of ethanol. PMID:21762461

  19. Fluoxetine, but not sertraline or citalopram, potentiates the locomotor stimulant effect of cocaine: possible pharmacokinetic effects.

    PubMed

    Fletcher, Paul J; Sinyard, Judy; Salsali, Mahnaz; Baker, Glen B

    2004-07-01

    The selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances some of the behavioural effects of cocaine, including locomotor stimulation. While this effect has often been interpreted as evidence for a serotonergic component to the behavioural effects of cocaine, direct evidence for this hypothesis is lacking. One alternative explanation is that fluoxetine, by inhibiting cytochrome P450 (CYP) enzymes, interferes with the metabolism of cocaine. These experiments were undertaken to: 1) compare the effects of fluoxetine with those of two other SSRIs, sertraline and citalopram, on cocaine-induced locomotor activity, 2) examine the effects of fluoxetine on cocaine-stimulated locomotion in rats depleted of serotonin (5-hydroxytryptamine; 5-HT), and 3) determine the effect of fluoxetine on cocaine levels in the brain. Locomotor activity was measured, using photocell based activity monitors, in rats habituated to those monitors. Depletion of 5-HT was achieved by injecting 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei. Cocaine levels in whole brain were measured using high-performance liquid chromatography with ultraviolet detection. In experiment 1, 5 mg/kg fluoxetine enhanced the ability of 10 and 15 mg/kg cocaine to increase locomotor activity. Neither citalopram nor sertraline (5 and 10 mg/kg) altered the stimulant effect of 10 mg/kg cocaine. Experiment 2 showed that this effect of fluoxetine was also apparent in rats with large and widespread depletion of brain 5-HT levels. The 5-HT depletion also failed to alter the response to cocaine itself. In experiment 3, brain levels of cocaine were elevated in rats pretreated with fluoxetine compared with rats that received cocaine alone. Fluoxetine enhanced the ability of cocaine to increase locomotor activity. This effect appears not to depend upon increasing 5-HT function since fluoxetine was also effective in rats with substantial 5-HT depletions, and two other SSRIs did not alter the

  20. Potentiation of the expression of cocaine-induced sensitization by a conditioned stressor.

    PubMed

    Sasaki, Aya; Sivanathan, Shathveekan; Hussain, Atif; Shanmuganathan, Purathani; Sivakumaran, Archana; Erb, Suzanne

    2015-10-01

    Repeated exposures to physical stressors cross-sensitize to the locomotor activating effects of psychostimulants in rodents. In the present study, we examined the effect of a conditioned stressor on expression of cocaine-induced sensitization in rats. We determined whether a mint odor cue previously paired with footshock stress (FS) would elicit a sensitized locomotor response in cocaine pre-exposed rats. Rats were given once daily injections of cocaine (30 mg/kg, i.p.) or saline for 6 days in activity monitoring chambers. Subsequently, and in a different and distinct context, equal numbers of rats in each drug condition were exposed to 10 min of brief, intermittent FS or no FS, either in the presence or absence of the mint odor cue. Upon re-exposure to the activity chambers (in which cocaine exposures had been given), all rats previously exposed to cocaine showed robust conditioned locomotion. In response to a cocaine challenge (10 mg/kg, i.p.), cocaine relative to saline pre-exposed rats showed a sensitized locomotor response. Finally, in those cocaine pre-exposed rats that had been given prior odor-FS pairings, concurrent delivery of the cocaine challenge and presentation of the odor cue markedly potentiated the expression of sensitization. To our knowledge, this is the first report of a facilitation of cocaine-induced locomotor sensitization by a conditioned stressor.

  1. Sensitization to the locomotor stimulant effects of "bath salt" constituents, 4-methylmethcathinone (4-MMC) and 3,4-methylenedioxypyrovalerone (MDPV), in male Sprague-Dawley rats.

    PubMed

    Berquist, Michael D; Traxler, Haily K; Mahler, Alyssa M; Baker, Lisa E

    2016-07-01

    Synthetic cathinones, 4-methylmethcathinone (4-MMC) and 3,4-methylenedioxypyrovalerone (MDPV), serve as a substrate or blocker at monoaminergic transporters, respectively, and produce locomotor stimulant effects in rodents. The present study investigated in rats the effects of repeated exposure to 4-MMC, MDPV, or mixtures of the two on the induction of locomotor sensitization and expression of cross-sensitization to cocaine. Seventy-two male Sprague-Dawley rats received daily intraperitoneal injections of saline, MDPV (0.5mg/kg), 4-MMC (0.5, 1.0, or 2.0mg/kg) or mixtures of 0.5mg/kg MDPV+4-MMC (0.5, 1.0, or 2.0mg/kg) for seven consecutive days. Locomotor activity was recorded on days 1 and 7 and again after an acute injection of 5mg/kg cocaine following a 10day drug washout period. Rats injected with 0.5mg/kg MDPV, 0.5, 1.0, or 2.0mg/kg 4-MMC, or 2.0mg/kg 4-MMC+0.5mg/kg MDPV displayed time-dependent increases in horizontal activity that were augmented on day 7 compared to day 1. In addition, rats pretreated with 0.5mg/kg MDPV, 2.0mg/kg 4-MMC, or mixtures of 4-MMC+MDPV displayed an enhanced response to cocaine. Locomotor responses sensitize to MDPV and to certain mixtures of MDPV and 4-MMC following repeated dosing. Furthermore, previous exposure to these substances may produce cross-sensitization to the locomotor stimulant effects of cocaine. Considered together with recent findings that 4-MMC and MDPV have different sites of action, but both influence monoaminergic functioning, further investigations utilizing a variety of behavioral assays may prove informative regarding the abuse liability of synthetic cathinone mixtures. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Sensitization to the Locomotor Stimulant Effects of “Bath Salt” Constituents, 4-Methylmethcathinone (4-MMC) and 3,4-Methylenedioxypyrovalerone (MDPV), in Male Sprague-Dawley Rats

    PubMed Central

    Berquist, Michael D.; Traxler, Haily K.; Mahler, Alyssa M.; Baker, Lisa E.

    2016-01-01

    Background Synthetic cathinones, 4-methylmethcathinone (4-MMC) and 3,4-methylenedioxypyrovalerone (MDPV), serve as a substrate or blocker at monoaminergic transporters, respectively, and produce locomotor stimulant effects in rodents. The present study investigated in rats the effects of repeated exposure to 4-MMC, MDPV, or mixtures of the two on the induction of locomotor sensitization and expression of cross-sensitization to cocaine. Methods Seventy-two male Sprague-Dawley rats received daily intraperitoneal injections of saline, MDPV (0.5 mg/kg), 4-MMC (0.5, 1.0, or 2.0 mg/kg) or mixtures of 0.5 mg/kg MDPV + 4-MMC (0.5, 1.0, or 2.0 mg/kg) for seven consecutive days. Locomotor activity was recorded on days 1 and 7 and again after an acute injection of 5 mg/kg cocaine following a 10 day drug washout period. Results Rats injected with 0.5 mg/kg MDPV, 0.5, 1.0, or 2.0 mg/kg 4-MMC, or 2.0 mg/kg 4-MMC + 0.5 mg/kg MDPV displayed time-dependent increases in horizontal activity that were augmented on day 7 compared to day 1. In addition, rats pretreated with 0.5 mg/kg MDPV, 2.0 mg/kg 4-MMC, or mixtures of 4-MMC + MDPV displayed an enhanced response to cocaine. Conclusions Locomotor responses sensitize to MDPV and to certain mixtures of MDPV and 4-MMC following repeated dosing. Furthermore, previous exposure to these substances may produce cross-sensitization to the locomotor stimulant effects of cocaine. Considered together with recent findings that 4-MMC and MDPV have different sites of action, but both influence monoaminergic functioning, further investigations utilizing a variety of behavioral assays may prove informative regarding the abuse liability of synthetic cathinone mixtures. PMID:27181413

  3. The expression of MC4Rs in D1R neurons regulates food intake and locomotor sensitization to cocaine

    PubMed Central

    Cui, H.; Lutter, M.

    2013-01-01

    While it is known that mice lacking melanocortin 4 receptor (MC4R) expression develop hyperphagia resulting in early-onset obesity, the specific neural circuits that mediate this process remain unclear. Here, we report that selective restoration of MC4R expression within dopamine-1 receptor-expressing neurons [MC4R/dopamine 1 receptor (D1R) mice] partially blunts the severe obesity seen in MC4R-nullmice by decreasing meal size, but not meal frequency, in the dark cycle. We also report that both acute cocaine-induced anorexia and the development of locomotor sensitization to repeated administration of cocaine are blunted in MC4R-null mice and normalized in MC4R/D1R mice. Neuronal retrograde tracing identifies the lateral hypothalamic area as the primary target ofMC4R-expressing neurons in the nucleus accumbens. Biochemical studies in the ventral striatum show that phosphorylation of DARPP-32Thr-34 and GluR1Ser-845 is diminished in MC4R-null mice after chronic cocaine administration but rescued in MC4R/D1R mice. These findings highlight a physiological role of MC4R-mediated signaling within D1R neurons in the long-term regulation of energy balance and behavioral responses to cocaine. PMID:23786641

  4. Effects of Repeated Ethanol Exposures on NMDA Receptor Expression and Locomotor Sensitization in Mice Expressing Ethanol Resistant NMDA Receptors

    PubMed Central

    den Hartog, Carolina R.; Gilstrap, Meghin; Eaton, Bethany; Lench, Daniel H.; Mulholland, Patrick J.; Homanics, Gregg. E.; Woodward, John J.

    2017-01-01

    ethanol injections and this was associated with differences in NMDAR subunit expression across brain regions thought to be involved in drug sensitization. Overall, while the results of the study suggest that NMDARs with reduced sensitivity to ethanol favor the development of locomotor sensitization, they also show that intrinsic ethanol sensitivity is not the sole determinant underlying changes in NMDAR expression following repeated exposures to ethanol. PMID:28270746

  5. Addictive potential of modafinil and cross-sensitization with cocaine: a pre-clinical study.

    PubMed

    Wuo-Silva, Raphael; Fukushiro, Daniela F; Borçoi, Aline R; Fernandes, Helaine A; Procópio-Souza, Roberta; Hollais, André W; Santos, Renan; Ribeiro, Luciana T C; Corrêa, Jussara M R M; Talhati, Fernanda; Saito, Luis P; Aramini, Tatiana C F; Kameda, Sonia R; Bittencourt, Lia R A; Tufik, Sergio; Frussa-Filho, Roberto

    2011-10-01

    Repeated or even a single exposure to drugs of abuse can lead to persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross-sensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre-clinical evidence for the addictive potential of modafinil. Our data also strongly suggest that similar neural substrates are involved in the psychomotor/rewarding effects of modafinil and cocaine.

  6. Food restriction alters pramipexole-induced yawning, hypothermia, and locomotor activity in rats: Evidence for sensitization of dopamine D2 receptor-mediated effects

    PubMed Central

    Collins, Gregory T.; Calinski, Diane M.; Newman, Amy Hauck; Grundt, Peter; Woods, James H.

    2014-01-01

    Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggests that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor, however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of pramipexole to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of D2 receptor activity as the D2 antagonist, L-741,626, recovered pramipexole-induced yawning to free-fed levels, while yawning and PE were suppressed following pretreatment with the D3 antagonist, PG01037. The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect on the D3-mediated effects of pramipexole. PMID:18305018

  7. Escalation of food-maintained responding and sensitivity to the locomotor stimulant effects of cocaine in mice.

    PubMed

    Goeders, James E; Murnane, Kevin S; Banks, Matthew L; Fantegrossi, William E

    2009-07-01

    Escalation of drug self-administration is a consequence of extended drug access and is thought to be specifically related to addiction, but few studies have investigated whether intake of non-drug reinforcers may also escalate with extended-access. The goal of these studies was to determine the effects of limited and extended-access to food reinforcers on behavioral and pharmacological endpoints in mice. In distinct groups, responding on a lever was maintained by liquid reinforcement, or nose-poke responses were maintained by sucrose pellets or liquid food in sessions lasting 1 h (limited-access) or 10 h (extended-access). The reinforcing strength of each food, as well as reinforcer-associated cues, was tested before and after extended-access using a progressive ratio (PR) schedule, and locomotor activity in response to novelty and increasing doses of cocaine was assessed in an open field setting in all animals after access to food reinforcers. Escalation of lever-pressing behavior reinforced by liquid food, but not nose-poke behavior reinforced by liquid food or sucrose pellets, was observed across successive extended-access sessions. A concomitant increase in the reinforcing strength of liquid food and its associated cues was apparent in mice that escalated their responding, but not in mice that did not escalate. Finally, extended reinforcer access leading to behavioral escalation was accompanied by an increased sensitivity to the psychostimulant effects of cocaine compared to limited-access. These findings indicate that behavioral escalation can develop as a consequence of extended-access to a non-drug reinforcer, although both the nature of the reinforcer (liquid versus solid food) and the topography of the operant response (lever versus nose-poke) modulate its development. These data also suggest that some of the behavioral and pharmacological corrolaries of behavioral escalation observed following extended-access to drug self-administration may not be due to

  8. Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

    PubMed

    Fredrickson, Paul; Boules, Mona; Stennett, Bethany; Richelson, Elliott

    2014-03-01

    Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a "gateway drug". Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  9. Methylphenidate enhances the abuse-related behavioral effects of nicotine in rats: intravenous self-administration, drug discrimination, and locomotor cross-sensitization.

    PubMed

    Wooters, Thomas E; Neugebauer, Nichole M; Rush, Craig R; Bardo, Michael T

    2008-04-01

    Stimulant drugs, including D-amphetamine, cocaine, and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination, and locomotor cross-sensitization procedures. Adult male Sprague-Dawley rats were trained to respond for intravenous nicotine (0.01 or 0.03 mg/kg/infusion) or sucrose, and the acute effects of methylphenidate (1.25-10 mg/kg) were determined; in addition, separate groups of rats were treated with methylphenidate (2.5 mg/kg) or saline before 12 consecutive nicotine (0.03 mg/kg/infusion) self-administration sessions. Next, the discriminative stimulus effects of nicotine (0.03-0.3 mg/kg) and methylphenidate (1.25-10 mg/kg), alone and in combination with a low nicotine dose (0.056 mg/kg), were tested in nicotine-trained rats. Finally, the locomotor effect of repeated methylphenidate (2.5 mg/kg) was tested in rats previously treated with nicotine (0.2-0.8 mg/kg). Results indicated that acute methylphenidate increased the rate of nicotine self-administration at doses that reduced sucrose-maintained responding; furthermore, tolerance to this effect was not apparent following repeated methylphenidate. Methylphenidate, while not substituting for nicotine alone, dose-dependently enhanced the discriminative stimulus effect of a low nicotine dose. In addition, repeated nicotine exposure promoted the development of locomotor sensitization to methylphenidate. Taken together with recent clinical findings, these results suggest that methylphenidate may enhance the abuse-related behavioral effects of nicotine, perhaps increasing vulnerability to tobacco dependence.

  10. Effects of gender on locomotor sensitivity to amphetamine, body weight, and fat mass in regulator of G protein signaling 9 (RGS9) knockout mice.

    PubMed

    Walker, Paul D; Jarosz, Patricia A; Bouhamdan, Mohamad; MacKenzie, Robert G

    2015-01-01

    Regulator of G-protein signaling (RGS) protein 9-2 is enriched in the striatum where it modulates dopamine and opioid receptor-mediated signaling. RGS9 knockout (KO) mice show increased psychostimulant-induced behavioral sensitization, as well as exhibit higher body weights and greater fat accumulation compared to wild-type (WT) littermates. In the present study, we found gender influences on each of these phenotypic characteristics. Female RGS9 KO mice exhibited greater locomotor sensitization to amphetamine (1.0mg/kg) treatment as compared to male RGS9 KO mice. Male RGS9 KO mice showed increased body weights as compared to male WT littermates, while no such differences were detected in female mice. Quantitative magnetic resonance showed that male RGS9 KO mice accumulated greater fat mass vs. WT littermates at 5months of age. Such observations could not be explained by increased caloric consumption since male and female RGS9 KO mice demonstrated equivalent daily food intake as compared to their respective WT littermates. Although indirect calorimetry methods found decreased oxygen consumption and carbon dioxide production during the 12-hour dark phase in male RGS9 KO vs. WT mice which are indicative of less energy expenditure, male RGS9 KO mice exhibited lower levels of locomotor activity during this period. Genotype had no effect on metabolic activities when KO and WT groups were compared under fasting vs. feeding treatments. In summary, these results highlight the importance of factoring gender into the experimental design since many studies conducted in RGS9 KO mice utilize locomotor activity as a measured outcome. Copyright © 2014. Published by Elsevier Inc.

  11. Differential patterns of expression of neuropeptide Y throughout abstinence in outbred Swiss mice classified as susceptible or resistant to ethanol-induced locomotor sensitization.

    PubMed

    de Pauli, Ricardo Fontão; Coelhoso, Cássia Canha; Tesone-Coelho, Carolina; Linardi, Alessandra; Mello, Luiz Eugênio; Silveira, Dartiu Xavier; Santos, Jair Guilherme

    2014-02-01

    Several studies have focused on the negative emotional state associated with drug abstinence. The peptide NPY plays an important role given its involvement in drug addiction, anxiety, and mood disorders. Interestingly, it is well established that outbred Swiss mice exhibit a prominent behavioral variability to ethanol-induced locomotor sensitization. Here, we investigated whether mice that were either susceptible or resistant to ethanol sensitization differed in their NPY expression during abstinence. The mice were treated daily with ethanol (2 g/kg, i.p.) or saline for 21 days. According to the locomotor activity after the last injection, the ethanol group was classified as sensitized (EtOH_High) or non-sensitized (EtOH_Low). To evaluate NPY expression, some of the mice were sacrificed at 18 h or 5 days of abstinence, and others were challenged at the 5th day of abstinence with ethanol (1.4 g/kg) and sacrificed after 1.5 h. At 5 days of abstinence, NPY expression increased in the orbital cortex, dorsomedial striatum, and dentate gyrus in the EtOH_High mice. These changes were counteracted by the ethanol challenge. In the EtOH_Low mice, NPY expression increased in the dentate gyrus only after 18 h of abstinence. Lastly, a decreased level of NPY was found in the prelimbic cortex of the EtOH_Low mice at 5 days of abstinence, and this was reversed by ethanol challenge. Therefore, behavioral variability in ethanol sensitization confers differential neurochemical features during the subsequent abstinence, including distinct patterns of NPY expression.

  12. An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis

    PubMed Central

    Heinz, Beverly A.; Schaus, John M.; Beck, James P.; Hao, Junliang; Krushinski, Joseph H.; Reinhard, Matthew R.; Cohen, Michael P.; Hellman, Sarah L.; Getman, Brian G.; Wang, Xushan; Menezes, Michelle M.; Maren, Deanna L.; Falcone, Julie F.; Anderson, Wesley H.; Wright, Rebecca A.; Morin, S. Michelle; Knopp, Kelly L.; Adams, Benjamin L.; Rogovoy, Borys; Okun, Ilya; Suter, Todd M.; Statnick, Michael A.; Gehlert, Donald R.; Nelson, David L.; Lucaites, Virginia L.; Emkey, Renee; DeLapp, Neil W.; Wiernicki, Todd R.; Cramer, Jeffrey W.; Yang, Charles R.; Bruns, Robert F.

    2017-01-01

    Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3–20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30–240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists. PMID:27811173

  13. Selectively bred crossed high-alcohol-preferring mice drink to intoxication and develop functional tolerance, but not locomotor sensitization during free-choice ethanol access.

    PubMed

    Matson, Liana M; Kasten, Chelsea R; Boehm, Stephen L; Grahame, Nicholas J

    2014-01-01

    Crossed high-alcohol-preferring (cHAP) mice were selectively bred from a cross of the HAP1 × HAP2 replicate lines and demonstrate blood ethanol concentrations (BECs) during free-choice drinking reminiscent of those observed in alcohol-dependent humans. In this report, we investigated the relationship between free-choice drinking, intoxication, tolerance, and sensitization in cHAP mice. We hypothesized that initially mice would become ataxic after drinking alcohol, but that increased drinking over days would be accompanied by increasing tolerance to the ataxic effects of ethanol (EtOH). Male and female cHAP mice had free-choice access to 10% EtOH and water (E), while Water mice (W) had access to water alone. In experiment 1, the first drinking experience was monitored during the dark portion of the cycle. Once E mice reached an average intake rate of ≥1.5 g/kg/h, they, along with W mice, were tested for footslips on a balance beam, and BECs were assessed. In experiments 2, 3, and 4, after varying durations of free-choice 10% EtOH access (0, 3, 14, or 21 days), mice were challenged with 20% EtOH and tested for number of footslips on a balance beam or locomotor stimulant response. Blood was sampled for BEC determination. We found that cHAP mice rapidly acquire alcohol intakes that lead to ataxia. Over time, cHAP mice developed behavioral tolerance to the ataxic effects of alcohol, paralleled by escalating alcohol consumption. However, locomotor sensitization did not develop following 14 days of free-choice EtOH access. Overall, we observed increases in free-choice drinking with extended alcohol access paralleled by increases in functional tolerance, but not locomotor sensitization. These data support our hypothesis that escalating free-choice drinking over days in cHAP mice is driven by tolerance to alcohol's behavioral effects. These data are the first to demonstrate that escalating free-choice consumption is accompanied by increasing alcohol tolerance. In

  14. Bromocriptine and quinpirole, but not 7-OH-DPAT or SKF 38393, potentiate the inhibitory effect of L-NAME on ethanol-induced locomotor activity in mice.

    PubMed

    Uzbay, I Tayfun; Kayir, Hakan

    2003-04-01

    The effects of N(G)-nitro- l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, SKF 38393, bromocriptine (BRM), quinpirole (QPR) and 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), dopamine receptor agonists, and combinations of the dopamine agonists and L-NAME on ethanol-induced locomotor activity in adult male Swiss-Webster mice were investigated. The mice were given ethanol (0.5-2 g/kg), L-NAME (15-60 mg/kg), SKF 38393 (5-20 mg/kg), BRM (2.5 and 5 mg/kg), QPR (0.25 and 0.5 mg/kg), 7-OH-DPAT (0.5 and 1.0 mg/kg), a combination of l-arginine (1 g/kg) and L-NAME (60 mg/kg), combinations of SKF 38393, BRM, QPR or 7-OH-DPAT with L-NAME (60 mg/kg) or ethanol (0.5 g/kg) and saline or vehicle by i.p. injection. Triple combinations (dopaminergic agonist, 60 mg/kg L-NAME and 0.5 g/kg ethanol) were also given. Locomotor activity was measured for 30 min immediately following ethanol injections. Ethanol (0.5 g/kg) significantly increased locomotor activity. L-NAME, BRM, QPR and 7-OH-DPAT blocked the ethanol (0.5 g/kg)-induced locomotor hyperactivity dose dependently and at doses that did not affect locomotor activity in naive mice when administered alone. The inhibitory effects of L-NAME (60 mg/kg) were not prevented by pretreatment with l-arginine. BRM and QPR, but not 7-OH-DPAT, significantly and dose-dependently potentiated the inhibitory effect of L-NAME. Our results suggest that L-NAME inhibits ethanol-induced locomotor hyperactivity in mice by a mechanism not involving NO. The inhibitory effect of L-NAME may be related to the activation of presynaptic dopamine D(2) receptors rather than dopamine D(3) receptors.

  15. Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse.

    PubMed

    Puhl, Matthew D; Berg, Alexandra R; Bechtholt, Anita J; Coyle, Joseph T

    2015-06-01

    Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse.

  16. The acute effects of olanzapine on ghrelin secretion, CCK sensitivity, meal size, locomotor activity and body temperature.

    PubMed

    van der Zwaal, E M; Merkestein, M; Lam, Y K; Brans, M A D; Luijendijk, M C M; Bok, L I H; Verheij, E R; la Fleur, S E; Adan, R A H

    2012-02-01

    Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear. In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature. Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA.

  17. The potentiating effect of sertraline and fluoxetine on amphetamine-induced locomotor activity is not mediated by serotonin.

    PubMed

    Sills, T L; Greenshaw, A J; Baker, G B; Fletcher, P J

    1999-04-01

    Sertraline dose-dependently increased the locomotor stimulating effect of amphetamine. At the highest dose, 20 mg/kg sertraline had a biphasic effect on amphetamine-induced hyperactivity, producing an initial reduction in amphetamine-induced hyperactivity that was later followed by an augmentation of amphetamine-induced hyperactivity in the last hour of the 3-h test. Sertraline, at doses of 5 and 10 mg/kg, produced an augmentation of amphetamine-induced hyperactivity over the last 2 h of the 3-h test session. Further, there was an increase in the concentration of amphetamine in the brain in rats pretreated with 5 mg/kg sertraline. Both sertraline (5 mg/kg) and fluoxetine (5 mg/kg) produced an augmentation of amphetamine-induced hyperactivity that was unaltered by a serotonergic lesion of the median and dorsal raphe nuclei that resulted in a greater than 90% depletion of serotonin in hippocampus, striatum, and nucleus accumbens. Further, both sertraline and fluoxetine inhibited spontaneous locomotor activity and this effect was also unaltered by the depletion of serotonin. Thus, serotonergic neurotransmission is not essential for the effects of sertraline and fluoxetine on spontaneous and amphetamine-induced locomotion. It is probable that sertraline and fluoxetine augment the locomotor stimulatory effect of amphetamine by decreasing the metabolism of amphetamine, perhaps via actions on cytochrome P450 isozymes.

  18. Locomotor therapy in neurorehabilitation.

    PubMed

    Hesse, S

    2001-01-01

    Gait rehabilitation is a major aspect of neurological rehabilitation. This review is on locomotor therapy by treadmill stimulation with partial body weight support evolving as a very promising treatment concept over the last years. It enables severely affected patients the repetitive practice of complex gait cycles and thus follows modern aspects of motor learning favoring a task-specific approach. Several studies have shown its potential in patients after stroke, spinal cord injury, M. Parkinson and cerebral palsy. An electromechanical gait trainer relieving the strenuous effort of the therapists and controlling the trunk in a phase-dependent manner is a new alternative.

  19. Stress-Induced Locomotor Sensitization to Amphetamine in Adult, but not in Adolescent Rats, Is Associated with Increased Expression of ΔFosB in the Nucleus Accumbens

    PubMed Central

    Carneiro de Oliveira, Paulo E.; Leão, Rodrigo M.; Bianchi, Paula C.; Marin, Marcelo T.; Planeta, Cleopatra da Silva; Cruz, Fábio C.

    2016-01-01

    While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 h once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both the adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats. PMID:27672362

  20. SLO-1-Channels of Parasitic Nematodes Reconstitute Locomotor Behaviour and Emodepside Sensitivity in Caenorhabditis elegans slo-1 Loss of Function Mutants

    PubMed Central

    Schniederjans, Monika; Miltsch, Sandra M.; Krücken, Jürgen; Guest, Marcus; Holden-Dye, Lindy; Harder, Achim; von Samson-Himmelstjerna, Georg

    2011-01-01

    The calcium-gated potassium channel SLO-1 in Caenorhabditis elegans was recently identified as key component for action of emodepside, a new anthelmintic drug with broad spectrum activity. In this study we identified orthologues of slo-1 in Ancylostoma caninum, Cooperia oncophora, and Haemonchus contortus, all important parasitic nematodes in veterinary medicine. Furthermore, functional analyses of these slo-1 orthologues were performed using heterologous expression in C. elegans. We expressed A. caninum and C. oncophora slo-1 in the emodepside-resistant genetic background of the slo-1 loss-of-function mutant NM1968 slo-1(js379). Transformants expressing A. caninum slo-1 from C. elegans slo-1 promoter were highly susceptible (compared to the fully emodepside-resistant slo-1(js379)) and showed no significant difference in their emodepside susceptibility compared to wild-type C. elegans (p = 0.831). Therefore, the SLO-1 channels of A. caninum and C. elegans appear to be completely functionally interchangeable in terms of emodepside sensitivity. Furthermore, we tested the ability of the 5′ flanking regions of A. caninum and C. oncophora slo-1 to drive expression of SLO-1 in C. elegans and confirmed functionality of the putative promoters in this heterologous system. For all transgenic lines tested, expression of either native C. elegans slo-1 or the parasite-derived orthologue rescued emodepside sensitivity in slo-1(js379) and the locomotor phenotype of increased reversal frequency confirming the reconstitution of SLO-1 function in the locomotor circuits. A potent mammalian SLO-1 channel inhibitor, penitrem A, showed emodepside antagonising effects in A. caninum and C. elegans. The study combined the investigation of new anthelmintic targets from parasitic nematodes and experimental use of the respective target genes in C. elegans, therefore closing the gap between research approaches using model nematodes and those using target organisms. Considering the still

  1. Interviewing people about potentially sensitive topics.

    PubMed

    Elmir, Rakime; Schmied, Virginia; Jackson, Debra; Wilkes, Lesley

    2011-01-01

    This paper explores the challenges of interviewing people about sensitive topics. It uses existing literature and the first author's experience of interviewing women traumatised by having an emergency hysterectomy following a severe postpartum haemorrhage. It also highlights the strategies that can assist interviews. Interviewing participants about sensitive topics requires skill and special techniques. Certain research topics have the potential to cause participants and researchers distress and discomfort. Identifying ways to prevent vicarious traumatisation and researcher burnout is imperative to the integrity of the research. Twenty one Australian women took part in in-depth, tape-recorded, face-to-face, email, internet and telephone interviews. This is a methodology paper on the first author's experience of interviewing women on potentially sensitive topics. Some participants may find telling their stories to be cathartic, providing them with a sense of relief. Implementing techniques that may be helpful in initiating the interview process can be challenging.

  2. Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization.

    PubMed

    Peng, Qinghua; Sun, Xi; Liu, Ziyong; Yang, Jianghua; Oh, Ki-Wan; Hu, Zhenzhen

    2014-09-01

    Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5'-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55-102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55-102 peptides (1.0 or 2.5μg, 0.5μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55-102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55-102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55-102. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine.

    PubMed

    Berezniuk, Iryna; Rodriguiz, Ramona M; Zee, Michael L; Marcus, David J; Pintar, John; Morgan, Daniel J; Wetsel, William C; Fricker, Lloyd D

    2017-09-07

    To identify neuropeptides that are regulated by cocaine, we used a quantitative peptidomic technique to examine the relative levels of neuropeptides in several regions of mouse brain following daily intraperitoneal administration of 10 mg/kg cocaine or saline for seven days. A total of 102 distinct peptides were identified in one or more of the following brain regions: nucleus accumbens, caudate putamen, frontal cortex, and ventral tegmental area. None of the peptides detected in the caudate putamen or frontal cortex were altered by cocaine administration. Three peptides in the nucleus accumbens and seven peptides in the ventral tegmental area were significantly decreased in cocaine-treated mice. Five of these ten peptides are derived from proSAAS, a secretory pathway protein and neuropeptide precursor. To investigate whether proSAAS peptides contribute to the physiological effects of psychostimulants, we examined acute responses to cocaine and amphetamine in the open field with wild-type (WT) and proSAAS knockout (KO) mice. Locomotion was stimulated more robustly in the WT compared to mutant mice for both psychostimulants. Behavioral sensitization to amphetamine was not maintained in proSAAS KO mice and these mutants failed to sensitize to cocaine. To determine whether the rewarding effects of cocaine were altered, mice were tested in conditioned place preference (CPP). Both WT and proSAAS KO mice showed dose-dependent CPP to cocaine that was not distinguished by genotype. Taken together, these results suggest that proSAAS-derived peptides contribute differentially to the behavioral sensitization to psychostimulants, while the rewarding effects of cocaine appear intact in mice lacking proSAAS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  4. A Role for Casein Kinase 1 Epsilon in the Locomotor Stimulant Response to Methamphetamine

    PubMed Central

    Bryant, Camron D.; Graham, Melissa E.; Distler, Margaret G.; Munoz, Michaelanne B.; Li, Dongdong; Vezina, Paul; Sokoloff, Greta; Palmer, Abraham A.

    2009-01-01

    Rationale We previously co-localized a quantitative trait locus (QTL) for sensitivity to the locomotor stimulant effect of methamphetamine (MA) with a QTL for expression of casein kinase 1 epsilon (Csnk1-ε) in the nucleus accumbens (NAc). Subsequently, we identified a single nucleotide polymorphism in CSNK1E (rs135745) that was associated with increased sensitivity to the subjective effects of d-amphetamine in healthy human subjects. Based on these results, we hypothesized that differential expression of Csnk1-ε causes differential sensitivity to MA-induced locomotor activity in mice. Objective In the present study, we used PF-670462 (PF), which is a selective inhibitor of Csnk1-ε, to directly evaluate the role of Csnk1-ε in the locomotor response to MA in male C57BL/6J mice. Methods We administered vehicle, PF, MA or MA+PF, either via intraperitoneal injections or bilateral intra-NAc microinjections. We also examined Darpp-32 phosphorylation in mice receiving intraperitoneal injections. Results Intraperitoneal PF (20-40 mg/kg) attenuated the locomotor response to MA (2 mg/kg) without affecting baseline activity. The high dose of PF also significantly inhibited MA-induced phosphorylation of Darpp-32, providing a potential mechanism by which Csnk1-ε contributes to MA-induced locomotor activity. Furthermore, microinjection of PF (5 μg/side) into the NAc completely blocked the locomotor response to MA (2.5 μg/side) without affecting baseline activity. Conclusions These results provide direct evidence that Csnk1-ε is crucial for the locomotor stimulant response to a moderate dose of MA and are consistent with the hypothesis that genetic polymorphisms in Csnk1-ε influence sensitivity to amphetamines in both mice and humans. PMID:19050854

  5. Subchronic MK-801 treatment and post-weaning social isolation in rats: differential effects on locomotor activity and hippocampal long-term potentiation.

    PubMed

    Ashby, Donovan M; Habib, Diala; Dringenberg, Hans C; Reynolds, James N; Beninger, Richard J

    2010-09-01

    Subchronic NMDA receptor antagonist treatment and post-weaning social isolation are two animal models of schizophrenia symptoms. However, behavioral and physiological changes following a combination of these two procedures have not been investigated. Thus, we examined effects of a novel, "double hit" model combining these two treatments, comparing them to standard models involving only NMDA antagonist treatment or social isolation. Male, Sprague-Dawley rats were either group-housed or maintained in social isolation (starting at postnatal day [PD] 21 and continuing throughout the study). Each housing condition was further subdivided into two groups, receiving either subchronic treatment with either saline or MK-801 (0.5mg/kg, i.p., 2xday for seven days starting at PD 56). Post-weaning social isolation increased locomotor activity (assessed at PD 70) in response to a novel environment and an acute amphetamine injection, while subchronic MK-801 increased only amphetamine induced locomotor activity. Subsequent electrophysiological experiments (under urethane anesthesia) assessing changes in plasticity of hippocampal synapses showed that subchronic MK-801 treatment resulted in an increase in long-term potentiation in area CA1 in response to high frequency stimulation of the contralateral CA3 area, while housing condition had no effect. No other changes in hippocampal electrophysiology (input-output curves, paired-pulse facilitation) were observed. These data are the first to demonstrate an enhancement in hippocampal long-term plasticity in vivo following subchronic MK-801 administration, an effect that may be related to the well-characterized changes in glutamatergic and GABAergic systems seen after subchronic NMDA receptor blockade. That lack of additive or synergistic effects in the "double hit model" suggests that combining isolation and subchronic MK-801 treatment does not necessarily produce greater behavioral or physiological dysfunction than that seen with either

  6. Supplementation of Spirulina (Arthrospira platensis) Improves Lifespan and Locomotor Activity in Paraquat-Sensitive DJ-1β(Δ93) Flies, a Parkinson's Disease Model in Drosophila melanogaster.

    PubMed

    Kumar, Ajay; Christian, Pearl K; Panchal, Komal; Guruprasad, B R; Tiwari, Anand K

    2017-09-03

    Spirulina (Arthrospira platensis) is a cyanobacterium (blue-green alga) consumed by humans and other animals because of its nutritional values and pharmacological properties. Apart from high protein contents, it also contains high levels of antioxidant and anti-inflammatory compounds, such as carotenoids, β-carotene, phycocyanin, and phycocyanobilin, indicating its possible pharmaco-therapeutic utility. In the present study using DJ-1β(Δ93) flies, a Parkinson's disease model in Drosophila, we have demonstrated the therapeutic effect of spirulina and its active component C-phycocyanin (C-PC) in the improvement of lifespan and locomotor behavior. Our findings indicate that dietary supplementation of spirulina significantly improves the lifespan and locomotor activity of paraquat-fed DJ-1β(Δ93) flies. Furthermore, supplementation of spirulina and C-PC individually and independently reduced the cellular stress marked by deregulating the expression of heat shock protein 70 and Jun-N-terminal kinase signaling in DJ-1β(Δ93) flies. A significant decrease in superoxide dismutase and catalase activities in spirulina-fed DJ-1β(Δ93) flies tends to indicate the involvement of antioxidant properties associated with spirulina in the modulation of stress-induced signaling and improvement in lifespan and locomotor activity in Drosophila DJ-1β(Δ93) flies. Our results suggest that antioxidant boosting properties of spirulina can be used as a nutritional supplement for improving the lifespan and locomotor behavior in Parkinson's disease.

  7. Food restriction alters N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: evidence for sensitization of dopamine D2 receptor-mediated effects.

    PubMed

    Collins, Gregory T; Calinski, Diane M; Newman, Amy Hauck; Grundt, Peter; Woods, James H

    2008-05-01

    Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect

  8. Dopamine and the Brainstem Locomotor Networks: From Lamprey to Human

    PubMed Central

    Ryczko, Dimitri; Dubuc, Réjean

    2017-01-01

    In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson's disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia. However, a descending dopaminergic pathway originating from the substantia nigra pars compacta was recently discovered. It innervates the mesencephalic locomotor region (MLR) from basal vertebrates to mammals. This pathway was shown to increase locomotor output in lampreys, and could very well play an important role in mammals. Here, we provide a detailed account on the newly found dopaminergic pathway in lamprey, salamander, rat, monkey, and human. In lampreys and salamanders, dopamine release in the MLR is associated with the activation of reticulospinal neurons that carry the locomotor command to the spinal cord. Dopamine release in the MLR potentiates locomotor movements through a D1-receptor mechanism in lampreys. In rats, stimulation of the substantia nigra pars compacta elicited dopamine release in the pedunculopontine nucleus, a known part of the MLR. In a monkey model of Parkinson's disease, a reduced dopaminergic innervation of the brainstem locomotor networks was reported. Dopaminergic fibers are also present in human pedunculopontine nucleus. We discuss the conserved locomotor role of this pathway from lamprey to mammals, and the hypothesis that this pathway could play a role in the locomotor deficits reported in Parkinson's disease. PMID:28603482

  9. Locomotor exercise in weightlessness

    NASA Technical Reports Server (NTRS)

    Thornton, W.; Whitmore, H.

    1991-01-01

    The requirements for exercise in space by means of locomotion are established and addressed with prototype treadmills for use during long-duration spaceflight. The adaptation of the human body to microgravity is described in terms of 1-G locomotor biomechanics, the effects of reduced activity, and effective activity-replacement techniques. The treadmill is introduced as a complement to other techniques of force replacement with reference given to the angle required for exercise. A motor-driven unit is proposed that can operate at a variety of controlled speeds and equivalent grades. The treadmills permit locomotor exercise as required for long-duration space travel to sustain locomotor and cardiorespiratory capacity at a level consistent with postflight needs.

  10. Dietary supplementation with fish oil prevents high fat diet-induced enhancement of sensitivity to the locomotor stimulating effects of cocaine in adolescent female rats.

    PubMed

    Serafine, Katherine M; Labay, Caitlin; France, Charles P

    2016-08-01

    Eating a diet high in fat can lead to obesity, chronic metabolic disease, and increased inflammation in both the central and peripheral nervous systems. Dietary supplements that are high in omega-3 polyunsaturated fatty acids can reduce or prevent these negative health consequences in rats. Eating high fat chow also increases the sensitivity of rats to behavioral effects of drugs acting on dopamine systems (e.g., cocaine), and this effect is greatest in adolescent females. The present experiment tested the hypothesis that dietary supplementation with fish oil prevents high fat chow induced increases in sensitivity to cocaine in adolescent female rats. Female Sprague-Dawley rats (post-natal day 25-27) ate standard laboratory chow (5.7% fat), high fat chow (34.4% fat), or high fat chow supplemented with fish oil (20% w/w). Cocaine dose dependently (1-17.8mg/kg) increased locomotion and induced sensitization across 6 weeks of once-weekly testing in all rats; however, these effects were greatest in rats eating high fat chow. Dietary supplementation with fish oil prevented enhanced locomotion and sensitization in rats eating high fat chow. There were no differences in inflammatory markers in plasma or the hypothalamus among dietary conditions. These results demonstrate that dietary supplementation with fish oil can prevent high fat diet-induced sensitization to cocaine, but they fail to support the view that these effects are due to changes in proinflammatory cytokines. These data add to a growing literature on the relationship between diet and drug abuse and extend the potential health benefits of fish oil to stimulant drug abuse prevention. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Species sensitivities and prediction of teratogenic potential.

    PubMed Central

    Schardein, J L; Schwetz, B A; Kenel, M F

    1985-01-01

    Many chemicals shown to be teratogenic in laboratory animals are not known to be teratogenic in humans. However, it remains to be determined if the unresponsiveness of humans is due to lessened sensitivity, to generally subteratogenic exposure levels, or to the lack of an appropriate means of identifying human teratogens. On the other hand, with the exception of the coumarin anticoagulant drugs, those agents well accepted as human teratogens have been shown to be teratogenic in one or more laboratory species. Yet, no single species has clearly distinguished itself as being more advantageous in the detection of human teratogens over any other. Among the species used for testing, the rat and mouse most successfully model the human reaction, but the rabbit is less likely than other species to give a false positive finding. Among species less commonly used for testing, primates offered a higher level of predicability than others. Regarding concordance of target malformations, the mouse and rat produced the greatest number of concordant defects, but they also were responsible for the most noncorcordant responses as well. Since no other species is clearly more predictive of the human response, it is concluded that safety decisions should be based on all reproductive and developmental toxicity data in light of the agent's known pharmacokinetic, metabolic and toxicologic parameters. PMID:3905381

  12. Statistical Analysis of Zebrafish Locomotor Response

    PubMed Central

    Zhang, Gaonan; Venkatraman, Prahatha; Brown, Skye Ashton; Pang, Chi-Pui; Zhang, Mingzhi; Ma, Ping; Leung, Yuk Fai

    2015-01-01

    Zebrafish larvae display rich locomotor behaviour upon external stimulation. The movement can be simultaneously tracked from many larvae arranged in multi-well plates. The resulting time-series locomotor data have been used to reveal new insights into neurobiology and pharmacology. However, the data are of large scale, and the corresponding locomotor behavior is affected by multiple factors. These issues pose a statistical challenge for comparing larval activities. To address this gap, this study has analyzed a visually-driven locomotor behaviour named the visual motor response (VMR) by the Hotelling’s T-squared test. This test is congruent with comparing locomotor profiles from a time period. Different wild-type (WT) strains were compared using the test, which shows that they responded differently to light change at different developmental stages. The performance of this test was evaluated by a power analysis, which shows that the test was sensitive for detecting differences between experimental groups with sample numbers that were commonly used in various studies. In addition, this study investigated the effects of various factors that might affect the VMR by multivariate analysis of variance (MANOVA). The results indicate that the larval activity was generally affected by stage, light stimulus, their interaction, and location in the plate. Nonetheless, different factors affected larval activity differently over time, as indicated by a dynamical analysis of the activity at each second. Intriguingly, this analysis also shows that biological and technical repeats had negligible effect on larval activity. This finding is consistent with that from the Hotelling’s T-squared test, and suggests that experimental repeats can be combined to enhance statistical power. Together, these investigations have established a statistical framework for analyzing VMR data, a framework that should be generally applicable to other locomotor data with similar structure. PMID

  13. Phenolsulfonphthalein transport by potential-sensitive urate transport system.

    PubMed

    Itagaki, Shirou; Shimamoto, Soji; Sugawara, Mitsuru; Kobayashi, Michiya; Miyazaki, Katsumi; Hirano, Takeshi; Iseki, Ken

    2005-08-22

    The purpose of this study was to elucidate the transporter-mediated secretion systems for phenolsulfonphthalein in brush-border membranes. In human and rat renal brush-border membranes, a potential-sensitive transport system has been shown to be involved in the efflux of organic anions. The uptake of phenolsulfonphthalein into rat renal brush-border membrane vesicles was stimulated by an inside-positive membrane potential. This potential-sensitive uptake of phenolsulfonphthalein was inhibited by probenecid, pyrazinoate and urate. p-Aminohippurate had no effect on the potential-sensitive uptake of phenolsulfonphthalein. Moreover, urate competitively inhibited the uptake of phenolsulfonphthalein. On the other hand, the uptake of phenolsulfonphthalein was slightly increased in the presence of an outward Cl- gradient. These results suggest that phenolsulfonphthalein has high affinity for the potential-sensitive urate transport system but has low affinity for an anion exchanger.

  14. Panic disorder and locomotor activity

    PubMed Central

    Sakamoto, Noriyuki; Yoshiuchi, Kazuhiro; Kikuchi, Hiroe; Takimoto, Yoshiyuki; Kaiya, Hisanobu; Kumano, Hiroaki; Yamamoto, Yoshiharu; Akabayashi, Akira

    2008-01-01

    Background Panic disorder is one of the anxiety disorders, and anxiety is associated with some locomotor activity changes such as "restlessness". However, there have been few studies on locomotor activity in panic disorder using actigraphy, although many studies on other psychiatric disorders have been reported using actigraphy. Therefore, the aim of the present study was to investigate the relationship between panic disorder and locomotor activity pattern using a wrist-worn activity monitor. In addition, an ecological momentary assessment technique was used to record panic attacks in natural settings. Methods Sixteen patients with panic disorder were asked to wear a watch-type computer as an electronic diary for recording panic attacks for two weeks. In addition, locomotor activity was measured and recorded continuously in an accelerometer equipped in the watch-type computer. Locomotor activity data were analyzed using double cosinor analysis to calculate mesor and the amplitude and acrophase of each of the circadian rhythm and 12-hour harmonic component. Correlations between panic disorder symptoms and locomotor activity were investigated. Results There were significant positive correlations between the frequency of panic attacks and mesor calculated from double cosinor analysis of locomotor activity (r = 0.55) and between HAM-A scores and mesor calculated from double cosinor analysis of locomotor activity (r = 0.62). Conclusion Panic disorder patients with more panic attacks and more anxiety have greater objectively assessed locomotor activity, which may reflect the "restlessness" of anxiety disorders. PMID:19017383

  15. Long-lasting changes in morphine-induced locomotor sensitization and tolerance in Long-Evans mother rats as a result of periodic postpartum separation from the litter: a novel model of increased vulnerability to drug abuse?

    PubMed

    Kalinichev, Mikhail; Easterling, Keith W; Holtzman, Stephen G

    2003-02-01

    Daily postpartum separations from the litter produce enduring changes in anxiety and sensitivity to the antinociceptive effects of morphine in Long-Evans dams. We tested whether postpartum experience alters sensitivity to the effects of morphine on locomotor activity. Dams were tested 4-6 weeks after their pups were weaned, and had one of the following backgrounds: daily separation from the litter on postpartum days 2-14 for either 3 h (prolonged separation-LS) or 15 min (brief separation-BS), or no separation (nonhandled control-NH). After 2 consecutive days (B1-2) of baseline activity measurements, subjects were tested daily after s.c. injections of either morphine (10 mg/kg) or saline for 7 days and again on day 10. Beginning 5 days later, saline and 1.0-10 mg/kg of morphine were tested in all dams. On B1, LS and BS dams habituated slower than NH controls, yielding higher horizontal counts. LS dams failed to habituate across baseline days and were more active than other dams on B2. Sensitization, a progressive increase in horizontal activity, was more rapid and robust in LS and BS dams compared to NH animals. LS was the only group that developed tolerance to morphine-induced decreases in vertical activity. In LS dams with the history of morphine treatment, injection of saline resulted in higher horizontal activity and center time compared to saline-treated counterparts, indicative of conditioning. Among animals with a history of saline treatment, LS dams were more sensitive to morphine challenges than BS and NH dams. As a result of the robust and long-lasting increases in the ability of morphine to induce behavioral sensitization in litter-separated dams, periodic postpartum separation may represent a new animal model of increased vulnerability to substance abuse.

  16. *Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential

    EPA Science Inventory

    Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens fol...

  17. *Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential

    EPA Science Inventory

    Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens fol...

  18. Eating high fat chow, but not drinking sucrose or saccharin, enhances the development of sensitization to the locomotor effects of cocaine in adolescent female rats

    PubMed Central

    Serafine, Katherine M.; Bentley, Todd A.; Koek, Wouter; France, Charles P.

    2014-01-01

    Eating high fat chow accelerates the development of sensitization to cocaine-induced locomotion in female rats. It is not known whether consumption of sucrose or saccharin also increases sensitivity to the behavioral effects of cocaine or whether continuous (or intermittent) access to these feeding conditions is necessary to change sensitivity. Adolescent female Sprague-Dawley rats were assigned to 1 of 7 feeding conditions from post natal day (PND) 25 through 60. Rats ate either high fat (60% kcal from fat) chow and drank water, or standard (17% kcal from fat) chow and drank either water, 10% sucrose solution, or 0.1% saccharin solution. Rats had either continuous access to high fat chow, sucrose or saccharin or they had intermittent access (i.e. 2 days per week) to these substances with access to water and standard chow on other days. As compared with rats eating standard chow, continuous (but not intermittent) access to high fat chow enhanced the development of sensitization to cocaine-induced (1–17.8 mg/kg) locomotion; drinking sucrose or saccharin (continuous or intermittent access) did not alter the development of sensitization to cocaine-induced locomotion. The impact of feeding condition on behavioral effects of cocaine varies between sexes and across dietary composition. PMID:25485647

  19. Eating high fat chow, but not drinking sucrose or saccharin, enhances the development of sensitization to the locomotor effects of cocaine in adolescent female rats.

    PubMed

    Serafine, Katherine M; Bentley, Todd A; Koek, Wouter; France, Charles P

    2015-04-01

    Eating high fat chow accelerates the development of sensitization to cocaine-induced locomotion in female rats. It is not known whether consumption of sucrose or saccharin also increases sensitivity to the behavioral effects of cocaine or whether continuous (or intermittent) access to these feeding conditions is necessary to change sensitivity. Adolescent female Sprague-Dawley rats were assigned to one of seven feeding conditions from postnatal day 25 through to postnatal day 60. The rats either ate high fat (60% kcal from fat) chow and drank water or ate standard (17% kcal from fat) chow and drank either water, a 10% sucrose solution, or a 0.1% saccharin solution. The rats either had continuous access to high fat chow, sucrose, or saccharin, or had intermittent access (i.e. 2 days/week) to these substances, with access to water and standard chow on other days. As compared with standard chow, continuous (but not intermittent) access to high fat chow enhanced the development of sensitization to cocaine-induced (1-17.8 mg/kg) locomotion; drinking sucrose or saccharin (continuous or intermittent access) did not alter the development of sensitization to cocaine-induced locomotion. The impact of feeding condition on the behavioral effects of cocaine varies between sexes and across dietary composition.

  20. Corneal Sensitivity as a Potential Marker of Diabetic Neuropathy.

    PubMed

    Sitompul, Ratna

    2017-04-01

    Diabetes mellitus (DM) is a complex and chronic metabolic disorder leading to many complications. One of the most common complications of DM is diabetic neuropathy. There are many studies exploring corneal sensitivity as a potential marker of diabetic neuropathy. This review aims to explore association between corneal sensitivity and diabetic neuropathy. In diabetic neuropathy, corneal sensitivity is impaired due to low level of corneal nerve trophic factors, impaired sensory nerve fibers, and lost communication of dendtritic cell. In diabetic patients, this condition can be assessed by several techniques, such as Cochet Bonnet aesthesiometry, non-contact corneal aesthesiometry, and confocal microscopy. Few promising therapeutic targets for impaired corneal sensitivity include stem cell and growth factor therapy that can be used to prevent complication in patient with diabetic neurotrophic keratopathy. Impaired corneal sensitivity serve as a potential marker of diabetic neuropathy. Doctors, opthalmologists and internists, should anticipate the possibility of observing the following changes in diabetic patients with neuropathy by using corneal sensitivity assessment test.

  1. Locomotor adaptations of some gelatinous zooplankton.

    PubMed

    Bone, Q

    1985-01-01

    Swimming behaviour and locomotor adaptations are described in chaetognaths, larvacean tunicates, some cnidaria, and thaliacean tunicates. The first two groups swim by oscillating a flattened tail, the others by jet propulsion. In chaetognaths, the locomotor muscle fibres are extensively coupled and relatively sparsely innervated, they exhibit compound spike-like potentials. The motoneurons controlling the rhythmic activity of the locomotor muscle lie in a ventral ganglion whose organization is briefly described. Rhythmic swimming bursts in larvaceans are similarly driven by a caudal ganglion near the base of the tail, but each caudal muscle cell is separately innervated by two sets of motor nerves, as well as being coupled to its neighbours. The external epithelium is excitable, and linked to the caudal ganglion by the axons of central cells. Mechanical stimulation of the epithelium evokes receptor potentials followed by action potentials and by bursts of rapid swimming. The trachyline medusa Aglantha and the small siphonophore Chelophyes also show rapid escape responses; in Aglantha these are driven by a specialized giant axon system lacking in other hydromedusae, and in Chelophyes. Slow swimming in Aglantha apparently involves a second nerve supply to the same muscle sheets used in rapid swimming, whereas in Chelophyes slow swimming results from the activity of the smaller posterior nectophore. Slow swimming in siphonophores is more economical than the rapid responses. In the hydrozoan medusa Polyorchis (as in Chelophyes) action potentials in the locomotor muscle sheet change in shape during swimming bursts, and their duration is related to the size of the medusa; they are not simply triggers of muscular contraction. The two groups of thaliacean tunicates are specialized differently. Doliolum is adapted for single rapid jet pulses (during which it achieves instantaneous velocities of 50 body lengths s-l), whilst salps are adapted for slow continuous swimming. The

  2. Non-animal test methods for predicting skin sensitization potentials.

    PubMed

    Mehling, Annette; Eriksson, Tove; Eltze, Tobias; Kolle, Susanne; Ramirez, Tzutzuy; Teubner, Wera; van Ravenzwaay, Bennard; Landsiedel, Robert

    2012-08-01

    Contact allergies are complex diseases, and it is estimated that 15-20 % of the general population suffers from contact allergy, with increasing prevalence. Evaluation of the sensitization potential of a substance is usually carried out in animal models. Nowadays, there is much interest in reducing and ultimately replacing current animal tests. Furthermore, as of 2013, the EU has posed a ban on animal testing of cosmetic ingredients that includes skin sensitization. Therefore, predictive and robust in vitro tests are urgently needed. In order to establish alternatives to animal testing, the in vitro tests must mimic the very complex interactions between the sensitizing chemical and the different parts of the immune system. This review article summarizes recent efforts to develop in vitro tests for predicting skin sensitizers. Cell-based assays, in chemico methods and, to a lesser extent, in silico methods are presented together with a discussion of their current status. With considerable progress having been achieved during the last years, the rationale today is that data from different non-animal test methods will have to be combined in order to obtain reliable hazard and potency information on potential skin sensitizers.

  3. Auditory evoked potential could reflect emotional sensitivity and impulsivity

    PubMed Central

    Kim, Ji Sun; Kim, Sungkean; Jung, Wookyoung; Im, Chang-Hwan; Lee, Seung-Hwan

    2016-01-01

    Emotional sensitivity and impulsivity could cause interpersonal conflicts and neuropsychiatric problems. Serotonin is correlated with behavioral inhibition and impulsivity. This study evaluated whether the loudness dependence of auditory evoked potential (LDAEP), a potential biological marker of central serotonergic activity, could reflect emotional sensitivity and impulsivity. A total of 157 healthy individuals were recruited, who performed LDAEP and Go/Nogo paradigms during electroencephalogram measurement. Barratt impulsivity scale (BIS), Conners’ Adult ADHD rating scale (CAARS), and affective lability scale (ALS) were evaluated. Comparison between low and high LDAEP groups was conducted for behavioural, psychological, and event-related potential (ERP) measures. The high LDAEP group showed significantly increased BIS, a subscale of the CAARS, ALS, and false alarm rate of Nogo stimuli compared to the low LDAEP group. LDAEP showed significant positive correlations with the depression scale, ALS scores, subscale of the CAARS and Nogo-P3 amplitude. In the source activity of Nogo-P3, the cuneus, lingual gyrus, and precentral gyrus activities were significantly increased in the high LDAEP group. Our study revealed that LDAEP could reflect emotional sensitivity and impulsivity. LDAEP, an auditory evoked potential could be a useful tool to evaluate emotional regulation. PMID:27910865

  4. Sex differences in locomotor effects of morphine in the rat

    PubMed Central

    Craft, Rebecca M.; Clark, James L.; Hart, Stephen P.; Pinckney, Megan K.

    2007-01-01

    Sex differences in reinforcing, analgesic and other effects of opioids have been demonstrated; however, the extent to which sex differences in motoric effects of opioids contribute to apparent sex differences in their primary effects is not known. The goal of this study was to compare the effects of the prototypic mu opioid agonist morphine on locomotor activity in male vs. female rats. Saline or morphine (1-10 mg/kg) was administered s.c. to adult Sprague-Dawley rats, which were placed into a photobeam apparatus for 3-5 hr to measure activity. Modulation of morphine's effects by gonadal hormones and by handling (either during the test session or for 4 days before the test session) were examined. Morphine initially suppressed and later increased locomotor activity in both sexes relative to their saline-injected controls, but males were more sensitive than females to the initial locomotor suppressant effect of morphine. Intermittent, brief handling during the 3-hr test session blunted morphine-induced locomotor activation in both sexes. Females in proestrus were the most sensitive to morphine's locomotor-stimulant effect, with females in estrus showing the least response to morphine. Gonadectomized (GDX) males with or without testosterone were equally sensitive to morphine's effects, whereas GDX females treated with estradiol showed a blunted response to morphine's effects, similar to intact females in estrus. Brief handling on each of 4 consecutive days pre-test attenuated morphine's locomotor suppressant effect in males but had no effect in females, thereby eliminating the sex difference. These data suggest that sex differences in morphine's effects on locomotor activity can be attributed to gonadal hormones in females, and to differential stress-induced modulation of morphine's effects in males vs. females. PMID:17217999

  5. Peripheral sensitization reduces laser-evoked potential habituation.

    PubMed

    Hüllemann, P; Watfeh, R; Shao, Y-Q; Nerdal, A; Binder, A; Baron, R

    2015-12-01

    Laser-evoked potential (LEP) habituation was investigated under the influence of capsaicin-induced peripheral and central sensitization. Fifteen subjects received 100 repetitive painful laser stimuli at the right hand dorsum at primary (application area; condition I) and secondary areas (beyond application area; condition II) in two different sessions after applying capsaicin topically. Conditions I and II were compared to a control condition without capsaicin application. N1, N2, and P2 latencies and N1 and N2/P2 amplitudes were recorded by EEG. Quantitative sensory testing (QST) and the Liewald Diary reaction time experiment were used as control tests. QST documented heat hyperalgesia as a sign of peripheral sensitization in the primary area and pinprick hyperalgesia in the primary and secondary area as a sign of central sensitization, after applying capsaicin. The N2/P2 amplitude habituation was significantly reduced in the primary area compared to controls (the primary area represents peripheral sensitization). The LEPs of the secondary area (the secondary area represents central sensitization) showed no significant N2/P2 amplitude habituation compared to controls. The comparison between conditions I vs. II showed no significant difference regarding N2/P2 amplitude and laser pain rating. Capsaicin-induced central sensitization does not alter LEP habituation. The physiological habituation of LEP amplitudes is reduced due to peripheral mechanisms after applying capsaicin topically. These findings form a basis for future studies, which use the habituation paradigm to investigate pain conditions promoted by sensitization phenomena. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  6. Sensitivity of Global Warming Potentials to the assumed background atmosphere

    SciTech Connect

    Wuebbles, D.J.; Patten, K.O.

    1992-03-05

    This is the first in a series of papers in which we will examine various aspects of the Global Warming Potential (GWP) concept and the sensitivity and uncertainties associated with the GWP values derived for the 1992 updated scientific assessment report of the Intergovernmental Panel on Climate Change (IPCC). One of the authors of this report (DJW) helped formulate the GWP concept for the first IPCC report in 1990. The Global Warming Potential concept was developed for that report as an attempt to fulfill the request from policymakers for a way of relating the potential effects on climate from various greenhouse gases, in much the same way as the Ozone Depletion Potential (ODP) concept (Wuebbles, 1981) is used in policy analyses related to concerns about the relative effects of CFCs and other compounds on stratospheric ozone destruction. We are also coauthors of the section on radiative forcing and Global Warming Potentials for the 1992 IPCC update; however, there was too little time to prepare much in the way of new research material for that report. Nonetheless, we have recognized for some time that there are a number of uncertainties and limitations associated with the definition of GWPs used in both the original and new IPCC reports. In this paper, we examine one of those uncertainties, namely, the effect of the assumed background atmospheric concentrations on the derived GWPs. Later papers will examine the sensitivity of GWPs to other uncertainties and limitations in the current concept.

  7. Listening to membrane potential: photoacoustic voltage-sensitive dye recording

    NASA Astrophysics Data System (ADS)

    Zhang, Haichong K.; Yan, Ping; Kang, Jeeun; Abou, Diane S.; Le, Hanh N. D.; Jha, Abhinav K.; Thorek, Daniel L. J.; Kang, Jin U.; Rahmim, Arman; Wong, Dean F.; Boctor, Emad M.; Loew, Leslie M.

    2017-04-01

    Voltage-sensitive dyes (VSDs) are designed to monitor membrane potential by detecting fluorescence changes in response to neuronal or muscle electrical activity. However, fluorescence imaging is limited by depth of penetration and high scattering losses, which leads to low sensitivity in vivo systems for external detection. By contrast, photoacoustic (PA) imaging, an emerging modality, is capable of deep tissue, noninvasive imaging by combining near-infrared light excitation and ultrasound detection. Here, we show that voltage-dependent quenching of dye fluorescence leads to a reciprocal enhancement of PA intensity. We synthesized a near-infrared photoacoustic VSD (PA-VSD), whose PA intensity change is sensitive to membrane potential. In the polarized state, this cyanine-based probe enhances PA intensity while decreasing fluorescence output in a lipid vesicle membrane model. A theoretical model accounts for how the experimental PA intensity change depends on fluorescence and absorbance properties of the dye. These results not only demonstrate PA voltage sensing but also emphasize the interplay of both fluorescence and absorbance properties in the design of optimized PA probes. Together, our results demonstrate PA sensing as a potential new modality for recording and external imaging of electrophysiological and neurochemical events in the brain.

  8. Recording membrane potential changes through photoacoustic voltage sensitive dye

    NASA Astrophysics Data System (ADS)

    Zhang, Haichong K.; Kang, Jeeun; Yan, Ping; Abou, Diane S.; Le, Hanh N. D.; Thorek, Daniel L. J.; Kang, Jin U.; Gjedde, Albert; Rahmim, Arman; Wong, Dean F.; Loew, Leslie M.; Boctor, Emad M.

    2017-03-01

    Monitoring of the membrane potential is possible using voltage sensitive dyes (VSD), where fluorescence intensity changes in response to neuronal electrical activity. However, fluorescence imaging is limited by depth of penetration and high scattering losses, which leads to low sensitivity in vivo systems for external detection. In contrast, photoacoustic (PA) imaging, an emerging modality, is capable of deep tissue, noninvasive imaging by combining near infrared light excitation and ultrasound detection. In this work, we develop the theoretical concept whereby the voltage-dependent quenching of dye fluorescence leads to a reciprocal enhancement of PA intensity. Based on this concept, we synthesized a novel near infrared photoacoustic VSD (PA-VSD) whose PA intensity change is sensitive to membrane potential. In the polarized state, this cyanine-based probe enhances PA intensity while decreasing fluorescence output in a lipid vesicle membrane model. With a 3-9 μM VSD concentration, we measured a PA signal increase in the range of 5.3 % to 18.1 %, and observed a corresponding signal reduction in fluorescence emission of 30.0 % to 48.7 %. A theoretical model successfully accounts for how the experimental PA intensity change depends on fluorescence and absorbance properties of the dye. These results not only demonstrate the voltage sensing capability of the dye, but also indicate the necessity of considering both fluorescence and absorbance spectral sensitivities in order to optimize the characteristics of improved photoacoustic probes. Together, our results demonstrate photoacoustic sensing as a potential new modality for sub-second recording and external imaging of electrophysiological and neurochemical events in the brain.

  9. Evaluation of the skin sensitizing potential of biodegradable magnesium alloys.

    PubMed

    Witte, Frank; Abeln, Inken; Switzer, Elinor; Kaese, Volker; Meyer-Lindenberg, Andrea; Windhagen, Henning

    2008-09-15

    Corroding metals made of magnesium alloys represent a new class of degradable implants for musculoskeletal surgery. These implants may be associated with skin sensitizing reactions because of the release of metal ions. This study was conducted to compare the sensitizing potential of four different magnesium alloys (AZ31, AZ91, WE43, and LAE442) to current implant materials such as titanium (TiAl6V4) and a degradable polymer (SR-PLA96). Solutions and solid chips of these materials were prepared and tested in 156 guinea pigs according to the Magnusson-Kligman test. A standard allergen (hydroxy-cinnamon-aldehyde) causing allergic erythema was used as positive control and a standard irritant (sodium-lauryl-sulfate) causing local skin irritation for less than 24 h was used as negative control. All erythema were graded immediately and 24 h after patch removal by three independent observers. Histomorphological analyses were performed on skin biopsies taken 24 h after patch removal. We found that initial erythema in animals treated with solid chips diminished within 24 h and were caused by local skin irritation. Local skin irritation was also determined in erythema remaining for 24 h after patch removal in animals treated with dissolved test materials. No allergenic reactions according to the histomorphological criteria were observed in skin biopsies. We conclude that no skin sensitizing potential were detected for standard materials as well as for all tested magnesium alloys by the used methods.

  10. Murine and human CFTR exhibit different sensitivities to CFTR potentiators

    PubMed Central

    Cui, Guiying

    2015-01-01

    Development of therapeutic molecules with clinical efficacy as modulators of defective CFTR includes efforts to identify potentiators that can overcome or repair the gating defect in mutant CFTR channels. This has taken a great leap forward with the identification of the potentiator VX-770, now available to patients as “Kalydeco.” Other small molecules with different chemical structure also are capable of potentiating the activity of either wild-type or mutant CFTR, suggesting that there are features of the protein that may be targeted to achieve stimulation of channel activity by structurally diverse compounds. However, neither the mechanisms by which these compounds potentiate mutant CFTR nor the site(s) where these compounds bind have been identified. This knowledge gap partly reflects the lack of appropriate experimental models to provide clues toward the identification of binding sites. Here, we have compared the channel behavior and response to novel and known potentiators of human CFTR (hCFTR) and murine (mCFTR) expressed in Xenopus oocytes. Both hCFTR and mCFTR were blocked by GlyH-101 from the extracellular side, but mCFTR activity was increased with GlyH-101 applied directly to the cytoplasmic side. Similarly, glibenclamide only exhibited a blocking effect on hCFTR but both blocked and potentiated mCFTR in excised membrane patches and in intact oocytes. The clinically used CFTR potentiator VX-770 transiently increased hCFTR by ∼13% but potentiated mCFTR significantly more strongly. Our results suggest that mCFTR pharmacological sensitivities differ from hCFTR, which will provide a useful tool for identifying the binding sites and mechanism for these potentiators. PMID:26209275

  11. Murine and human CFTR exhibit different sensitivities to CFTR potentiators.

    PubMed

    Cui, Guiying; McCarty, Nael A

    2015-10-01

    Development of therapeutic molecules with clinical efficacy as modulators of defective CFTR includes efforts to identify potentiators that can overcome or repair the gating defect in mutant CFTR channels. This has taken a great leap forward with the identification of the potentiator VX-770, now available to patients as "Kalydeco." Other small molecules with different chemical structure also are capable of potentiating the activity of either wild-type or mutant CFTR, suggesting that there are features of the protein that may be targeted to achieve stimulation of channel activity by structurally diverse compounds. However, neither the mechanisms by which these compounds potentiate mutant CFTR nor the site(s) where these compounds bind have been identified. This knowledge gap partly reflects the lack of appropriate experimental models to provide clues toward the identification of binding sites. Here, we have compared the channel behavior and response to novel and known potentiators of human CFTR (hCFTR) and murine (mCFTR) expressed in Xenopus oocytes. Both hCFTR and mCFTR were blocked by GlyH-101 from the extracellular side, but mCFTR activity was increased with GlyH-101 applied directly to the cytoplasmic side. Similarly, glibenclamide only exhibited a blocking effect on hCFTR but both blocked and potentiated mCFTR in excised membrane patches and in intact oocytes. The clinically used CFTR potentiator VX-770 transiently increased hCFTR by ∼13% but potentiated mCFTR significantly more strongly. Our results suggest that mCFTR pharmacological sensitivities differ from hCFTR, which will provide a useful tool for identifying the binding sites and mechanism for these potentiators.

  12. Large pi-aromatic molecules as potential sensitizers for highly efficient dye-sensitized solar cells.

    PubMed

    Imahori, Hiroshi; Umeyama, Tomokazu; Ito, Seigo

    2009-11-17

    Recently, dye-sensitized solar cells have attracted much attention relevant to global environmental issues. Thus far, ruthenium(II) bipyridyl complexes have proven to be the most efficient TiO(2) sensitizers in dye-sensitized solar cells. However, a gradual increment in the highest power conversion efficiency has been recognized in the past decade. More importantly, considering that ruthenium is a rare metal, novel dyes without metal or using inexpensive metal are desirable for highly efficient dye-sensitized solar cells. Large pi-aromatic molecules, such as porphyrins, phthalocyanines, and perylenes, are important classes of potential sensitizers for highly efficient dye-sensitized solar cells, owing to their photostability and high light-harvesting capabilities that can allow applications in thinner, low-cost dye-sensitized solar cells. Porphyrins possess an intense Soret band at 400 nm and moderate Q bands at 600 nm. Nevertheless, the poor light-harvesting properties relative to the ruthenium complexes have limited the cell performance of porphyrin-sensitized TiO(2) cells. Elongation of the pi conjugation and loss of symmetry in porphyrins cause broadening and a red shift of the absorption bands together with an increasing intensity of the Q bands relative to that of the Soret band. On the basis of the strategy, the cell performance of porphyrin-sensitized solar cells has been improved intensively by the enhanced light absorption. Actually, some push-pull-type porphyrins have disclosed a remarkably high power conversion efficiency (6-7%) that was close to that of the ruthenium complexes. Phthalocyanines exhibit strong absorption around 300 and 700 nm and redox features that are similar to porphyrins. Moreover, phthalocyanines are transparent over a large region of the visible spectrum, thereby enabling the possibility of using them as "photovoltaic windows". However, the cell performance was poor, owing to strong aggregation and lack of directionality in the

  13. Movement Exploration and Locomotor Skills.

    ERIC Educational Resources Information Center

    National Center on Educational Media and Materials for the Handicapped, Columbus, OH.

    Selected from the National Instructional Materials Information System (NIMIS)--a computer based on-line interactive retrieval system on special education materials--the bibliography covers 23 materials for teaching movement exploration and locomotor skills to handicapped students at all educational levels. Entries are presented in order of NIMIS…

  14. White - cGMP Interaction Promotes Fast Locomotor Recovery from Anoxia in Adult Drosophila

    PubMed Central

    2017-01-01

    Increasing evidence indicates that the white (w) gene in Drosophila possesses extra-retinal functions in addition to its classical role in eye pigmentation. We have previously shown that w+ promotes fast and consistent locomotor recovery from anoxia, but how w+ modulates locomotor recovery is largely unknown. Here we show that in the absence of w+, several PDE mutants, especially cyclic guanosine monophosphate (cGMP)-specific PDE mutants, display wildtype-like fast locomotor recovery from anoxia, and that during the night time, locomotor recovery was light-sensitive in white-eyed mutant w1118, and light-insensitive in PDE mutants under w1118 background. Data indicate the involvement of cGMP in the modulation of recovery timing and presumably, light-evoked cGMP fluctuation is associated with light sensitivity of locomotor recovery. This was further supported by the observations that w-RNAi-induced delay of locomotor recovery was completely eliminated by upregulation of cGMP through multiple approaches, including PDE mutation, simultaneous overexpression of an atypical soluble guanylyl cyclase Gyc88E, or sildenafil feeding. Lastly, prolonged sildenafil feeding promoted fast locomotor recovery from anoxia in w1118. Taken together, these data suggest that a White-cGMP interaction modulates the timing of locomotor recovery from anoxia. PMID:28060942

  15. Locomotor training improves premotoneuronal control after chronic spinal cord injury.

    PubMed

    Knikou, Maria; Mummidisetty, Chaithanya K

    2014-06-01

    Spinal inhibition is significantly reduced after spinal cord injury (SCI) in humans. In this work, we examined if locomotor training can improve spinal inhibition exerted at a presynaptic level. Sixteen people with chronic SCI received an average of 45 training sessions, 5 days/wk, 1 h/day. The soleus H-reflex depression in response to low-frequency stimulation, presynaptic inhibition of soleus Ia afferent terminals following stimulation of the common peroneal nerve, and bilateral EMG recovery patterns were assessed before and after locomotor training. The soleus H reflexes evoked at 1.0, 0.33, 0.20, 0.14, and 0.11 Hz were normalized to the H reflex evoked at 0.09 Hz. Conditioned H reflexes were normalized to the associated unconditioned H reflex evoked with subjects seated, while during stepping both H reflexes were normalized to the maximal M wave evoked after the test H reflex at each bin of the step cycle. Locomotor training potentiated homosynaptic depression in all participants regardless the type of the SCI. Presynaptic facilitation of soleus Ia afferents remained unaltered in motor complete SCI patients. In motor incomplete SCIs, locomotor training either reduced presynaptic facilitation or replaced presynaptic facilitation with presynaptic inhibition at rest. During stepping, presynaptic inhibition was modulated in a phase-dependent manner. Locomotor training changed the amplitude of locomotor EMG excitability, promoted intralimb and interlimb coordination, and altered cocontraction between knee and ankle antagonistic muscles differently in the more impaired leg compared with the less impaired leg. The results provide strong evidence that locomotor training improves premotoneuronal control after SCI in humans at rest and during walking. Copyright © 2014 the American Physiological Society.

  16. Modelling the locomotor energetics of extinct hominids.

    PubMed

    Kramer, P A

    1999-10-01

    Bipedality is the defining characteristic of Hominidae and, as such, an understanding of the adaptive significance and functional implications of bipedality is imperative to any study of human evolution. Hominid bipedality is, presumably, a solution to some problem for the early hominids, one that has much to do with energy expenditure. Until recently, however, little attention could be focused on the quantifiable energetic aspects of bipedality as a unique locomotor form within Primates because of the inability to measure empirically the energy expenditure of non-modern hominids. A recently published method provides a way of circumventing the empirical measurement dilemma by calculating energy expenditure directly from anatomical variables and movement profiles. Although the origins of bipedality remain clouded, two discernible forms of locomotor anatomy are present in the hominid fossil record: the australopithecine and modern configurations. The australopithecine form is best represented by AL 288-1, a partial skeleton of Australopithecus afarensis, and is characterized as having short legs and a wide pelvis. The modern form is represented by modern humans and has long legs and a narrow pelvis. Human walking is optimized to take advantage of the changing levels of potential and kinetic energy that occur as the body and limbs move through the stride cycle. Although this optimization minimizes energy expenditure, some energy is required to maintain motion. I quantify this energy by developing a dynamic model that uses kinematic equations to determine energy expenditure. By representing both configurations with such a model, I can compare their rates of energy expenditure. I find that the australopithecine configuration uses less energy than that of a modern human. Despite arguments presented in the anthropological literature, the shortness of the legs of AL 288-1 provides no evidence that she was burdened with a compromised or transitional locomotor anatomy

  17. Exendin-4 Decreases Amphetamine-induced Locomotor Activity

    PubMed Central

    Erreger, Kevin; Davis, Adeola R.; Poe, Amanda M.; Greig, Nigel H.; Stanwood, Gregg D.; Galli, Aurelio

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) is released in response to nutrient ingestion and is a regulator of energy metabolism and consummatory behaviors through both peripheral and central mechanisms. The GLP-1 receptor (GLP-1R) is widely distributed in the central nervous system, however little is known about how GLP-1Rs regulate ambulatory behavior. The abused psychostimulant amphetamine (AMPH) promotes behavioral locomotor activity primarily by inducing the release of the neurotransmitter dopamine. Here, we identify the GLP-1R agonist exendin-4 (Ex-4) as a modulator of behavioral activation by AMPH. We report that in rats a single acute administration of Ex-4 decreases both basal locomotor activity as well as AMPH-induced locomotor activity. Ex-4 did not induce behavioral responses reflecting anxiety or aversion. Our findings implicate GLP-1R signaling as a novel modulator of psychostimulant-induced behavior and therefore a potential therapeutic target for psychostimulant abuse. PMID:22465309

  18. Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential

    SciTech Connect

    Pucheu-Haston, Cherie M.; Copeland, Lisa B.; Vallanat, Beena; Boykin, Elizabeth; Ward, Marsha D.W.

    2010-04-15

    Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens following an acute exposure in naive individuals. Female BALB/c mice received a single intratracheal aspiration exposure to Metarhizium anisopliae crude antigen (MACA) or bovine serum albumin (BSA) in Hank's Balanced Salt Solution (HBSS) or HBSS alone. Mice were terminated after 1, 3, 6, 12, 18 and 24 h. Bronchoalveolar lavage fluid (BALF) was evaluated to determine total and differential cellularity, total protein concentration and LDH activity. RNA was isolated from lung tissue for microarray analysis and qRT-PCR. MACA administration induced a rapid increase in BALF neutrophils, lymphocytes, eosinophils and total protein compared to BSA or HBSS. Microarray analysis demonstrated differential expression of genes involved in cytokine production, signaling, inflammatory cell recruitment, adhesion and activation in 3 and 12 h MACA-treated samples compared to BSA or HBSS. Further analyses allowed identification of approx 100 candidate biomarker genes. Eleven genes were selected for further assessment by qRT-PCR. Of these, 6 demonstrated persistently increased expression (Ccl17, Ccl22, Ccl7, Cxcl10, Cxcl2, Saa1), while C3ar1 increased from 6-24 h. In conclusion, a single respiratory exposure of mice to an allergenic mold extract induces an inflammatory response which is distinct in phenotype and gene transcription from the response to a control protein. Further validation of these biomarkers with additional allergens and irritants is needed. These biomarkers may facilitate improvements in screening methods.

  19. Sensitivity of direct global warming potentials to key uncertainties

    SciTech Connect

    Wuebbles, D.J.; Patten, K.O.; Grant, K.E. ); Jain, A.K. )

    1992-07-01

    A series of sensitivity studies examines the effect of several uncertainties in Global Wanning Potentials (GWPs). For example, the original evaluation of GWPs for the Intergovernmental Panel on Climate Change (EPCC, 1990) did not attempt to account for the possible sinks of carbon dioxide (CO{sub 2}) that could balance the carbon cycle and produce atmospheric concentrations of C0{sub 2} that match observations. In this study, a balanced carbon cycle model is applied in calculation of the radiative forcing from C0{sub 2}. Use of the balanced model produces up to 20 percent enhancement of the GWPs for most trace gases compared with the EPCC (1990) values for time horizons up to 100 years, but a decreasing enhancement with longer time horizons. Uncertainty limits of the fertilization feedback parameter contribute a 10 percent range in GWP values. Another systematic uncertainty in GWPs is the assumption of an equilibrium atmosphere (one in which the concentration of trace gases remains constant) versus a disequilibrium atmosphere. The latter gives GWPs that are 15 to 30 percent greater than the former, dependening upon the carbon dioxide emission scenario chosen. Seven scenarios are employed: constant emission past 1990 and the six EPCC (1992) emission scenarios. For the analysis of uncertainties in atmospheric lifetime ({tau}), the GWP changes in direct proportion to {tau} for short-lived gases, but to a lesser extent for gases with {tau} greater than the time horizon for the GWP calculation.

  20. An in vitro human skin test for assessing sensitization potential.

    PubMed

    Ahmed, S S; Wang, X N; Fielding, M; Kerry, A; Dickinson, I; Munuswamy, R; Kimber, I; Dickinson, A M

    2016-05-01

    Sensitization to chemicals resulting in an allergy is an important health issue. The current gold-standard method for identification and characterization of skin-sensitizing chemicals was the mouse local lymph node assay (LLNA). However, for a number of reasons there has been an increasing imperative to develop alternative approaches to hazard identification that do not require the use of animals. Here we describe a human in-vitro skin explant test for identification of sensitization hazards and the assessment of relative skin sensitizing potency. This method measures histological damage in human skin as a readout of the immune response induced by the test material. Using this approach we have measured responses to 44 chemicals including skin sensitizers, pre/pro-haptens, respiratory sensitizers, non-sensitizing chemicals (including skin-irritants) and previously misclassified compounds. Based on comparisons with the LLNA, the skin explant test gave 95% specificity, 95% sensitivity, 95% concordance with a correlation coefficient of 0.9. The same specificity and sensitivity were achieved for comparison of results with published human sensitization data with a correlation coefficient of 0.91. The test also successfully identified nickel sulphate as a human skin sensitizer, which was misclassified as negative in the LLNA. In addition, sensitizers and non-sensitizers identified as positive or negative by the skin explant test have induced high/low T cell proliferation and IFNγ production, respectively. Collectively, the data suggests the human in-vitro skin explant test could provide the basis for a novel approach for characterization of the sensitizing activity as a first step in the risk assessment process. Copyright © 2015 John Wiley & Sons, Ltd.

  1. Locomotor Experience and Use of Social Information Are Posture Specific

    ERIC Educational Resources Information Center

    Adolph, Karen E.; Tamis-LeMonda, Catherine S.; Ishak, Shaziela; Karasik, Lana B.; Lobo, Sharon A.

    2008-01-01

    The authors examined the effects of locomotor experience on infants' perceptual judgments in a potentially risky situation--descending steep and shallow slopes--while manipulating social incentives to determine where perceptual judgments are most malleable. Twelve-month-old experienced crawlers and novice walkers were tested on an adjustable…

  2. Greater Ethanol-Induced Locomotor Activation in DBA/2J versus C57BL/6J Mice Is Not Predicted by Presynaptic Striatal Dopamine Dynamics

    PubMed Central

    Rose, Jamie H.; Calipari, Erin S.; Mathews, Tiffany A.; Jones, Sara R.

    2013-01-01

    A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum. PMID:24349553

  3. The potential effectiveness of nanoparticles as radio sensitizers for radiotherapy

    PubMed Central

    Babaei, Mohammad; Ganjalikhani, Maryam

    2014-01-01

    Introduction: Application of nanoparticles as radio sensitizer is a promising field to improve efficiency of radiotherapy. Methods: This study was conducted to review nano radio sensitizers. PubMed, Ovid Medline, Science Direct, Scopus, ISI web of knowledge, and Springer databases were searched from 2000 to May 2013 to identify relevant studies. Search was restricted to English language. Results: We included any study that evaluated nanoparticles, volunteer of radio enhancement at radiotherapy on animals or cell lines. Nanoparticles can increase radio sensitivity of tumor cells. This effect was shown in vivo and in vitro, at kilovltage or megavoltage energies, in 24 reviewed studies. Focus of studies was on gold nanoparticles. Radio sensitizing effects of nanoparticles depend on nanoparticles’ size, type, concentration, intracellular localization, used irradiation energy and tested cell line. Conclusion: Literature suggests potency of nanoparticles for increasing cell radio sensitivity. Reviewed results are promising and warrant future clinical trials. PMID:24790894

  4. Limits to human locomotor performance: phylogenetic origins and comparative perspectives.

    PubMed

    Dudley, R

    2001-09-01

    Studies of human exercise physiology have been conducted from a largely ahistorical perspective. This approach usefully elucidates proximate limits to locomotor performance, but ignores potential sources of biomechanical and physiological variation that derive from adaptation to ancestral environments. Phylogenetic reconstruction suggests that multiple hominoid lineages, including that leading to Homo sapiens, evolved in African highlands at altitudes of 1000-2000 m. The evolution of human locomotor physiology therefore occurred under conditions of hypobaric hypoxia. In contrast to present-day humans running on treadmills or exercising in otherwise rectilinear trajectories, ancestral patterns of hominid locomotion probably involved intermittent knuckle-walking over variable terrain, occasional bouts of arboreality and an evolving capacity for bipedalism. All such factors represent potential axes of locomotor variation at present unstudied in extant hominoid taxa. As with humans, hummingbirds evolved in mid-montane contexts but pose an extreme contrast with respect to body size, locomotor mode and metabolic capacity. Substantial biomechanical and physiological challenges are associated with flight in hypobaria. Nonetheless, hummingbird lineages demonstrate a progressive invasion of higher elevations and a remarkable tolerance to hypoxia during hovering. Upregulation of aerobic capacity and parallel resistance to hypoxia may represent coupled evolutionary adaptations to flight under high-altitude conditions.

  5. Development of action potentials and apamin-sensitive after-potentials in mouse vestibular nucleus neurones.

    PubMed

    Dutia, M B; Johnston, A R

    1998-01-01

    The postnatal maturation of medial vestibular nucleus (MVN) neurones was examined in slices of the dorsal brainstem prepared from balb/c mice at specific stages during the first postnatal month. Using spike-shape averaging to analyse the intracellularly recorded action potentials and after-hyperpolarizations (AHPs) in each cell, all the MVN neurones recorded in the young adult (postnatal day 30; P30) mouse were shown to have either a single deep AHP (type A cells), or an early fast and a delayed slow AHP (type B cells). The relative proportions of the two subtypes were similar to those in the young adult rat. At P5, all the MVN cells recorded showed immature forms of either the type A or the type B action potential shape. Immature type A cells had broad spontaneous spikes, and the characteristic single AHP was small in amplitude. Immature type B cells had somewhat narrower spontaneous spikes that were followed by a delayed, apamin-sensitive AHP. The delayed AHP was separated from the repolarisation phase of the spike by a period of isopotentiality. Over the period P10-P15, the mean resting potentials of the MVN cells became more negative, their action potential fall-times became shorter, the single AHP in type A cells became deeper, and the early fast AHP appeared in type B cells. Until P15 cells of varying degrees of electrophysiological maturity were found in the MVN but by P30 all MVN cells recorded were typical adult type A or type B cells. Exposure to the selective blocker of SK-type Ca-activated K channels, apamin (0.3 microM), induced depolarising plateaux and burst firing in immature type B cells at rest. The duration of the apamin-induced bursts and the spike frequency during the bursts were reduced but not abolished after blockade of Ca channels in Ca-free artificial cerebrospinal fluid containing Cd2+. By contrast, in mature type B cells at rest apamin selectively abolished the delayed slow AHP but did not induce bursting activity. Apamin had no effect

  6. Biomarkers of Acute Respiratory Allergen Exposure: Screening For Sensitization Potential

    EPA Science Inventory

    Rationale: An in vitro assay to identify respiratory sensitizers will provide a rapid screen and reduce animal use. The study goal was to identify biomarkers that differentiate allergen versus non-allergen responses following an acute exposure. Methods: Female BALB/c mice rec...

  7. Biomarkers of Acute Respiratory Allergen Exposure: Screening For Sensitization Potential

    EPA Science Inventory

    Rationale: An in vitro assay to identify respiratory sensitizers will provide a rapid screen and reduce animal use. The study goal was to identify biomarkers that differentiate allergen versus non-allergen responses following an acute exposure. Methods: Female BALB/c mice rec...

  8. Dermal Sensitization Potential of Guanidine Hydrochloride in Guinea Pigs

    DTIC Science & Technology

    1986-01-09

    Landsteiner K, Jacobs J. Studies on sensitization of animals with . simple chemical compounds. J Exp Med 1935; 61:643-656. 4. Buehler EV. Delayed...An.flytical data/pnirity: Water content 0.1% by Karl Fischer analysts.* The material is at least 98% pure and chromatographs 6 as one spot by thin

  9. Novel and Direct Access to the Human Locomotor Spinal Circuitry

    PubMed Central

    Gerasimenko, Yury; Gorodnichev, Ruslan; Machueva, Ekaterina; Pivovarova, Elena; Semyenov, Denis; Savochin, Alexandr; Roy, Roland R.; Edgerton, V. Reggie

    2010-01-01

    The degree of automaticity of locomotion in primates compared to other mammals remains unclear. Here we examine the possibility for activation of the spinal locomotor circuitry in non-injured humans by spinal electromagnetic stimulation (SEMS). SEMS (3 Hz and 1.3 to 1.82 Tesla) at the T11–T12 vertebrae induced involuntary bilateral locomotor-like movements in the legs of individuals placed in a gravity-neutral position. The formation of locomotor-like activity during SEMS started with a latency of 0.68 ± 0.1 sec after delivering the first stimulus, unlike continuous vibration of muscles that requires several seconds. The first EMG burst in response to SEMS was observed most often in a proximal flexor muscle. We speculate that SEMS directly activates the circuitry intrinsic to the spinal cord, as suggested by the immediate response and the electrophysiological observations demonstrating an absence of strictly time-linked responses within the EMG burst associated with individual stimuli during SEMS. SEMS in the presence of vibration of the leg muscles was more effective in facilitating locomotor-like activity than SEMS alone. The present results suggest that SEMS could be an effective noninvasive clinical tool to determine the potential of an individual to recover locomotion after a spinal cord injury as well as being an effective rehabilitation tool itself. PMID:20220003

  10. Novel and direct access to the human locomotor spinal circuitry.

    PubMed

    Gerasimenko, Yury; Gorodnichev, Ruslan; Machueva, Ekaterina; Pivovarova, Elena; Semyenov, Denis; Savochin, Alexandr; Roy, Roland R; Edgerton, V Reggie

    2010-03-10

    The degree of automaticity of locomotion in primates compared with other mammals remains unclear. Here, we examine the possibility for activation of the spinal locomotor circuitry in noninjured humans by spinal electromagnetic stimulation (SEMS). SEMS (3 Hz and 1.3-1.82 tesla) at the T11-T12 vertebrae induced involuntary bilateral locomotor-like movements in the legs of individuals placed in a gravity-neutral position. The formation of locomotor-like activity during SEMS started with a latency of 0.68 +/- 0.1 s after delivering the first stimulus, unlike continuous vibration of muscles, which requires several seconds. The first EMG burst in response to SEMS was observed most often in a proximal flexor muscle. We speculate that SEMS directly activates the circuitry intrinsic to the spinal cord, as suggested by the immediate response and the electrophysiological observations demonstrating an absence of strictly time-linked responses within the EMG burst associated with individual stimuli during SEMS. SEMS in the presence of vibration of the leg muscles was more effective in facilitating locomotor-like activity than SEMS alone. The present results suggest that SEMS could be an effective noninvasive clinical tool to determine the potential of an individual to recover locomotion after a spinal cord injury, as well as being an effective rehabilitation tool itself.

  11. Neurotrophic factor expression after CNS viral injury produces enhanced sensitivity to psychostimulants: potential mechanism for addiction vulnerability.

    PubMed

    Solbrig, M V; Koob, G F; Parsons, L H; Kadota, T; Horscroft, N; Briese, T; Lipkin, W I

    2000-11-01

    Hypothesized risk factors for psychostimulant, amphetamine, and cocaine abuse include dopamine (DA) receptor polymorphisms, HIV infection, schizophrenia, drug-induced paranoias, and movement disorders; however, the molecular, cellular, and biochemical mechanisms that predispose to drug sensitivity or drive the development of addiction are incompletely understood. Using the Borna disease rat, an animal model of viral-induced encephalopathy wherein sensitivity to the locomotor and stereotypic behavioral effects of d-amphetamine and cocaine is enhanced (Solbrig et al., 1994, 1998), we identify a specific neurotrophin expression pattern triggered by striatal viral injury that increases tyrosine hydroxylase activity, an early step in DA synthesis, to produce a phenotype of enhanced amphetamine sensitivity. The reactive neurotrophin pattern provides a molecular framework for understanding how CNS viral injury, as well as other CNS adaptations producing similar growth factor activation profiles, may influence psychostimulant sensitivity.

  12. Emerging contaminants: a potential human health concern for sensitive populations.

    PubMed

    Mangalgiri, Kiranmayi P; He, Ke; Blaney, Lee

    2015-01-01

    Pharmaceuticals and other xenobiotic molecules are being increasingly detected in drinking water, food crops, and breast milk. This issue represents a novel toxicological concern, especially for sensitive populations like pregnant women and breastfeeding infants. This commentary calls for more interdisciplinary research efforts focused on elucidating the transfer of contaminants of emerging concern from mother to child, as well as the relevant toxicological impacts on the child. The need for more tangible efforts to reduce pharmaceutical loads in environmental systems is also highlighted.

  13. Characterization of a potential radiation-sensitive fragile site

    SciTech Connect

    Jordan, R.; Oroskar, A.A.; Sedita, B.A.

    1995-11-01

    We have been characterizing a Chinese hamster ovary cell line, CHO-K1 10T5, into which a gpt-containing retroviral shuttle vector has been stably integrated. This normally stable locus in CHO-K1 10T5 cells is very sensitive to deletion mutation following ionizing radiation exposure and shows an LET response with an RBE of 3 for {alpha} particles. Almost all of the gpt mutants are total gene deletions. The gpt gene has been localized to chromosome 5q15, within 100-1000 kb of a large region of interstitial telomere repeats. In addition, sequences showing homology to telomere repeat sequences have been identified at the integration site both 5` and 3` to the gpt gene locus. The integration site has been cloned and is presently being sequenced. Preliminary data suggest that there is a hotspot for breakage and/or recombination 5` of the integration site. We hypothesize that (1) the gpt vector has integrated into a region containing telomere repeat sequences, (2) this region of the genome is a radiation-sensitive fragile site, and (3) the radiation sensitivity of this site is due to the telomere sequences, which act by either serving as a site for further telomerase action and chromosome terminilization, or by providing repeat structures to facilitate radiation-induced recombination.

  14. Capturing the Potential of Dye-Sensitized Solar Cells

    NASA Astrophysics Data System (ADS)

    Benson, James

    2010-10-01

    Dye-sensitized solar cells are a continually developing type of low-cost solar cells that have commercial efficiency around 6-10%. The proposed research here will be focusing on the photo-bleaching and improving techniques for electron transport. Nature has given us a goal to reach towards with proven techniques for converting light into energy with around 30-40% efficiency, however, chlorophyll, the light absorber in plants, is expensive and it is not practical to make solar cells with only chlorophyll as the absorber. One such alternative to chlorophyll is phthalocyanines which is a common industrial dye used in many applications. This dye has a common similar ring without the long phytol chain that chlorophyll has. Previous research has shown that encapsulating organic dyes can magnify the properties of dye from the increased concentration with a possible benefit of stabilizing the dye allowing it to slow down the photo bleaching significantly. Likewise, such encapsulation may help with thermal stability since many dye-sensitized solar cells require a liquid or gel solution that is sensitive to thermal expansion. Many researchers are also finding new ways to encapsulate the dyes or dope the p-n layers with nano and meso tubes to help with electron transport or build the p-n layers right in the tubes. This allows for countless layers and an overall more efficient design.

  15. Integrated Computational Solution for Predicting Skin Sensitization Potential of Molecules

    PubMed Central

    Desai, Aarti; Singh, Vivek K.; Jere, Abhay

    2016-01-01

    Introduction Skin sensitization forms a major toxicological endpoint for dermatology and cosmetic products. Recent ban on animal testing for cosmetics demands for alternative methods. We developed an integrated computational solution (SkinSense) that offers a robust solution and addresses the limitations of existing computational tools i.e. high false positive rate and/or limited coverage. Results The key components of our solution include: QSAR models selected from a combinatorial set, similarity information and literature-derived sub-structure patterns of known skin protein reactive groups. Its prediction performance on a challenge set of molecules showed accuracy = 75.32%, CCR = 74.36%, sensitivity = 70.00% and specificity = 78.72%, which is better than several existing tools including VEGA (accuracy = 45.00% and CCR = 54.17% with ‘High’ reliability scoring), DEREK (accuracy = 72.73% and CCR = 71.44%) and TOPKAT (accuracy = 60.00% and CCR = 61.67%). Although, TIMES-SS showed higher predictive power (accuracy = 90.00% and CCR = 92.86%), the coverage was very low (only 10 out of 77 molecules were predicted reliably). Conclusions Owing to improved prediction performance and coverage, our solution can serve as a useful expert system towards Integrated Approaches to Testing and Assessment for skin sensitization. It would be invaluable to cosmetic/ dermatology industry for pre-screening their molecules, and reducing time, cost and animal testing. PMID:27271321

  16. Locomotor Expertise Predicts Infants' Perseverative Errors

    ERIC Educational Resources Information Center

    Berger, Sarah E.

    2010-01-01

    This research examined the development of inhibition in a locomotor context. In a within-subjects design, infants received high- and low-demand locomotor A-not-B tasks. In Experiment 1, walking 13-month-old infants followed an indirect path to a goal. In a control condition, infants took a direct route. In Experiment 2, crawling and walking…

  17. The effects of distal limb segment shortening on locomotor efficiency in sloped terrain: implications for Neandertal locomotor behavior.

    PubMed

    Higgins, Ryan W; Ruff, Christopher B

    2011-11-01

    Past studies of human locomotor efficiency focused on movement over flat surfaces and concluded that Neandertals were less efficient than modern humans due to a truncated limb morphology, which may have developed to aid thermoregulation in cold climates. However, it is not clear whether this potential locomotor disadvantage would also exist in nonflat terrain. This issue takes on added importance since Neandertals likely spent a significant proportion of their locomotor schedule on sloped, mountainous terrains in the Eurasian landscape. Here a model is developed that determines the relationship between lower limb segment lengths, terrain slope, excursion angle at the hip, and step length. The model is applied to Neandertal and modern human lower limb reconstructions. In addition, for a further independent test that also allows more climateterrain cross comparisons, the same model is applied to bovids living in different terrains and climates. Results indicate that: (1) Neandertals, despite exhibiting shorter lower limbs, would have been able to use similar stride frequencies per speed as longer-limbed modern humans on sloped terrain, due to their lower crural indices; and (2) shortened distal limb segments are characteristic of bovids that inhabit more rugged terrains, regardless of climate. These results suggest that the shortened distal lower limb segments of Neandertals were not a locomotor disadvantage within more rugged environments.

  18. The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects.

    PubMed

    Dafny, Nachum; Yang, Pamela B

    2006-02-15

    Children with attention deficit hyperactivity disorder (ADHD) are treated for extended periods of time with the psychostimulant methylphenidate (MPD). The psychostimulants cocaine, amphetamine, and MPD exhibit similar structural configuration and pharmacological profile. The consequence of the long-term use of psychostimulants such as MPD as treatment for ADHD in the developing brain of children is unknown. Repeated treatment with psychostimulants has been shown to elicit adverse effects in behavior, such as dependence, paranoia, schizophrenia, and behavioral sensitization. Behavioral sensitization and cross-sensitization between two drugs are used as experimental markers to determine the potential of a drug to develop dependence/addiction. Although there are many reviews written about behavioral sensitization involving psychostimulants, scarcely any have focused specifically on MPD-elicited behavioral sensitization and cross-sensitization with other psychostimulants. Moreover, the response to MPD and the expression of ADHD vary among females and males and among different populations due to genetic variability. Since the interpretation and synthesis of the data reported are controversial, this review focuses on the adverse effects of MPD and the role of age, sex, and genetic composition on the acute and chronic effects of MPD, such as MPD-elicited behavioral sensitization and cross-sensitization with amphetamine in animal models. Animal models of drug-induced locomotor stimulation, particularly locomotor sensitization, can be used to understand the mechanisms underlying human drug-induced dependence.

  19. Dermal Sensitization Potential of Niclosamide in Guinea Pigs

    DTIC Science & Technology

    1988-09-01

    compound were observed in any of the animals that remained in the study. Pathologic changes consistent with subclinical salmonellosis were observed in...potential. The presence of subclinical salmonellosis in the study animals did not appear to compromise the study results. Ten study animals assigned...the negative control group showed evidence of salmonellosis . None of these animals responded to the challenge dose of the test compound, which indicates

  20. Skin sensitizers induce antioxidant response element dependent genes: application to the in vitro testing of the sensitization potential of chemicals.

    PubMed

    Natsch, Andreas; Emter, Roger

    2008-03-01

    Tests for skin sensitization are required prior to the market launch of new cosmetic ingredients and in vitro tests are needed to replace the current animal tests. Protein reactivity is the common feature of skin sensitizers and it is a crucial question whether a cellular in vitro assay can detect protein reactivity of diverse test chemicals. The signaling pathway involving the repressor protein Keap1 and the transcription factor nuclear factor-erythroid 2-related factor 2, which binds to the antioxidant response element (ARE) in the promoter of many phase II detoxification genes, is a potential cellular marker because Keap1 had been shown to be covalently modified by electrophiles which leads to activation of ARE-dependent genes. To evaluate whether this regulatory pathway can be used to develop a predictive cellular in vitro test for sensitization, 96 different chemicals of known skin sensitization potential were added to Hepa1C1C7 cells and the induction of the ARE-regulated quinone reductase (QR) activity was determined. In parallel, 102 chemicals were tested on the reporter cell line AREc32, which contains an eightfold repeat of the ARE sequence upstream of a luciferase gene. Among the strong/extreme skin sensitizers 14 out of 15 and 30 out of 34 moderate sensitizers induced the ARE-dependent luciferase activity and in many cases this response was paralleled by an induction of QR activity in Hepa1C1C7 cells. Sixty percent of the weak sensitizers also induced luciferase activity, and the overall accuracy of the assay was 83 percent. Only four of 30 tested nonsensitizers induced low levels of luciferase activity, indicating a high specificity of the assay. Thus, measurement of the induction of this signaling pathway provides an interesting in vitro test to screen for the skin sensitization potential of novel chemicals.

  1. Intestinal microflora as potential modifiers of sensitizer activity in vivo

    SciTech Connect

    Sheldon, P.W.; Clarke, C.; Dawson, K.B.; Simpson, W.; Simmons, D.J.C.

    1984-08-01

    Treatment of mice (some bearing Lewis lung tumors), with penicillin (PEN) at 500 mg/l drinking water for one week prior to treatment with misonidazole (MIS), resulted in: the elimination of their anaerobic cecal flora; a decrease in MIS-induced neurotoxicity; an increase in pharmacological exposure to MIS; a decrease in MIS chemopotentiation; a probable increase in MIS radiosensitization; an increase in MIS induced hypothermia. Assuming no chemical interaction between PEN and MIS, these observations indicate that the intestinal microflora can influence the activity of MIS in vivo. The observed reduction in the neurotoxic but not the radiosensitizing potential of MIS following PEN treatment indicates a therapeutic benefit.

  2. Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals

    PubMed Central

    Bonsall, David R.; Kim, Hyunji; Tocci, Catherine; Ndiaye, Awa; Petronzio, Abbey; McKay-Corkum, Grace; Molyneux, Penny C.; Scammell, Thomas E.; Harrington, Mary E.

    2015-01-01

    Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson’s Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β). We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively), all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel treatments for

  3. [Semax potentiates effects of D-amphetamine on the level of extracellular dopamine in the Sprague-Dawley rat striatum and on the locomotor activity of C57BL/6 mice].

    PubMed

    Eremin, K O; Saransaari, P; Oja, S; Raevskiĭ, K S

    2004-01-01

    The synthetic peptide semax (a fragment of ACTH 4-7 Pro-Gly-Pro) enhances the release of extracell dopamine (DA) induced by D-amphetamine (5 mg/kg) in the striatum of Spraig-Dowley (SD) rats and increases the locomotor activity stimulated by D-amphetamine (2 mg/kg) in C57/BL6 mice. The basal content of DA, 3,4-dihydroxyphenylacetic acid (DHPAA), and homovanillic acid (HVA) in dialysate of SD rats was 0.5-1.0, 996 +/- 25, and 761 +/- 37 pmole/ml, respectively (n = 7). D-amphetamine (5 mg/kg) induced a sharp increases in the DA level (up to 20 pmole/ml) 20-40 min after treatment and reduced the extracell DHPAA content to 30% of the basal level for a prolonged time (over the entire experimental period). Preliminary (20 min before D-amphetamine) administration of semax resulted in a greater peak of DA concentration (p < 0.05) and a more pronounced drop in DHPAA level (p < 0.01) as compared to the effects produced by the psychostimulant alone. In behavioral tests on C57/BL6 mice, D-amphetamine (2 mg/kg) increased the locomotor activity to a level of 182% (p < 0.01). Simultaneous introduction of semax (0.6 mg/kg) and D-amphetamine (2 mg/kg) led to a more pronounced increase in the locomotor activity of mice (261%, p < 0.01). It is suggested that the peptide modulates dopaminergic systems involved in the formation of the psychostimulant effect.

  4. Dynamics and plasticity of spinal locomotor circuits.

    PubMed

    El Manira, Abdeljabbar

    2014-12-01

    Spinal circuits generate coordinated locomotor movements. These hardwired circuits are supplemented with neuromodulation that provide the necessary flexibility for animals to move smoothly through their environment. This review will highlight some recent insights gained in understanding the functional dynamics and plasticity of the locomotor circuits. First the mechanisms governing the modulation of the speed of locomotion will be discussed. Second, advantages of the modular organization of the locomotor networks with multiple circuits engaged in a task-dependent manner will be examined. Finally, the neuromodulation and the resulting plasticity of the locomotor circuits will be summarized with an emphasis on endocannabinoids and nitric oxide. The intention is to extract general principles of organization and discuss some onto-genetic and phylogenetic divergences.

  5. Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell

    PubMed Central

    Xu, Cheng-Zhi; Shi, Run-Jie; Chen, Dong; Sun, Yi-Yuan; Wu, Qing-Wei; Wang, Tao; Wang, Pei-Hua

    2013-01-01

    Paclitaxel has been proved to be active in treatment and larynx preservation of HNSCC, however, the fact that about 20-40% patients do not respond to paclitaxel makes it urgent to figure out the biomarkers for paclitaxel-based treatment in Hypopharynx cancer (HPC) patients to improve the therapy effect. In this work, Fadu cells, treated or untreated with low dose of paclitaxel for 24 h, were applied to DNA microarray chips. The differential expression in mRNAs and miRs was analyzed and the network between expression-altered mRNAs and miRs was constructed. Differentially expressed genes were mainly enriched in superpathway of cholesterol biosynthesis (ACAT2, MSMO1, LSS, FDFT1 and FDPS etc.), complement system (C3, C1R, C1S, CFR and CFB etc.), interferon signaling (IFIT1, IFIT3, IFITM1 and MX1 etc.), mTOR signaling (MRAS, PRKAA2, PLD1, RND3 and EIF4A1 etc.) and IGF1 signaling (MRAS, IGFBP7, JUN and FOS etc.), most of these pathways are implicated in tumorigenesis or chemotherapy resistance. The first three pathways were predicted to be suppressed, while the last two pathways were predicted to be induced by paclitaxel, suggesting the combination therapy with mTOR inhibition and paclitaxel might be better than single one. The dramatically expression-altered miRs were miR-112, miR-7, miR-1304, miR-222*, miR-29b-1* (these five miRs were upregulated) and miR-210 (downregulated). The 26 putative target genes mediated by the 6 miRs were figured out and the miR-gene network was constructed. Furthermore, immunoblotting assay showed that ERK signaling in Fadu cells was active by low dose of paclitaxel but repressed by high dose of paclitaxel. Collectively, our data would provide potential biomarkers and therapeutic targets for paclitaxel-based therapy in HPC patients. PMID:24294361

  6. Multi-terrain locomotor interactions in flying snakes

    NASA Astrophysics Data System (ADS)

    Yeaton, Isaac; Baumgardner, Grant; Ross, Shane; Socha, John

    Arboreal snakes of the genus Chrysopelea are the only known snakes to glide. To execute aerial locomotion, a snake uses one of several stereotyped jumps from a tree into the air, while simultaneously flattening its body into an aerodynamically favorable shape. Large amplitude traveling waves are propagated posteriorly during the stable glide, while landing involves body wrapping, passive body compression, and energy absorption through compliance in the landing substrate to dissipate the accumulated kinetic energy from the glide. In all of these locomotor events, from interacting with cylindrical branches, falling through the air, grasping compliant tree branches and leaves, to landing on solid ground, snakes appropriate the same body morphology and perhaps the same basic neural mechanisms. Here we discuss our use of computational models and animal experiments to understand how flying snakes interact with and locomote on and through multiple media, potentially providing principles for legless locomotor designs. Supported by NSF 1351322.

  7. Dengue Infection Increases the Locomotor Activity of Aedes aegypti Females

    PubMed Central

    Luz, Paula M.; Castro, Márcia G.; Lourenço-de-Oliveira, Ricardo; Sorgine, Marcos H. F.; Peixoto, Alexandre A.

    2011-01-01

    Background Aedes aegypti is the main vector of the virus causing Dengue fever, a disease that has increased dramatically in importance in recent decades, affecting many tropical and sub-tropical areas of the globe. It is known that viruses and other parasites can potentially alter vector behavior. We investigated whether infection with Dengue virus modifies the behavior of Aedes aegypti females with respect to their activity level. Methods/Principal Findings We carried out intrathoracic Dengue 2 virus (DENV-2) infections in Aedes aegypti females and recorded their locomotor activity behavior. We observed an increase of up to ∼50% in the activity of infected mosquitoes compared to the uninfected controls. Conclusions Dengue infection alters mosquito locomotor activity behavior. We speculate that the higher levels of activity observed in infected Aedes aegypti females might involve the circadian clock. Further studies are needed to assess whether this behavioral change could have implications for the dynamics of Dengue virus transmission. PMID:21408119

  8. Repeatability of locomotor performance and morphology-locomotor performance relationships.

    PubMed

    Conradsen, Cara; Walker, Jeffrey A; Perna, Catherine; McGuigan, Katrina

    2016-09-15

    There is good evidence that natural selection drives the evolution of locomotor performance, but the processes that generate the among-individual variation for selection to act on are relatively poorly understood. We measured prolonged swimming performance, Ucrit, and morphology in a large cohort (n=461) of wild-type zebrafish (Danio rerio) at ∼6 months and again at ∼9 months. Using mixed-model analyses to estimate repeatability as the intraclass correlation coefficient, we determined that Ucrit was significantly repeatable (r=0.55; 95% CI: 0.45-0.64). Performance differences between the sexes (males 12% faster than females) and changes with age (decreasing 0.07% per day) both contributed to variation in Ucrit and, therefore, the repeatability estimate. Accounting for mean differences between sexes within the model decreased the estimate of Ucrit repeatability to 21% below the naïve estimate, while fitting age in the models increased the estimate to 14% above the naïve estimate. Greater consideration of factors such as age and sex is therefore necessary for the interpretation of performance repeatability in wild populations. Body shape significantly predicted Ucrit in both sexes in both assays, with the morphology-performance relationship significantly repeatable at the population level. However, morphology was more strongly predicative of performance in older fish, suggesting a change in the contribution of morphology relative to other factors such as physiology and behaviour. The morphology-performance relationship changed with age to a greater extent in males than females.

  9. Sex-related effects of agmatine on caffeine-induced locomotor activity in Swiss Webster mice.

    PubMed

    Uzbay, Tayfun; Kose, Akin; Kayir, Hakan; Ulusoy, Gokhan; Celik, Turgay

    2010-03-25

    In mammalian brain, agmatine is an endogenous amine that is synthesized through the decarboxylation of l-arginine by arginine decarboxylase. It has been proposed as a new neurotransmitter and/or neuromodulator. It was shown that agmatine had some beneficial effects in animal models of opioid and alcohol addiction. Locomotor stimulant properties of drugs such as ethanol, caffeine, nicotine and amphetamine have been linked to their addictive properties. The present study investigates the effects of agmatine on caffeine-induced locomotor activity both in male and female mice. Adult Swiss Webster mice were used in the study. Locomotor activity was measured for 30min immediately following caffeine (2.5, 5, 10 and 20mg/kg, i.p.) or saline treatments. Agmatine (5, 10 and 20mg/kg, i.p.) were injected 20min before caffeine (2.5 and 5mg/kg, i.p.) administration. In both sexes, agmatine (5-20mg/kg) were also tested for ability to depress or stimulate locomotor activity in the absence of caffeine. Caffeine (5mg/kg) induced a significant increase in locomotor activity of both male and female mice. There was no significant difference in the locomotor-activating effects of caffeine between male and female mice. Agmatine blocked the caffeine (5mg/kg)-induced locomotor stimulation dose dependently in male but not female mice. Agmatine had not any effect on the lower dose (2.5mg/kg) of caffeine in both sexes. These results suggest that agmatine has sex-related inhibitory effects on caffeine-induced locomotor activity in Swiss Webster mice, and male mice are more sensitive than the females to the effect of agmatine.

  10. Development of a Countermeasure to Enhance Postflight Locomotor Adaptability

    NASA Technical Reports Server (NTRS)

    Bloomberg, Jacob J.

    2006-01-01

    Astronauts returning from space flight experience locomotor dysfunction following their return to Earth. Our laboratory is currently developing a gait adaptability training program that is designed to facilitate recovery of locomotor function following a return to a gravitational environment. The training program exploits the ability of the sensorimotor system to generalize from exposure to multiple adaptive challenges during training so that the gait control system essentially learns to learn and therefore can reorganize more rapidly when faced with a novel adaptive challenge. We have previously confirmed that subjects participating in adaptive generalization training programs using a variety of visuomotor distortions can enhance their ability to adapt to a novel sensorimotor environment. Importantly, this increased adaptability was retained even one month after completion of the training period. Adaptive generalization has been observed in a variety of other tasks requiring sensorimotor transformations including manual control tasks and reaching (Bock et al., 2001, Seidler, 2003) and obstacle avoidance during walking (Lam and Dietz, 2004). Taken together, the evidence suggests that a training regimen exposing crewmembers to variation in locomotor conditions, with repeated transitions among states, may enhance their ability to learn how to reassemble appropriate locomotor patterns upon return from microgravity. We believe exposure to this type of training will extend crewmembers locomotor behavioral repertoires, facilitating the return of functional mobility after long duration space flight. Our proposed training protocol will compel subjects to develop new behavioral solutions under varying sensorimotor demands. Over time subjects will learn to create appropriate locomotor solution more rapidly enabling acquisition of mobility sooner after long-duration space flight. Our laboratory is currently developing adaptive generalization training procedures and the

  11. Identification of multisegmental nociceptive afferents that modulate locomotor circuits in the neonatal mouse spinal cord.

    PubMed

    Mandadi, Sravan; Hong, Peter; Tran, Michelle A; Bráz, Joao M; Colarusso, Pina; Basbaum, Allan I; Whelan, Patrick J

    2013-08-15

    Compared to proprioceptive afferent collateral projections, less is known about the anatomical, neurochemical, and functional basis of nociceptive collateral projections modulating lumbar central pattern generators (CPG). Quick response times are critical to ensure rapid escape from aversive stimuli. Furthermore, sensitization of nociceptive afferent pathways can contribute to a pathological activation of motor circuits. We investigated the extent and role of collaterals of capsaicin-sensitive nociceptive sacrocaudal afferent (nSCA) nerves that directly ascend several spinal segments in Lissauer's tract and the dorsal column and regulate motor activity. Anterograde tracing demonstrated direct multisegmental projections of the sacral dorsal root 4 (S4) afferent collaterals in Lissauer's tract and in the dorsal column. Subsets of the traced S4 afferent collaterals expressed transient receptor potential vanilloid 1 (TRPV1), which transduces a nociceptive response to capsaicin. Electrophysiological data revealed that S4 dorsal root stimulation could evoke regular rhythmic bursting activity, and our data suggested that capsaicin-sensitive collaterals contribute to CPG activation across multiple segments. Capsaicin's effect on S4-evoked locomotor activity was potent until the lumbar 5 (L5) segments, and diminished in rostral segments. Using calcium imaging we found elevated calcium transients within Lissauer's tract and dorsal column at L5 segments when compared to the calcium transients only within the dorsal column at the lumbar 2 (L2) segments, which were desensitized by capsaicin. We conclude that lumbar locomotor networks in the neonatal mouse spinal cord are targets for modulation by direct multisegmental nSCA, subsets of which express TRPV1 in Lissauer's tract and the dorsal column. J. Comp. Neurol. 521:2870-2887, 2013. © 2013 Wiley Periodicals, Inc.

  12. Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens.

    PubMed

    Singer, Bryan F; Neugebauer, Nichole M; Forneris, Justin; Rodvelt, Kelli R; Li, Dongdong; Bubula, Nancy; Vezina, Paul

    2014-10-01

    Intermittent systemic exposure to psychostimulants leads to several forms of long-lasting behavioral plasticity including nonassociative sensitization and associative conditioning. In the nucleus accumbens (NAcc), the protein serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) and its phosphorylation target, the guanine-nucleotide exchange factor kalirin-7 (Kal7), may contribute to the neuroadaptations underlying the formation of conditioned associations. Pharmacological inhibition of Cdk5 in the NAcc prevents the increases in dendritic spine density normally observed in this site following repeated cocaine. Mice lacking the Kal7 gene display similar effects. As increases in spine density may relate to the formation of associative memories and both Cdk5 and Kal7 regulate the generation of spines following repeated drug exposure, we hypothesized that either inhibiting Cdk5 or preventing its phosphorylation of Kal7 in the NAcc may prevent the induction of drug conditioning. In the present experiments, blockade in rats of NAcc Cdk5 activity with roscovitine (40 nmol/0.5 μl/side) prior to each of 4 injections of amphetamine (1.5 mg/kg; i.p.) prevented the accrual of contextual locomotor conditioning but spared the induction of locomotor sensitization as revealed on tests conducted one week later. Similarly, transient viral expression in the NAcc exclusively during amphetamine exposure of a threonine-alanine mutant form of Kal7 [mKal7(T1590A)] that is not phosphorylated by Cdk5 also prevented the accrual of contextual conditioning and spared the induction of sensitization. These results indicate that signaling via Cdk5 and Kal7 in the NAcc is necessary for the formation of context-drug associations, potentially through the modulation of dendritic spine dynamics in this site.

  13. An assessment of the comparative sensitization potential of some common isothiazolinones.

    PubMed

    Alexander, B R

    2002-04-01

    The isothiazolinones are known contact sensitizers. Data are presented which demonstrate that, in comparison with the chlorinated and dichlorinated compounds which share immunological cross-reactivity, the unchlorinated isothiazolinones have a lower potential for sensitization and no documented immunological cross-reaction with the chlorinated isothiazolinones.

  14. Sigma ligand S14905 and locomotor activity in mice.

    PubMed

    Hascoet, M; Bourin, M; Payeur, R; Lombet, A; Peglion, J L

    1995-12-01

    The binding and locomotor profile of a new sigma ligand, S14905, (isobutyl-N-(1-indan-2yl-piperid-4-yl)N-methyl carbamate, furamate) was studied. The binding data revealed that S14905 has a high affinity for sigma receptors and very low affinity for both dopamine D1 and D2 receptors. We have demonstrated that this sigma ligand prevents the locomotor stimulation induced by morphine (32 and 64 mg/kg), cocaine (16 mg/kg), amphetamine (4 mg/kg) and adrafinil (32 mg/kg) at doses lower than those required to depress spontaneous locomotor activity. The antagonism observed in the present study seems to be more specific of morphine induced hyperlocomotion. The high affinity of this compound for sigma receptors makes it a good choice to study the role of this receptor in the CNS. In addition, S14905 does not directly block dopamine receptors but may modulate them in some manner, and would thus warrant further study as a potential atypical antipsychotic agent, and an antagonist for the hyperactivity induced by opiate drug.

  15. Locomotor experience and use of social information are posture specific.

    PubMed

    Adolph, Karen E; Tamis-LeMonda, Catherine S; Ishak, Shaziela; Karasik, Lana B; Lobo, Sharon A

    2008-11-01

    The authors examined the effects of locomotor experience on infants' perceptual judgments in a potentially risky situation--descending steep and shallow slopes--while manipulating social incentives to determine where perceptual judgments are most malleable. Twelve-month-old experienced crawlers and novice walkers were tested on an adjustable sloping walkway as their mothers encouraged and discouraged descent. A psychophysical procedure was used to estimate infants' ability to crawl/walk down slopes, followed by test trials in which mothers encouraged and discouraged infants to crawl/walk down. Both locomotor experience and social incentives affected perceptual judgments. In the encourage condition, crawlers only attempted safe slopes within their abilities, but walkers repeatedly attempted impossibly risky slopes, replicating previous work. The discourage condition showed where judgments are most malleable. When mothers provided negative social incentives, crawlers occasionally avoided safe slopes, and walkers occasionally avoided the most extreme 50 degrees increment, although they attempted to walk on more than half the trials. Findings indicate that both locomotor experience and social incentives play key roles in adaptive responding, but the benefits are specific to the posture that infants use for balance and locomotion.

  16. Locomotor Experience and Use of Social Information Are Posture Specific

    PubMed Central

    Adolph, Karen E.; Tamis-LeMonda, Catherine S.; Ishak, Shaziela; Karasik, Lana B.; Lobo, Sharon A.

    2015-01-01

    The authors examined the effects of locomotor experience on infants’ perceptual judgments in a potentially risky situation—descending steep and shallow slopes—while manipulating social incentives to determine where perceptual judgments are most malleable. Twelve-month-old experienced crawlers and novice walkers were tested on an adjustable sloping walkway as their mothers encouraged and discouraged descent. A psychophysical procedure was used to estimate infants’ ability to crawl/walk down slopes, followed by test trials in which mothers encouraged and discouraged infants to crawl/walk down. Both locomotor experience and social incentives affected perceptual judgments. In the encourage condition, crawlers only attempted safe slopes within their abilities, but walkers repeatedly attempted impossibly risky slopes, replicating previous work. The discourage condition showed where judgments are most malleable. When mothers provided negative social incentives, crawlers occasionally avoided safe slopes, and walkers occasionally avoided the most extreme 50° increment, although they attempted to walk on more than half the trials. Findings indicate that both locomotor experience and social incentives play key roles in adaptive responding, but the benefits are specific to the posture that infants use for balance and locomotion. PMID:18999332

  17. Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats

    PubMed Central

    Leong, Kah-Chung; Zhou, Luyi; Ghee, Shannon M.; See, Ronald E.; Reichel, Carmela M.

    2015-01-01

    Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin’s impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin’s attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin’s effect on cocaine seeking may be mediated by different mechanisms in male and females. PMID:26523890

  18. Induction of locomotor activity by the glutamate antagonist DNQX injected into the ventral tegmental area.

    PubMed

    Dalia, A; Uretsky, N J; Wallace, L J

    1996-07-29

    DNQX, an antagonist of AMPA/kainate receptors, was injected into the ventral tegmental area (VTA) to test the hypothesis that AMPA/kainate receptors in this brain region might be involved in regulation of locomotor activity. Bilateral injection of 1 microgram DNQX into the VTA increased locomotor activity. In addition, unilateral injection of DNQX into this site produced contraversive turning, which was potentiated by coadministration of amphetamine (1 mg/kg, i.p.). These results suggest that a glutamatergic afferent to the VTA is tonically active in inhibiting locomotor activity. The locomotor stimulation produced by DNQX was not associated with a change in DOPAC/DA level in the nucleus accumbens or the striatum. However, the locomotor stimulation produced by DNQX was markedly attenuated following blockade of dopaminergic receptors by haloperidol (0.5 mg/kg, s.c.) or following dopamine depletion induced by reserpine plus alpha-methyl-para-tyrosine pretreatment. These results suggest that a basal activation of dopaminergic receptors is required for expression of the locomotor activity elicited by DNQX.

  19. Are somatosensory evoked potentials of the tibial nerve the most sensitive test in diagnosing multiple sclerosis?

    PubMed

    Djuric, S; Djuric, V; Zivkovic, M; Milosevic, V; Jolic, M; Stamenovic, J; Djordjevic, G; Calixto, M

    2010-01-01

    Multiple sclerosis (MS) is mostly diagnosed clinically, but the diagnosis has significantly improved through the use of brain magnetic resonance imaging (MRI), testing of cerebrospinal fluid, and multimodal evoked potentials (MEPs). Even though MRI is the superior method in diagnosing this illness, MEPs remain important because they can detect clinically silent lesions in the sensory and motor pathways of the central nervous system (CNS). The aim of the study is to test the diagnostic sensitivity of MEPs and MRI and the ratio of their sensitivity in patients with MS. The study subjects included 293 patients with MS with disease duration of two to six years: 249 patients with relapsing-remitting (RR) MS and 44 with primary-progressive (PP) MS. All patients were subjected to an MRI brain scan, visual evoked potentials (VEPs), median somatosensory evoked potentials (SEPs), tibial somatosensory evoked potentials (SEPs), and auditory evoked potentials (AEPs). Abnormal Findings Included : changed wave morphology, interside difference in wave amplitude, absolute and interwave latency increased by 2.5 SD as compared with the control group. The control group comprised of 35 healthy subjects. Results : In this study the most abnormal findings were tibial SEPs, median SEPs, and VEPs. Our results suggest different sensitivity of MEPs in patients suffering from different forms of MS. In RR-MS the sensitivity of tibial SEPs was statically significant (Fischer's exact probability test) as compared to other evoked potential modalities. Similarly VEPs were more sensitive as compared to AEPs. In the PP-MS, median SEPs have been found to be more sensitive than VEPs, while tibial SEPs have been found to be more sensitive than AEPs. There was no significant difference in the sensitivity of MRI and MEPs both the forms of MS. Tibial SEPs produce the most abnormal results and the highest sensitivity in the RR-MS. We propose that this test as useful criterion for the diagnosis of MS.

  20. Individual differences in rats' reactivity to novelty and the unconditioned and conditioned locomotor effects of methamphetamine.

    PubMed

    Bevins, Rick A; Peterson, Jessica L

    2004-09-01

    Rat's reactivity to inescapable novelty can predict the subsequent psychomotor effects of many stimulants. This relation has not been examined for methamphetamine. Experiment 1 assessed the locomotor effects of methamphetamine (0.0625-1.0 mg/kg). On average, acute administration of methamphetamine (0.25, 0.5, and 1 mg/kg) had a stimulant effect on activity; locomotor sensitization was seen after repeated administration of 0.5 and 1 mg/kg. In a subsequent drug-free test, rats that had the locomotor chamber paired with 0.25, 0.5, or 1 mg/kg methamphetamine on eight separate occasions were more active than controls--conditioned hyperactivity. Experiment 2 used the 0.5-mg/kg dose to examine whether forced novelty exposure (novelty-induced activity) or free-choice novelty (approach to novel environment or object interaction) was predictive of methamphetamine's psychomotor effects. Only reactivity to inescapable novelty was systematically correlated with methamphetamine-induced activity. Rats more reactive to novelty [high responders (HR)] were more active to the acute and chronic methamphetamine challenge. Furthermore, these HR showed more conditioned hyperactivity than low responders (LR). Although acute methamphetamine did not have a stimulant effect in LR, only the LR displayed locomotor sensitization after chronic methamphetamine. This research extends the predictive variable of reactivity to inescapable novelty to methamphetamine's conditioned and unconditioned locomotor effects.

  1. Locomotor activity and zonation of upper shore arthropods in a sandy beach of north central Chile

    NASA Astrophysics Data System (ADS)

    Jaramillo, E.; Contreras, H.; Duarte, C.; Avellanal, M. H.

    2003-10-01

    The tenebrionid beetle Phalerisida maculata Kulzer, the talitrid amphipod Orchestoidea tuberculata Nicolet and the oniscid isopod Tylos spinulosus Dana are semi-terrestrial burrowing species, which coexist on sandy beaches of north central Chile (28-30°S). During the night, these scavengers emerge to make downshore migrations. Given the similarity in niches of these three species (all are known to include macroalgal detritus in their diet) and their relatively high abundance on that beaches, there is the potential for some degree of interaction, both inter- and intraspecific. Field studies were carried out to examine zonation of these burrowing organisms and eventual time and/or space partitioning of locomotor activity during night hours. Locomotor activity on the beach surface was analyzed over 12 h periods during spring and neap tides of September and December 2000, and March 2001. Scavengers moving over the beach surface were captured using pitfall traps buried with their rims flush with the beach surface along a transect extended from the foot of the dunes to the highest levels reached by the swashes. Every 1 h the captured animals in the traps were collected. Locomotor activity was also studied in the laboratory with chambers equipped with infrared recording systems (actographs). Data downloaded from the actographs were graphed to obtain a display of locomotor activity per 15 min interval during the course of the 7 day experiments. Results show space partitioning of burrowed organisms and time partitioning in the locomotor activity of O. tuberculata, T. spinulosus and P. maculata over the beach surface. Circular statistics showed that usually the activity peaks of O. tuberculata were more different from those of P. maculata and T. spinulosus than those of the last two species when compared with each other. Intraspecific differences were also found in the surface locomotor activity, primarily between juveniles and adults of O. tuberculata. Interseasonal

  2. Locomotor expertise predicts infants' perseverative errors.

    PubMed

    Berger, Sarah E

    2010-03-01

    This research examined the development of inhibition in a locomotor context. In a within-subjects design, infants received high- and low-demand locomotor A-not-B tasks. In Experiment 1, walking 13-month-old infants followed an indirect path to a goal. In a control condition, infants took a direct route. In Experiment 2, crawling and walking 13-month-old infants crawled through a tunnel to reach a goal at the other end and received the same control condition as in Experiment 1. In both experiments, perseverative errors occurred more often in the high-demand condition than in the low-demand condition. Moreover, in Experiment 2, walkers perseverated more than crawlers, and extent of perseveration was related to infants' locomotor experience. In Experiment 3, the authors addressed a possible confound in Experiment 2 between locomotor expertise and locomotor posture. Novice crawlers perseverated in the difficult tunnels condition, behaving more like novice walkers than expert crawlers. As predicted by a cognitive capacity account of infant perseveration, overtaxed attentional resources resulted in a cognition-action trade-off. Experts who found the task less motorically effortful than novices had more cognitive resources available for problem solving.

  3. Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons

    PubMed Central

    Ren, Hongxia; Plum-Morschel, Leona; Gutierrez-Juarez, Roger; Lu, Taylor Y.; Kim-Muller, Ja Young; Heinrich, Garrett; Wardlaw, Sharon L.; Silver, Rae; Accili, Domenico

    2013-01-01

    Successful development of antiobesity agents requires detailed knowledge of neural pathways controlling body weight, eating behavior, and peripheral metabolism. Genetic ablation of FoxO1 in selected hypothalamic neurons decreases food intake, increases energy expenditure, and improves glucose homeostasis, highlighting the role of this gene in insulin and leptin signaling. However, little is known about potential effects of FoxO1 in other neurons. To address this question, we executed a broad-based neuronal ablation of FoxO1 using Synapsin promoter–driven Cre to delete floxed Foxo1 alleles. Lineage-tracing experiments showed that NPY/AgRP and POMC neurons were minimally affected by the knockout. Nonetheless, Syn-Cre-Foxo1 knockouts demonstrated a catabolic energy homeostatic phenotype with a blunted refeeding response, increased sensitivity to leptin and amino acid signaling, and increased locomotor activity, likely attributable to increased melanocortinergic tone. We confirmed these data in mice lacking the three Foxo genes. The effects on locomotor activity could be reversed by direct delivery of constitutively active FoxO1 to the mediobasal hypothalamus, but not to the suprachiasmatic nucleus. The data reveal that the integrative function of FoxO1 extends beyond the arcuate nucleus, suggesting that central nervous system inhibition of FoxO1 function can be leveraged to promote hormone sensitivity and prevent a positive energy balance. PMID:23835335

  4. Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons.

    PubMed

    Ren, Hongxia; Plum-Morschel, Leona; Gutierrez-Juarez, Roger; Lu, Taylor Y; Kim-Muller, Ja Young; Heinrich, Garrett; Wardlaw, Sharon L; Silver, Rae; Accili, Domenico

    2013-10-01

    Successful development of antiobesity agents requires detailed knowledge of neural pathways controlling body weight, eating behavior, and peripheral metabolism. Genetic ablation of FoxO1 in selected hypothalamic neurons decreases food intake, increases energy expenditure, and improves glucose homeostasis, highlighting the role of this gene in insulin and leptin signaling. However, little is known about potential effects of FoxO1 in other neurons. To address this question, we executed a broad-based neuronal ablation of FoxO1 using Synapsin promoter-driven Cre to delete floxed Foxo1 alleles. Lineage-tracing experiments showed that NPY/AgRP and POMC neurons were minimally affected by the knockout. Nonetheless, Syn-Cre-Foxo1 knockouts demonstrated a catabolic energy homeostatic phenotype with a blunted refeeding response, increased sensitivity to leptin and amino acid signaling, and increased locomotor activity, likely attributable to increased melanocortinergic tone. We confirmed these data in mice lacking the three Foxo genes. The effects on locomotor activity could be reversed by direct delivery of constitutively active FoxO1 to the mediobasal hypothalamus, but not to the suprachiasmatic nucleus. The data reveal that the integrative function of FoxO1 extends beyond the arcuate nucleus, suggesting that central nervous system inhibition of FoxO1 function can be leveraged to promote hormone sensitivity and prevent a positive energy balance.

  5. Classification of sensitizing and irritative potential in a combined in-vitro assay

    SciTech Connect

    Wanner, Reinhard; Sonnenburg, Anna; Quatchadze, Maria; Schreiner, Maximilian; Peiser, Matthias; Zuberbier, Torsten; Stahlmann, Ralf

    2010-06-01

    We have developed a coculture system which in parallel indicates the sensitizing and irritative potential of xenobiotics. The assay is named loose-fit coculture-based sensitization assay (LCSA) and may be performed within 5 days. The system is composed of human monocytes that differentiate to a kind of dendritic cells by 2-day culturing in the presence of allogenic keratinocytes. The culture medium is enriched by a cocktail of recombinant cytokines. On day 3, concentration series of probes are added. On day 5, cells are harvested and analyzed for expression range of CD86 as a marker of sensitizing potential and for uptake of the viability stain 7-AAD as a marker of irritative potential. Estimation of the concentration required to cause a half-maximal increase in CD86 expression allowed quantification of sensitizing potential, and estimation of the concentration required to reduce viability to 50% allowed quantification of irritative potential. Examination of substances with known potential resulted in categorization of test scores. To evaluate our data, we have compared results with those of the validated animal-based sensitization test, the murine local lymph node assay (LLNA, OECD TG 429). To a large extent, results from LCSA and from LLNA achieved analogous grouping of allergens into categories like weak-moderate-strong. However, the new assay showed an improved capacity to distinguish sensitizers from non-sensitizers and irritants. In conclusion, the LCSA contains potential to fulfil the requirements of the EU's programme for the safety of chemicals 'Registration, Evaluation, Authorisation and Restriction of chemical substances' (REACH, 2006) to replace animal models.

  6. Classification of sensitizing and irritative potential in a combined in-vitro assay.

    PubMed

    Wanner, Reinhard; Sonnenburg, Anna; Quatchadze, Maria; Schreiner, Maximilian; Peiser, Matthias; Zuberbier, Torsten; Stahlmann, Ralf

    2010-06-01

    We have developed a coculture system which in parallel indicates the sensitizing and irritative potential of xenobiotics. The assay is named loose-fit coculture-based sensitization assay (LCSA) and may be performed within 5 days. The system is composed of human monocytes that differentiate to a kind of dendritic cells by 2-day culturing in the presence of allogenic keratinocytes. The culture medium is enriched by a cocktail of recombinant cytokines. On day 3, concentration series of probes are added. On day 5, cells are harvested and analyzed for expression range of CD86 as a marker of sensitizing potential and for uptake of the viability stain 7-AAD as a marker of irritative potential. Estimation of the concentration required to cause a half-maximal increase in CD86 expression allowed quantification of sensitizing potential, and estimation of the concentration required to reduce viability to 50% allowed quantification of irritative potential. Examination of substances with known potential resulted in categorization of test scores. To evaluate our data, we have compared results with those of the validated animal-based sensitization test, the murine local lymph node assay (LLNA, OECD TG 429). To a large extent, results from LCSA and from LLNA achieved analogous grouping of allergens into categories like weak-moderate-strong. However, the new assay showed an improved capacity to distinguish sensitizers from non-sensitizers and irritants. In conclusion, the LCSA contains potential to fulfil the requirements of the EU's programme for the safety of chemicals "Registration, Evaluation, Authorization and Restriction of chemical substances" (REACH, 2006) to replace animal models.

  7. Mephedrone interactions with cocaine: prior exposure to the 'bath salt' constituent enhances cocaine-induced locomotor activation in rats.

    PubMed

    Gregg, Ryan A; Tallarida, Christopher S; Reitz, Allen B; Rawls, Scott M

    2013-12-01

    Concurrent use of mephedrone (4-methylmethcathinone; MEPH) and established drugs of abuse is now commonplace, but knowledge about interactions between these drugs is sparse. The present study was designed to test the hypothesis that prior MEPH exposure enhances the locomotor-stimulant effects of cocaine and methamphetamine (METH). For cocaine experiments, rats pretreated with saline, cocaine (15 mg/kg), or MEPH (15 mg/kg) for 5 days were injected with cocaine after 10 days of drug absence. For METH experiments, rats pretreated with saline, METH (2 mg/kg), or MEPH (15 mg/kg) were injected with METH after 10 days of drug absence. Cocaine challenge produced greater locomotor activity after pretreatment with cocaine or MEPH than after pretreatment with saline. METH challenge produced greater locomotor activity after METH pretreatment than after saline pretreatment; however, locomotor activity in rats pretreated with MEPH or saline and then challenged with METH was not significantly different. The locomotor response to MEPH (15 mg/kg) was not significantly affected by pretreatment with cocaine (15 mg/kg) or METH (0.5, 2 mg/kg). The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine efficacy. Interestingly, MEPH cross-sensitization was not bidirectional and did not extend to METH, suggesting that the phenomenon is sensitive to specific psychostimulants.

  8. HIGH ETHANOL DOSE DURING EARLY ADOLESCENCE INDUCES LOCOMOTOR ACTIVATION AND INCREASES SUBSEQUENT ETHANOL INTAKE DURING LATE ADOLESCENCE

    PubMed Central

    Acevedo, María Belén; Molina, Juan Carlos; Nizhnikov, Michael E.; Spear, Norman E.; Pautassi, Ricardo Marcos

    2011-01-01

    Adolescent initiation of ethanol consumption is associated with subsequent heightened probability of ethanol-use disorders. The present study examined the relationship between motivational sensitivity to ethanol initiation in adolescent rats and later ethanol intake. Experiment 1 determined that ethanol induces locomotor activation shortly after administration but not if tested at a later post-administration interval. In Experiment 2, adolescents were assessed for ethanol-induced locomotor activation on postnatal day 28. These animals were then evaluated for ethanol-mediated conditioned taste aversion and underwent a 16-day-long ethanol intake protocol. Ethanol-mediated aversive effects were unrelated to ethanol locomotor stimulation or subsequent ethanol consumption patterns. Ethanol intake during late adolescence was greatest in animals initiated to ethanol earliest at postnatal day 28. Females that were more sensitive to ethanol’s locomotor-activating effects showed a transient increase in ethanol self-administration. Blood ethanol concentrations during initiation were not related to ethanol-induced locomotor activation. Adolescent rats appeared sensitive to the locomotor-stimulatory effects of ethanol. Even brief ethanol exposure during adolescence may promote later ethanol intake. PMID:20373327

  9. Potential sensitivities in frequency modulation and heterodyne amplitude modulation Kelvin probe force microscopes

    PubMed Central

    2013-01-01

    In this paper, the potential sensitivity in Kelvin probe force microscopy (KPFM) was investigated in frequency modulation (FM) and heterodyne amplitude modulation (AM) modes. We showed theoretically that the minimum detectable contact potential difference (CPD) in FM-KPFM is higher than in heterodyne AM-KPFM. We experimentally confirmed that the signal-to-noise ratio in FM-KPFM is lower than that in heterodyne AM-KPFM, which is due to the higher minimum detectable CPD dependence in FM-KPFM. We also compared the corrugations in the local contact potential difference on the surface of Ge (001), which shows atomic resolution in heterodyne AM-KPFM. In contrast, atomic resolution cannot be obtained in FM-KPFM under the same experimental conditions. The higher potential resolution in heterodyne AM-KPFM was attributed to the lower crosstalk and higher potential sensitivity between topographic and potential measurements. PMID:24350866

  10. An exploratory study on the combined effects of external and internal morphology on load dissipation in primate capitates: its potential for an understanding of the positional and locomotor repertoire of early hominins.

    PubMed

    Macho, Gabriele A; Spears, Iain R; Leakey, Meave G; McColl, Daniel J; Jiang, Yong; Abel, Richard; Nakatsukasa, Masato; Kunimatsu, Yutaka

    2010-01-01

    This pilot study explored whether the redirection of stress through trabeculae within morphologically constrained capitates provides information about habitual/positional behaviours unavailable from the study of external morphology alone. To assess this possibility, an experimental finite element approach was taken, whereby no attempt was made to reconstruct the actual magnitudes and loading conditions experienced by the capitates in vivo. Rather, this work addressed fundamental biological questions relating to bone plasticity, i.e. internal versus external bone morphology. The capitates of 7 species with different and - in the case of fossils - inferred locomotor behaviours were selected. Virtual models of capitates were created, scaled to the same size and subjected to the same theoretical load. In the first set of analyses, models were assigned the material properties of bone throughout, whereas in the second set, models were assigned 11 different material properties representing the trabecular architecture derived from high-resolution CT. Species with arboreal behaviours consistently redirected loads towards the ulnar aspect of the capitate when trabeculae were introduced, while terrestrial species, and the bipedal Homo, redirected stress towards the radial side. From these preliminary analyses, it is tentatively concluded that Australopithecus anamensis habitually engaged in arboreal behaviours, whereas Australopithecus afarensis did not. Copyright © 2011 S. Karger AG, Basel.

  11. Altered locomotor and stereotyped responses to acute methamphetamine in adolescent, maternally separated rats.

    PubMed

    Pritchard, Laurel M; Hensleigh, Emily; Lynch, Sarah

    2012-09-01

    Neonatal maternal separation (MS) has been used to model the effects of early life stress in rodents. MS alters behavioral responses to a variety of abused drugs, but few studies have examined its effects on methamphetamine sensitivity. We sought to determine the effects of MS on locomotor and stereotyped responses to low-to-moderate doses of methamphetamine in male and female adolescent rats. Male and female rat pups were subjected to 3 h per day of MS on postnatal days (PN) 2-14 or a brief handling control procedure during the same period. During adolescence (approximately PN 40), all rats were tested for locomotor activity and stereotyped behavior in response to acute methamphetamine administration (0, 1.0, or 3.0 mg/kg, s.c.). MS rats of both sexes exhibited increased locomotor activity in a novel environment, relative to handled controls. MS increased the locomotor response to methamphetamine (METH), and this effect occurred at different doses for male (3.0 mg/kg) and female (1.0 mg/kg) rats. MS also increased stereotyped behavior in response to METH (1.0 mg/kg) in both sexes. MS enhances the locomotor response to METH in a dose- and sex-dependent manner. These results suggest that individuals with a history of early life stress may be particularly vulnerable to the psychostimulant effects of METH, even at relatively low doses.

  12. Targeting drug sensitivity predictors: New potential strategies to improve pharmacotherapy of human brain disorders.

    PubMed

    Kalueff, Allan V; Stewart, Adam Michael; Nguyen, Michael; Song, Cai; Gottesman, Irving I

    2015-12-03

    One of the main challenges in medicine is the lack of efficient drug therapies for common human disorders. For example, although depressed patients receive powerful antidepressants, many often remain resistant to psychopharmacotherapy. The growing recognition of complex interplay between the drug targets and the predictors of drug sensitivity requires an improved understanding of these two key aspects of drug action and their potentially shared molecular networks. Here, we apply the concept of endophenotypes and their interplay to drug action and sensitivity. Based on these analyses, we postulate that novel drugs may be developed by targeting specific molecular pathways that integrate drug targets with drug sensitivity predictors.

  13. Neuronal control of locomotor handedness in Drosophila

    PubMed Central

    Buchanan, Sean M.; Kain, Jamey S.; de Bivort, Benjamin L.

    2015-01-01

    Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality. PMID:25953337

  14. Locomotor Experience Affects Self and Emotion

    ERIC Educational Resources Information Center

    Uchiyama, Ichiro; Anderson, David I.; Campos, Joseph J.; Witherington, David; Frankel, Carl B.; Lejeune, Laure; Barbu-Roth, Marianne

    2008-01-01

    Two studies investigated the role of locomotor experience on visual proprioception in 8-month-old infants. "Visual proprioception" refers to the sense of self-motion induced in a static person by patterns of optic flow. A moving room apparatus permitted displacement of an entire enclosure (except for the floor) or the side walls and…

  15. Locomotor Experience Affects Self and Emotion

    ERIC Educational Resources Information Center

    Uchiyama, Ichiro; Anderson, David I.; Campos, Joseph J.; Witherington, David; Frankel, Carl B.; Lejeune, Laure; Barbu-Roth, Marianne

    2008-01-01

    Two studies investigated the role of locomotor experience on visual proprioception in 8-month-old infants. "Visual proprioception" refers to the sense of self-motion induced in a static person by patterns of optic flow. A moving room apparatus permitted displacement of an entire enclosure (except for the floor) or the side walls and…

  16. Neuronal control of locomotor handedness in Drosophila.

    PubMed

    Buchanan, Sean M; Kain, Jamey S; de Bivort, Benjamin L

    2015-05-26

    Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality.

  17. Camphor activates and sensitizes transient receptor potential melastatin 8 (TRPM8) to cooling and icilin.

    PubMed

    Selescu, Tudor; Ciobanu, Alexandru C; Dobre, Cristian; Reid, Gordon; Babes, Alexandru

    2013-09-01

    Camphor is known to potentiate both heat and cold sensations. Although the sensitization to heat could be explained by the activation of heat-sensitive transient receptor potential (TRP) channels TRPV1 and TRPV3, the camphor-induced sensitization to cooling remains unexplained. In this study, we present evidence for the activation of the cold- and menthol-sensitive channel transient receptor potential melastatin 8 (TRPM8) by camphor. Calcium transients evoked by camphor in HEK293 cells expressing human and rat TRPM8 are inhibited by the TRPM8 antagonists 4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide and 2-aminoethyl diphenylborinate. Camphor also sensitized the cold-induced calcium transients and evoked desensitizing outward-rectifying currents in TRPM8-expressing HEK293 cells. In the presence of ruthenium red (a blocker of TRPV1, TRPV3, and TRPA1), the camphor sensitivity of cultured rat dorsal root ganglion neurons was highest in a subpopulation of cold- and icilin-sensitive neurons, strongly suggesting that camphor activates native TRPM8. Camphor has a dual action on TRPM8: it not only activates the channel but also inhibits its response to menthol. The icilin-insensitive chicken TRPM8 was also camphor insensitive. However, camphor was able to activate an icilin-insensitive human TRPM8 mutant channel. The activation and sensitization to cold of mammalian TRPM8 are likely to be responsible for the psychophysical enhancement of innocuous cold and "stinging/burning" cold sensations by camphor.

  18. Perspectives on Non-Animal Alternatives for Assessing Sensitization Potential in Allergic Contact Dermatitis

    PubMed Central

    Sharma, Nripen S.; Jindal, Rohit; Mitra, Bhaskar; Lee, Serom; Li, Lulu; Maguire, Tim J.; Schloss, Rene; Yarmush, Martin L.

    2014-01-01

    Skin sensitization remains a major environmental and occupational health hazard. Animal models have been used as the gold standard method of choice for estimating chemical sensitization potential. However, a growing international drive and consensus for minimizing animal usage have prompted the development of in vitro methods to assess chemical sensitivity. In this paper, we examine existing approaches including in silico models, cell and tissue based assays for distinguishing between sensitizers and irritants. The in silico approaches that have been discussed include Quantitative Structure Activity Relationships (QSAR) and QSAR based expert models that correlate chemical molecular structure with biological activity and mechanism based read-across models that incorporate compound electrophilicity. The cell and tissue based assays rely on an assortment of mono and co-culture cell systems in conjunction with 3D skin models. Given the complexity of allergen induced immune responses, and the limited ability of existing systems to capture the entire gamut of cellular and molecular events associated with these responses, we also introduce a microfabricated platform that can capture all the key steps involved in allergic contact sensitivity. Finally, we describe the development of an integrated testing strategy comprised of two or three tier systems for evaluating sensitization potential of chemicals. PMID:24741377

  19. Perspectives on Non-Animal Alternatives for Assessing Sensitization Potential in Allergic Contact Dermatitis.

    PubMed

    Sharma, Nripen S; Jindal, Rohit; Mitra, Bhaskar; Lee, Serom; Li, Lulu; Maguire, Tim J; Schloss, Rene; Yarmush, Martin L

    2012-03-01

    Skin sensitization remains a major environmental and occupational health hazard. Animal models have been used as the gold standard method of choice for estimating chemical sensitization potential. However, a growing international drive and consensus for minimizing animal usage have prompted the development of in vitro methods to assess chemical sensitivity. In this paper, we examine existing approaches including in silico models, cell and tissue based assays for distinguishing between sensitizers and irritants. The in silico approaches that have been discussed include Quantitative Structure Activity Relationships (QSAR) and QSAR based expert models that correlate chemical molecular structure with biological activity and mechanism based read-across models that incorporate compound electrophilicity. The cell and tissue based assays rely on an assortment of mono and co-culture cell systems in conjunction with 3D skin models. Given the complexity of allergen induced immune responses, and the limited ability of existing systems to capture the entire gamut of cellular and molecular events associated with these responses, we also introduce a microfabricated platform that can capture all the key steps involved in allergic contact sensitivity. Finally, we describe the development of an integrated testing strategy comprised of two or three tier systems for evaluating sensitization potential of chemicals.

  20. Effect of chronic caffeine consumption on changes in locomotor activity of WAG/G and Fischer-344 rats induced by nicotine, ethanol, and morphine.

    PubMed

    Sudakov, S K; Rusakova, I V; Medvedeva, O F

    2003-12-01

    We studied the effect of single treatment with nicotine, ethanol, and morphine on locomotor activity of WAG/G and Fischer-344 rats chronically drinking caffeine solution. In Fischer-344 rats receiving caffeine locomotor activity in the open-field test was much lower than in animals drinking water, while in WAG/G rats no differences in locomotor activity were found. Chronic caffeine intake increased rat sensitivity to the stimulating effect of nicotine and ethanol, but decreased their sensitivity to the depressant effect of morphine. Chronic caffeine treatment most significantly modulated the effects of nicotine, ethanol, and morphine in Fischer-344 rats.

  1. Effects of sensitization and crevices on critical cracking potential for SCC of Alloy 600

    SciTech Connect

    Anzai, H.; Kuniya, J.; Shoji, T.; Yoshida, K.

    1992-12-31

    Effects of sensitization and crevices on critical cracking potential for stress corrosion cracking (SCC) of Alloy 600 were evaluated by slow strain rate tests (SSRTs). Tests were conducted under both potentiostatic controlled, and under free corrosion potential, conditions. For the former, boric acid and lithium hydroxide were added to pure water to maintain sufficient conductivity. Crevices were formed by inter-granular corrosion and wrapping stainless steel foil around the specimen. All tests were performed in 288{degrees}C water and applied strain rate was 7x10{sup {minus}7} (1/s). For the potentiostatic controlled condition, it was found that above a certain threshold potential SCC susceptibility increased with increasing applied potential. Sensitization lowered the critical cracking potential by around 200mV and inter-granular crevices shifted it even lower, by about 250mV. The critical cracking potentials obtained were not less than 200mV vs SHE, which is higher than those of sensitized stainless steel (0 to -230mV) and low alloy steel (-100 to -250mV).

  2. Photic entrainment in Drosophila assessed by locomotor activity recordings.

    PubMed

    Schlichting, Matthias; Helfrich-Förster, Charlotte

    2015-01-01

    Light is the most important Zeitgeber to entrain the circadian clock of the fruit fly Drosophila melanogaster to the 24-h cycle on earth. The fruit fly's circadian clock is very light sensitive, mainly because about half of the 150 clock neurons in the fly's brain express the blue-light photopigment, Cryptochrome, which provokes an immediate degradation of the clock protein Timeless upon activation by light. Consequently, Drosophila's molecular clock can reset very fast to measure the changes in environmental-lighting conditions. However, usually the responses of the molecular clock to light are not directly measured, but conclusions about entrainment of the circadian clock are drawn from recording the flies' locomotor activity rhythms. Here, we review how the flies' locomotor activity can be recorded under different light regimes and how entrainment can be analyzed and properly judged. We also summarize the influence of different recording and lighting methods on the flies' activity pattern, highlight their advantages and disadvantages, and stress general pitfalls. © 2015 Elsevier Inc. All rights reserved.

  3. Sensitivity of the International Skating Union's Mathematical Criteria to Flag Potential Scoring Anomalies

    ERIC Educational Resources Information Center

    Looney, Marilyn A.; Howell, Steven M.

    2015-01-01

    This article describes the "mathematical criteria" employed by the International Skating Union (ISU) to identify potential judging anomalies within competitive figure skating. The mathematical criteria have greater sensitivity to identify scoring anomalies for technical element scores than for the program component scores. This article…

  4. CYTOKINE MRNA PROFILES FOR ISOCYANATES WITH KNOWN AND UNKNOWN POTENTIAL TO INDUCE RESPIRATORY SENSITIZATION

    EPA Science Inventory

    Cytokine mRNA Profiles for Isocyanates with Known and Unknown Potential to Induce Respiratory Sensitization. Plitnick, L.M., Loveless, S.E., Ladics, G.S., Holsapple, M.P., Smialowicz, R.J., Woolhiser, M.R., Anderson, P.K., Smith, C., Sailstad, D.M. and Selgrade, M.J.K (2002) Tox...

  5. CYTOKINE MRNA PROFILES FOR ISOCYANATES WITH KNOWN AND UNKNOWN POTENTIAL TO INDUCE RESPIRATORY SENSITIZATION

    EPA Science Inventory

    Cytokine mRNA Profiles for Isocyanates with Known and Unknown Potential to Induce Respiratory Sensitization. Plitnick, L.M., Loveless, S.E., Ladics, G.S., Holsapple, M.P., Smialowicz, R.J., Woolhiser, M.R., Anderson, P.K., Smith, C., Sailstad, D.M. and Selgrade, M.J.K (2002) Tox...

  6. Locomotor function in the early stage of Parkinson's disease.

    PubMed

    Carpinella, Ilaria; Crenna, Paolo; Calabrese, Elena; Rabuffetti, Marco; Mazzoleni, Paolo; Nemni, Raffaello; Ferrarin, Maurizio

    2007-12-01

    The cardinal motor symptoms of Parkinson's disease (PD) have been widely investigated with particular reference to abnormalities of steady-state walking. The great majority of studies, however are related to severe forms of PD patients (phases > = 3 of Hoehn and Yahr scale), where locomotor abnormalities are clearly manifested. Goal of the present study was to quantitatively describe locomotor symptoms in subjects with mild PD. Accordingly, a multitask protocol involving instrumental analysis of steady-state linear walking, initiation of gait, and turning while walking was applied to a group of patients with idiopathic PD in their early clinical stage (phases 1 and 2 of Hoehn and Yahr scale), as well as in age-matched elderly controls. Kinematic, kinetic, and myoelectric measures were obtained by optoelectronic motion analysis, force platform, and telemetric electromyography. Results in PD patients showed a tendency to bradykinetic gait, with reduction of walking speed and cadence. Impairments of gait initiation consisted in reduction of the backward shift of the center of pressure (CoP) and prolongation of the stepping phase. Alterations of the turning task were more consistent and included delayed reorientation of the head toward the new direction, altered head-upper trunk rotational strategy, and adoption of a greater number of steps to complete the turning. It is concluded that patients in the early stage of PD reveal mild alterations of steady-state linear walking and more significant anomalies in the transitional conditions, especially during changes in the travel direction. Quantitative analysis of nonstationary locomotor tasks might be a potentially useful starting point for further studies on the pathophysiology of PD.

  7. An improvement of LLNA:DA to assess the skin sensitization potential of chemicals.

    PubMed

    Zhang, Hongwei; Shi, Ying; Wang, Chao; Zhao, Kangfeng; Zhang, Shaoping; Wei, Lan; Dong, Li; Gu, Wen; Xu, Yongjun; Ruan, Hongjie; Zhi, Hong; Yang, Xiaoyan

    2017-01-01

    We developed a modified local lymph node assay based on ATP (LLNA:DA), termed the Two-Stage LLNA:DA, to further reduce the animal numbers in the identification of sensitizers. In the Two-Stage LLNA:DA procedure, 13 chemicals ranging from non-sensitizers to extreme sensitizers were selected. The first stage used reduced LLNA:DA (rLLNA:DA) to screen out sensitive chemicals. The second stage used LLNA:DA based on OECD 442 (A) to classify those potential sensitizers screened out in the first stage. In the first stage, the SIs of the methyl methacrylate, salicylic acid, methyl salicylate, ethyl salicylate, isopropanol and propanediol were below 1.8 and need not to be tested in the second step. Others continued to be tested by LLNA:DA. In the second stage, sodium lauryl sulphate and xylene were classified as weak sensitizers. a-hexyl cinnamic aldehyde and eugenol were moderate sensitizers. Benzalkonium chloride and glyoxal were strong sensitizers, and phthalic anhydride was an extreme sensitizer. The 9/9, 11/12, 10/11, and 8/13 (positive or negative only) categories of the Two-Stage LLNA:DA were consistent with those from the other methods (LLNA, LLNA:DA, GPMT/BT and HMT/HPTA), suggesting that Two-Stage LLNA:DA have a high coincidence rate with reported data. In conclusion, The Two-Stage LLNA:DA is in line with the "3R" rules, and can be a modification of LLNA:DA but needs more study.

  8. Role of dopamine D1-like receptors in methamphetamine locomotor responses of D2 receptor knockout mice

    PubMed Central

    Kelly, M. A.; Low, M. J.; Rubinstein, M.; Phillips, T. J.

    2009-01-01

    Behavioral sensitization to psychostimulants manifests as an increased locomotor response with repeated administration. Dopamine systems are accepted to play a fundamental role in sensitization, but the role of specific dopamine receptor subtypes has not been completely defined. This study used the combination of dopamine D2 receptor-deficient mice and a D1-like antagonist to examine dopamine D1 and D2 receptor involvement in acute and sensitized locomotor responses to methamphetamine. Absence of the dopamine D2 receptor resulted in attenuation of the acute stimulant effects of methamphetamine. Mutant and wild-type mice exhibited sensitization that lasted longer within the time period of the challenge test in the mutant animals. Pretreatment with the D1-like receptor antagonist SCH 23390 produced more potent reductions in the acute and sensitized locomotor responses to methamphetamine in D2 receptor-deficient mice than in wild-type mice; however, the expression of locomotor sensitization when challenged with methamphetamine alone was equivalently attenuated by previous treatment with SCH 23390. These data suggest that dopamine D2 receptors play a key role in the acute stimulant and sensitizing effects of methamphetamine and act in concert with D1-like receptors to influence the acquisition of methamphetamine-induced behavioral sensitization, traits that may influence continued methamphetamine use. PMID:18363855

  9. Streaming potentials: a sensitive index of enzymatic degradation in articular cartilage.

    PubMed

    Frank, E H; Grodzinsky, A J; Koob, T J; Eyre, D R

    1987-01-01

    Under physiological conditions, the extracellular matrix of articular cartilage contains a high fixed-charge density, associated with its ionized proteoglycan (PG) molecules. Compression of the highly charged cartilage matrix within the physiologic range leads to the production of electrical streaming potentials. We observed significant changes in the potential response due to chemical modifications of the matrix, such as extraction of PG and glycosaminoglycan (GAG) moieties using chondroitinase-ABC adn trypsin. The streaming potential was a sensitive index of the degradative loss of these matrix constituents and of the kinetics of the enzymatic degradative process.

  10. Role of melanin-concentrating hormone in the nucleus accumbens shell in rats behaviourally sensitized to methamphetamine.

    PubMed

    Sun, Li-Li; Zhang, Yan; Liu, Jian-feng; Wang, Jun; Zhu, Wei-li; Zhao, Li-yan; Xue, Yan-xue; Lu, Lin; Shi, Jie

    2013-09-01

    Melanin-concentrating hormone (MCH) is a neuropeptide and its receptor is extensively expressed throughout the brain. MCH has been suggested to regulate the rewarding and reinforcing effects of psychostimulants by potentiating the dopaminergic system within the midbrain. Moreover, MCH and its receptor can regulate ERK activity. The present study investigated the role of MCH in the nucleus accumbens (NAc) in rats behaviourally sensitized to methamphetamine (Meth). We found that the development of Meth-induced locomotor sensitization was attenuated by MCH infused into the NAc shell but not core. Moreover, the elevation of ERK phosphorylation in the NAc shell induced by Meth was inhibited by locally infused MCH. Infusion of the MCH receptor 1 (MCHR1) antagonist SNAP 94847 into the NAc shell but not core augmented the initiation of locomotor sensitization and amplitude of elevated phosphorylated ERK levels induced by Meth. The expression of Meth-induced locomotor sensitization and ERK alterations after 1 wk withdrawal were not affected by either MCH or SNAP 94847 infused into the NAc shell or core. These results indicate that MCH in the NAc shell plays a critical role in the development but not expression of Meth-induced locomotor sensitization in rats, which might be mediated by the ERK signalling pathway. Our study suggests that MCH might be a potential target for the treatment of Meth addiction.

  11. Sensitivity of offset and onset cortical auditory evoked potentials to signals in noise.

    PubMed

    Baltzell, Lucas S; Billings, Curtis J

    2014-02-01

    The purpose of this study was to determine the effects of SNR and signal level on the offset response of the cortical auditory evoked potential (CAEP). Successful listening often depends on how well the auditory system can extract target signals from competing background noise. Both signal onsets and offsets are encoded neurally and contribute to successful listening in noise. Neural onset responses to signals in noise demonstrate a strong sensitivity to signal-to-noise ratio (SNR) rather than signal level; however, the sensitivity of neural offset responses to these cues is not known. We analyzed the offset response from two previously published datasets for which only the onset response was reported. For both datasets, CAEPs were recorded from young normal-hearing adults in response to a 1000-Hz tone. For the first dataset, tones were presented at seven different signal levels without background noise, while the second dataset varied both signal level and SNR. Offset responses demonstrated sensitivity to absolute signal level in quiet, SNR, and to absolute signal level in noise. Offset sensitivity to signal level when presented in noise contrasts with previously published onset results. This sensitivity suggests a potential clinical measure of cortical encoding of signal level in noise.

  12. High sensitivity of contact-heat evoked potentials in "snake-eye" appearance myelopathy.

    PubMed

    Ulrich, A; Min, K; Curt, A

    2015-10-01

    To evaluate the sensitivity of dermatomal contact-heat evoked potentials (dCHEPs) compared to dermatomal somatosensory evoked potentials (dSSEPs) and clinical sensory testing in patients with focal central cord myelopathy, referred to as "snake-eye" appearance myelopathy (SEAM). 33 patients with SEAM in neuroimaging underwent electrophysiological (dCHEPs, dSSEPs) and clinical testing of sensory function (light touch [LT] and pin prick [PP]) at segments above, at and below to the spinal cord lesion. In total, 151 dermatomes were tested (39 above, 112 at/below lesion). The sensitivity of dCHEPs (97.0%) was significantly higher compared to dSSEPs (23.3%, p<0.001), PP (66.7%, p=0.003) and LT (69.7%, p=0.006), respectively. The sensitivity of dCHEPs was highest when applied one to two segments caudally to the level of spinal cord lesion in MRI. dCHEPs are highly sensitive and superior to dSSEPs and clinical sensory testing in the diagnosis of SEAM. dCHEPs may complement the diagnosis in focal central cord myelopathies where clinical testing of sensory function and dSSEPs are less sensitive to provide conclusive findings. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  13. Sensitivity Analysis of CLIMEX Parameters in Modeling Potential Distribution of Phoenix dactylifera L.

    PubMed Central

    Shabani, Farzin; Kumar, Lalit

    2014-01-01

    Using CLIMEX and the Taguchi Method, a process-based niche model was developed to estimate potential distributions of Phoenix dactylifera L. (date palm), an economically important crop in many counties. Development of the model was based on both its native and invasive distribution and validation was carried out in terms of its extensive distribution in Iran. To identify model parameters having greatest influence on distribution of date palm, a sensitivity analysis was carried out. Changes in suitability were established by mapping of regions where the estimated distribution changed with parameter alterations. This facilitated the assessment of certain areas in Iran where parameter modifications impacted the most, particularly in relation to suitable and highly suitable locations. Parameter sensitivities were also evaluated by the calculation of area changes within the suitable and highly suitable categories. The low temperature limit (DV2), high temperature limit (DV3), upper optimal temperature (SM2) and high soil moisture limit (SM3) had the greatest impact on sensitivity, while other parameters showed relatively less sensitivity or were insensitive to change. For an accurate fit in species distribution models, highly sensitive parameters require more extensive research and data collection methods. Results of this study demonstrate a more cost effective method for developing date palm distribution models, an integral element in species management, and may prove useful for streamlining requirements for data collection in potential distribution modeling for other species as well. PMID:24722140

  14. Sensitivity analysis of CLIMEX parameters in modeling potential distribution of Phoenix dactylifera L.

    PubMed

    Shabani, Farzin; Kumar, Lalit

    2014-01-01

    Using CLIMEX and the Taguchi Method, a process-based niche model was developed to estimate potential distributions of Phoenix dactylifera L. (date palm), an economically important crop in many counties. Development of the model was based on both its native and invasive distribution and validation was carried out in terms of its extensive distribution in Iran. To identify model parameters having greatest influence on distribution of date palm, a sensitivity analysis was carried out. Changes in suitability were established by mapping of regions where the estimated distribution changed with parameter alterations. This facilitated the assessment of certain areas in Iran where parameter modifications impacted the most, particularly in relation to suitable and highly suitable locations. Parameter sensitivities were also evaluated by the calculation of area changes within the suitable and highly suitable categories. The low temperature limit (DV2), high temperature limit (DV3), upper optimal temperature (SM2) and high soil moisture limit (SM3) had the greatest impact on sensitivity, while other parameters showed relatively less sensitivity or were insensitive to change. For an accurate fit in species distribution models, highly sensitive parameters require more extensive research and data collection methods. Results of this study demonstrate a more cost effective method for developing date palm distribution models, an integral element in species management, and may prove useful for streamlining requirements for data collection in potential distribution modeling for other species as well.

  15. Development of a Countermeasure to Mitigate Postflight Locomotor Dysfunction

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Mulavara, A. P.; Peters, B. T.; Cohen, H. S.; Richards, J. T.; Miller, C. A.; Brady, R.; Warren, L. E.; Ruttley, T. M.

    2006-01-01

    Astronauts returning from space flight experience locomotor dysfunction following their return to Earth. Our laboratory is currently developing a gait adaptability training program that is designed to facilitate recovery of locomotor function following a return to a gravitational environment. The training program exploits the ability of the sensorimotor system to generalize from exposure to multiple adaptive challenges during training so that the gait control system essentially learns to learn and therefore can reorganize more rapidly when faced with a novel adaptive challenge. Evidence for the potential efficacy of an adaptive generalization gait training program can be obtained from numerous studies in the motor learning literature which have demonstrated that systematically varying the conditions of training enhances the ability of the performer to learn and retain a novel motor task. These variable practice training approaches have been used in applied contexts to improve motor skills required in a number of different sports. The central nervous system (CNS) can produce voluntary movement in an almost infinite number of ways. For example, locomotion can be achieved with many different combinations of joint angles, muscle activation patterns and forces. The CNS can exploit these degrees of freedom to enhance motor response adaptability during periods of adaptive flux like that encountered during a change in gravitational environment. Ultimately, the functional goal of an adaptive generalization countermeasure is not necessarily to immediately return movement patterns back to normal. Rather the training regimen should facilitate the reorganization of available sensory and motor subsystems to achieve safe and effective locomotion as soon as possible after long duration space flight. Indeed, this approach has been proposed as a basic feature underlying effective neurological rehabilitation. We have previously confirmed that subjects participating in an adaptive

  16. Development of a Countermeasure to Mitigate Postflight Locomotor Dysfunction

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Mulavara, A. P.; Peters, B. T.; Cohen, H. S.; Richards, J. T.; Miller, C. A.; Brady, R.; Warren, L. E.; Ruttley, T. M.

    2006-01-01

    Astronauts returning from space flight experience locomotor dysfunction following their return to Earth. Our laboratory is currently developing a gait adaptability training program that is designed to facilitate recovery of locomotor function following a return to a gravitational environment. The training program exploits the ability of the sensorimotor system to generalize from exposure to multiple adaptive challenges during training so that the gait control system essentially learns to learn and therefore can reorganize more rapidly when faced with a novel adaptive challenge. Evidence for the potential efficacy of an adaptive generalization gait training program can be obtained from numerous studies in the motor learning literature which have demonstrated that systematically varying the conditions of training enhances the ability of the performer to learn and retain a novel motor task. These variable practice training approaches have been used in applied contexts to improve motor skills required in a number of different sports. The central nervous system (CNS) can produce voluntary movement in an almost infinite number of ways. For example, locomotion can be achieved with many different combinations of joint angles, muscle activation patterns and forces. The CNS can exploit these degrees of freedom to enhance motor response adaptability during periods of adaptive flux like that encountered during a change in gravitational environment. Ultimately, the functional goal of an adaptive generalization countermeasure is not necessarily to immediately return movement patterns back to normal. Rather the training regimen should facilitate the reorganization of available sensory and motor subsystems to achieve safe and effective locomotion as soon as possible after long duration space flight. Indeed, this approach has been proposed as a basic feature underlying effective neurological rehabilitation. We have previously confirmed that subjects participating in an adaptive

  17. Potential Inhibitory Influence of miRNA 210 on Regulatory T Cells during Epicutaneous Chemical Sensitization

    PubMed Central

    Long, Carrie Mae; Lukomska, Ewa; Marshall, Nikki B.; Nayak, Ajay; Anderson, Stacey E.

    2016-01-01

    Toluene diisocyanate (TDI) is a potent low molecular weight chemical sensitizer and a leading cause of chemical-induced occupational asthma. The regulatory potential of microRNAs (miRNAs) has been recognized in a variety of disease states, including allergic disease; however, the roles of miRNAs in chemical sensitization are largely unknown. In a previous work, increased expression of multiple miRNAs during TDI sensitization was observed and several putative mRNA targets identified for these miRNAs were directly related to regulatory T-cell (Treg) differentiation and function including Foxp3 and Runx3. In this work, we show that miR-210 expression is increased in the mouse draining lymph node (dLN) and Treg subsets following dermal TDI sensitization. Alterations in dLN mRNA and protein expression of Treg related genes/putative miR-210 targets (foxp3, runx3, ctla4, and cd25) were observed at multiple time points following TDI exposure and in ex vivo systems. A Treg suppression assay, including a miR-210 mimic, was utilized to investigate the suppressive ability of Tregs. Cells derived from TDI sensitized mice treated with miR-210 mimic had less expression of miR-210 compared to the acetone control suggesting other factors, such as additional miRNAs, might be involved in the regulation of the functional capabilities of these cells. These novel findings indicate that miR-210 may have an inhibitory role in Treg function during TDI sensitization. Because the functional roles of miRNAs have not been previously elucidated in a model of chemical sensitization, these data contribute to the understanding of the potential immunologic mechanisms of chemical induced allergic disease. PMID:28035981

  18. Protein binding and metabolism influence the relative skin sensitization potential of cinnamic compounds.

    PubMed

    Elahi, Eiram N; Wright, Zoe; Hinselwood, David; Hotchkiss, Sharon A M; Basketter, David A; Pease, Camilla K Smith

    2004-03-01

    Skin protein modification (haptenation) is thought to be a key step in the manifestation of sensitization to low molecular mass chemicals (<500 g/mol). For sensitizing chemicals that are not protein reactive, it is hypothesised that metabolic activation can convert such chemicals into protein reactive toxins within the skin. trans-Cinnamaldehyde, alpha-amyl cinnamaldehyde, and trans-cinnamic alcohol are known sensitizers with differing potencies in man, where the former two are protein reactive and the latter is not. Here, we have used immunochemical methods to investigate the extent of protein-cinnamaldehyde binding in rat and human skin homogenates that have been incubated (for either 5, 15, 30, or 60 min) at 37 degrees C with cinnamaldehyde, alpha-amyl cinnamaldehyde (at concentrations of between 1 and 40 mM), and cinnamic alcohol (at higher concentrations of 200 or 400 mM). Cinnamaldehyde specific antiserum was raised specially. A broad range (in terms of molecular mass) of protein-cinnamaldehyde adducts was detected (as formed in a time- and concentration-dependent manner) in skin treated with cinnamaldehyde and cinnamic alcohol but not with alpha-amyl cinnamaldehyde. Mechanistic observations have been related to relative skin sensitization potential, as determined using the local lymph node assay (LLNA) as a biological read-out. The work presented here suggests that there is a common hapten involved in cinnamaldehyde and cinnamic alcohol sensitization and that metabolic activation (to cinnamaldehyde) is involved in the latter. Conversely, there does not appear to be a common hapten for cinnamaldehyde and alpha-amyl cinnamaldehyde. Such mechanistic work on protein modification is important in understanding the early mechanisms of skin sensitization. Such knowledge can then be used in order that effective and appropriate in vitro/in silico tools for predicting sensitization potential, with a high confidence, can be developed.

  19. Sensitivity analysis of potential events affecting the double-shell tank system and fallback actions

    SciTech Connect

    Knutson, B.J.

    1996-09-27

    Sensitivity analyses were performed for fall-back positions (i.e., management actions) to accommodate potential off-normal and programmatic change events overlaid on the waste volume projections and their uncertainties. These sensitivity analyses allowed determining and ranking tank system high-risk parameters and fall- back positions that will accommodate the respective impacts. This quantification of tank system impacts shows periods where tank capacity is sensitive to certain variables that must be carefully managed and/or evaluated. Identifying these sensitive variables and quantifying their impact will allow decision makers to prepare fall-back positions and focus available resources on the highest impact parameters where technical data are needed to reduce waste projection uncertainties. For noncomplexed waste, the period of capacity vulnerability occurs during the years of single-shell tank (SST) retrieval (after approximately 2009) due to the sensitivity to several variables. Ranked by importance these variables include the pretreatment rate and 200-East SST solids transfer volume. For complexed waste, the period of capacity vulnerability occurs during the period after approximately 2005 due to the sensitivity to several variables. Ranked by importance these variables include the pretreatment rate. 200-East SST solids transfer volume. complexed waste reduction factor using evaporation, and 200-west saltwell liquid porosity.

  20. A draining lymph node assay (DLNA) for assessing the sensitizing potential of proteins.

    PubMed

    Boverhof, Darrell R; Gollapudi, B Bhaskar; Hotchkiss, Jon A; Osterloh-Quiroz, Mandy; Woolhiser, Michael R

    2010-03-15

    There is a need for a simple and predictive model to identify the respiratory sensitization potential of (novel) proteins. The present study examined the use of a mouse draining lymph node assay (DLNA) approach, employing several routes of exposure, as a possible starting point for assessing protein sensitization potential. Consistent with the experimental procedure for the standard local lymph node assay (LLNA), female BALB/c mice were dosed dermally (topical), intranasally (IN) or by oropharyngeal aspiration (OP) on days 1, 2 and 3, and proliferation in the relevant draining lymph nodes was measured on day 6. For each route, the auricular, superficial cervical and tracheobronchial lymph nodes (TBLN) were evaluated following treatment with Subtilisin Carlsberg (SUB; a potent sensitizer/allergen), ovalbumin (OVA; a potent food allergen), beta-lactoglobulin (BLG; a moderate food allergen), and keyhole limpet hemocyanin (KLH; a strong immunogen with no reports of respiratory sensitization). Initial studies with OVA indicated that dermal administration did not stimulate lymph node proliferation. Responses in the tracheobronchial lymph node were most dramatic (stimulation indices up to 100) and reproducible for both the IN and OP routes. In a comparative experiment, all proteins induced lymph node proliferation with a rank order potency of SUB>KLH>OVA>BLG. The influence of the endotoxin content on lymph node proliferation was determined to be minimal, and did not impact the rank order potency. Molecular characterization of the TBLN at an equipotent proliferative dose was conducted for select gene transcripts based on research examining chemical sensitizers. Expression profiles differed among the four proteins, but the relevance of these responses was not clear and they did not further discriminate their allergic potential. These data illustrate both the opportunities and challenges associated with the examination of the draining lymph node proliferative response to

  1. The trace amine associated receptor 1 agonist RO5263397 attenuates the induction of cocaine behavioral sensitization in rats.

    PubMed

    Thorn, David A; Zhang, Chaogui; Zhang, Yanan; Li, Jun-Xu

    2014-04-30

    The trace amine associated receptor (TAAR) 1 is a new G protein coupled receptor that critically modulates central dopaminergic system. Recently, several selective TAAR 1 ligands have been described to possess antipsychotic and antidepressant-like activities. However, it is unknown of the role of these ligands in modulating psychostimulant-induced neurobehavioral plasticity. This study examined the effects of a selective TAAR 1 agonist, RO5263397, on cocaine induced behavioral sensitization in rats, a rodent model of drug-induced behavioral plasticity. Daily treatment with 15mg/kg cocaine (i.p., 7 days) induced robust locomotor sensitization in rats. RO5263397 (1-10mg/kg, i.p.) alone did not significantly alter the locomotor activity. Acute treatment with RO5263397 (3.2 and 10mg/kg) did not significantly modify cocaine-induced hyperactivity; however, the induction of locomotor sensitization was significantly blocked after 7 days of daily RO5263397 treatment. More importantly, the expression of locomotor sensitization remained significantly attenuated when rats were re-tested 7 days after the last drug treatment. The marked attenuation of cocaine sensitization was also evidenced by the suppression of the dose-effect function (3.2-32mg/kg) of cocaine sensitization. Together, these data represent the first to report a critical modulatory role of TAAR 1 agonists in cocaine-induced behavioral plasticity, which may be indicative of its potential role for altering other long-lasting behavioral maladaptations of cocaine including drug addiction.

  2. Withdrawal from THC during adolescence: sex differences in locomotor activity and anxiety.

    PubMed

    Harte-Hargrove, Lauren C; Dow-Edwards, Diana L

    2012-05-16

    Research suggests that the use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. Due to the localization of cannabinoid receptors within the limbic system and the established effects of cannabinoids on emotional states and anxiety levels of rats and humans, we studied the sex- and dose-related effects of Δ⁹-tetrahydrocannabinol (THC, the main psychoactive component in marijuana) on behavior and anxiety during spontaneous withdrawal. Male and female Sprague Dawley rats were administered 2, 7.5 or 15 mg/kg THC or vehicle from postnatal day 35-41 (approximating mid-adolescence in humans). Locomotor activity and anxiety-related behaviors were measured during drug administration and abstinence. THC caused significant dose-dependent locomotor depression during drug administration. Locomotor depression initially abated upon drug cessation, but re-emerged by the end of the abstinence period and was greater in female than male rats. We found sensitization to the locomotor-depressing effects of THC in middle- and high-dose rats and the subsequent development of tolerance in high-dose rats. The high dose of THC increased anxiety-like behaviors while the low dose decreased anxiety-like behaviors during drug administration, with females more sensitive to the anxiogenic effects of THC than males. During abstinence, females were again especially sensitive to the anxiogenic effects of THC. This study demonstrates sexually-dimorphic effects of THC on anxiety-related behaviors and locomotor activity during and after THC administration during adolescence. This information may be useful in the development of therapeutic approaches for the treatment of marijuana withdrawal in adolescents.

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

    PubMed

    Kliethermes, Christopher L

    2013-10-01

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

  4. Exploring the potential of context-sensitive CADe in screening mammography

    SciTech Connect

    Tourassi, Georgia D.; Mazurowski, Maciej A.; Harrawood, Brian P.; Krupinski, Elizabeth A.

    2010-11-15

    Purpose: Conventional computer-assisted detection (CADe) systems in screening mammography provide the same decision support to all users. The aim of this study was to investigate the potential of a context-sensitive CADe system which provides decision support guided by each user's focus of attention during visual search and reporting patterns for a specific case. Methods: An observer study for the detection of malignant masses in screening mammograms was conducted in which six radiologists evaluated 20 mammograms while wearing an eye-tracking device. Eye-position data and diagnostic decisions were collected for each radiologist and case they reviewed. These cases were subsequently analyzed with an in-house knowledge-based CADe system using two different modes: Conventional mode with a globally fixed decision threshold and context-sensitive mode with a location-variable decision threshold based on the radiologists' eye dwelling data and reporting information. Results: The CADe system operating in conventional mode had 85.7% per-image malignant mass sensitivity at 3.15 false positives per image (FPsI). The same system operating in context-sensitive mode provided personalized decision support at 85.7%-100% sensitivity and 0.35-0.40 FPsI to all six radiologists. Furthermore, context-sensitive CADe system could improve the radiologists' sensitivity and reduce their performance gap more effectively than conventional CADe. Conclusions: Context-sensitive CADe support shows promise in delineating and reducing the radiologists' perceptual and cognitive errors in the diagnostic interpretation of screening mammograms more effectively than conventional CADe.

  5. IATA for skin sensitization potential – 1 out of 2 or 2 out of 3? ...

    EPA Pesticide Factsheets

    To meet EU regulatory requirements and to avoid or minimize animal testing, there is a need for non-animal methods to assess skin sensitization potential. Given the complexity of the skin sensitization endpoint, there is an expectation that integrated testing and assessment approaches (IATA) will need to be developed which rely on assays representing key events in the pathway. Three non-animal assays have been formally validated: the direct peptide reactivity assay (DPRA), the KeratinoSensTM assay and the h-CLAT assay. At the same time, there have been many efforts to develop IATA with the “2 out of 3” approach attracting much attention whereby a chemical is classified on the basis of the majority outcome. A set of 271 chemicals with mouse, human and non-animal sensitization test data was evaluated to compare the predictive performances of the 3 individual non-animal assays, their binary combinations and the ‘2 out of 3’ approach. The analysis revealed that the most predictive approach was to use both the DPRA and h-CLAT: 1. Perform DPRA – if positive, classify as a sensitizer; 2. If negative, perform h-CLAT – a positive outcome denotes a sensitizer, a negative, a non-sensitizer. With this approach, 83% (LLNA) and 93% (human) of the non-sensitizer predictions were correct, in contrast to the ‘2 out of 3’ approach which had 69% (LLNA) and 79% (human) of non-sensitizer predictions correct. The views expressed are those of the authors and do not ne

  6. Locomotor activity and tissue levels following acute ...

    EPA Pesticide Factsheets

    Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5 h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to decrease activity by 50% were 2-fold lower for the γ-isomer (1.29 mg/kg) compared to λ-cyhalothrin (2.65 mg/kg). Salivation, typical of type II pyrethroids, was also observed at lower doses of γ-cyhalothrin. Administered dose correlated well with brain and plasma concentrations, which furthermore showed good correlations with activity changes. Brain and plasma levels were tightly correlated across doses. While γ-cyhalothrin was 2-fold more potent based on administ

  7. Locomotor head movements and semicircular canal morphology in primates

    PubMed Central

    Malinzak, Michael D.; Kay, Richard F.; Hullar, Timothy E.

    2012-01-01

    Animal locomotion causes head rotations, which are detected by the semicircular canals of the inner ear. Morphologic features of the canals influence rotational sensitivity, and so it is hypothesized that locomotion and canal morphology are functionally related. Most prior research has compared subjective assessments of animal “agility” with a single determinant of rotational sensitivity: the mean canal radius of curvature (R). In fact, the paired variables of R and body mass are correlated with agility and have been used to infer locomotion in extinct species. To refine models of canal functional morphology and to improve locomotor inferences for extinct species, we compare 3D vector measurements of head rotation during locomotion with 3D vector measures of canal sensitivity. Contrary to the predictions of conventional models that are based upon R, we find that axes of rapid head rotation are not aligned with axes of either high or low sensitivity. Instead, animals with fast head rotations have similar sensitivities in all directions, which they achieve by orienting the three canals of each ear orthogonally (i.e., along planes at 90° angles to one another). The extent to which the canal configuration approaches orthogonality is correlated with rotational head speed independent of body mass and phylogeny, whereas R is not. PMID:23045679

  8. Sensitivity of potential evaporation estimates to 100 years of climate variability

    NASA Astrophysics Data System (ADS)

    Bartholomeus, R. P.; Stagge, J. H.; Tallaksen, L. M.; Witte, J. P. M.

    2015-02-01

    Hydrological modeling frameworks require an accurate representation of evaporation fluxes for appropriate quantification of, e.g., the water balance, soil moisture budget, recharge and groundwater processes. Many frameworks have used the concept of potential evaporation, often estimated for different vegetation classes by multiplying the evaporation from a reference surface ("reference evaporation") by crop-specific scaling factors ("crop factors"). Though this two-step potential evaporation approach undoubtedly has practical advantages, the empirical nature of both reference evaporation methods and crop factors limits its usability in extrapolations under non-stationary climatic conditions. In this paper, rather than simply warning about the dangers of extrapolation, we quantify the sensitivity of potential evaporation estimates for different vegetation classes using the two-step approach when calibrated using a non-stationary climate. We used the past century's time series of observed climate, containing non-stationary signals of multi-decadal atmospheric oscillations, global warming, and global dimming/brightening, to evaluate the sensitivity of potential evaporation estimates to the choice and length of the calibration period. We show that using empirical coefficients outside their calibration range may lead to systematic differences between process-based and empirical reference evaporation methods, and systematic errors in estimated potential evaporation components. Quantification of errors provides a possibility to correct potential evaporation calculations and to rate them for their suitability to model climate conditions that differ significantly from the historical record, so-called no-analog climate conditions.

  9. AUTS2 in the nucleus accumbens is essential for heroin-induced behavioral sensitization.

    PubMed

    Zhu, Yongsheng; Xing, Bo; Dang, Wei; Ji, Yuanyuan; Yan, Peng; Li, Yunxiao; Qiao, Xiaomeng; Lai, Jianghua

    2016-10-01

    Autism susceptibility candidate 2 (AUTS2) is a gene associated with autism and mental retardation. Recent studies have suggested an association of the AUTS2 gene with heroin dependence, and reduced AUTS2 gene expression may confer increased susceptibility to heroin dependence. However, the functional role of the AUTS2 protein in regulating enduring neuroadaptations in response to heroin exposure has not been established. Here, we investigated the effects of acute and chronic heroin exposure on AUTS2 mRNA and protein expression in the nucleus accumbens (NAc) and caudate-putamen (CPu) to determine whether changes in AUTS2 expression are associated with heroin-induced locomotor sensitization in mice. Moreover, we explored whether AUST2 knockdown affects heroin-induced locomotor sensitization. AUTS2 mRNA and protein expression in the NAc, but not the CPu, was decreased after chronic heroin (1mg/kg) administration. In the NAc, the expression of heroin-induced locomotor sensitization was enhanced through the lentiviral-AUTS2-shRNA-mediated knockdown of AUTS2, while the overexpression of AUTS2 attenuated the locomotor-stimulant effects of heroin. Together, these results indicate that AUTS2 in the NAc, but not the CPu, suppresses the initiation and expression of heroin-induced behavioral sensitization, suggesting that AUST2 may be a potential target for the treatment of heroin dependence. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Differential roles of GABAB1 subunit isoforms on locomotor responses to acute and repeated administration of cocaine.

    PubMed

    Jacobson, Laura H; Sweeney, Fabian F; Kaupmann, Klemens; O'Leary, Olivia F; Gassmann, Martin; Bettler, Bernhard; Cryan, John F

    2016-02-01

    GABAB receptors are crucial modulators of the behavioural effects of drug abuse, and agonists and positive allosteric modulators show promise as pharmacological strategies for anti-addiction therapeutics. GABAB receptors are functional heterodimers of GABAB1 and GABAB2 subunits. The predominant neuronal GABAB1 subunit isoforms are GABAB1a and GABAB1b. Selective ablation of these isoforms in mice revealed differential behavioural responses in fear, cognition and stress sensitivity. However, the influence of the two GABAB1 isoforms on responses to drugs of abuse is unclear. Therefore we examined the responses of GABAB1 subunit isoform null mice to cocaine in acute locomotor activity and conditioned place preference (CPP) paradigms. During habituation for the acute locomotor activity assay, GABAB1b(-/-) mice showed higher levels of locomotor activity relative to wild-type (WT) and GABAB1a(-/-) mice, in accordance with previous studies. Acute cocaine (10 mg/kg) increased locomotor activity in habituated mice of all three genotypes, with GABAB1a(-/-) mice showing sustained hyperlocomotor responses 30 min after cocaine relative to WT and GABAB1b(-/-) mice. No genotypes demonstrated a cocaine-induced place preference, however, GABAB1a(-/-) mice demonstrated enhanced locomotor sensitisation to chronic cocaine in the CPP paradigm in comparison to WT mice, whereas GABAB1b(-/-) mice failed to develop locomotor sensitisation, despite higher levels of basal locomotor activity. These findings indicate that GABAB1a and GABAB1b isoforms differentially regulate behavioural responses to cocaine, with deletion of GABAB1a enhancing cocaine-induced locomotor activity and deletion of GABAB1b protecting from cocaine-induced sensitisation.

  11. Development and characterization of an equine behaviour chamber and the effects of amitraz and detomidine on spontaneous locomotor activity.

    PubMed

    Harkins, J D; Queiroz-Neto, A; Mundy, G D; West, D; Tobin, T

    1997-10-01

    This report describes the development of a behaviour chamber and the validation of the chamber of measure locomotor activity of a horse. Locomotor activity was detected by four Mini-beam sensors and recorded on a data logger every 5 min for 22 h. Horses were more active during daytime than in the evening, which was at least partially related to human activity in their surroundings. To validate the ability of the chambers to detect changes in activity, fentanyl citrate and xylazine HCl, agents well-characterized as a stimulant and a depressant, respectively, were administered to five horses. Fentanyl citrate (0.016 mg/kg) significantly increased locomotor activity which persisted for 30 min. Xylazine HCl (1 mg/kg) significantly reduced locomotor activity for 90 min. Amitraz produced a dose-dependent decrease in locomotor activity, lasting 75 min for the 0.05 mg/kg dose, 120 min for the 0.10 mg/kg dose, and 180 min for the 0.15 mg/kg dose. In a separate experiment, yohimbine administration immediately reversed the sedative effect of amitraz. This suggests there is a similarity in the mode of action of amitraz, xylazine and detomidine, as yohimbine acts primarily by blocking central alpha 2 -adrenoceptors that are stimulated by agents like xylazine. There was also a significant decrease in locomotor activity following injection of detomidine (0.02, 0.04 and 0.08 mg/kg) for 1.5, 3.5 and 5.0 h, respectively. The locomotor chamber is a useful, sensitive and highly reproducible tool for measuring spontaneous locomotor activity in the horse, which allows investigators to determine an agent's average time of onset, duration and intensity of effect on movement.

  12. Ozone sensitivity of currant tomato (Lycopersicon pimpinellifolium), a potential bioindicator species.

    PubMed

    Iriti, Marcello; Belli, Lucia; Nali, Cristina; Lorenzini, Giacomo; Gerosa, Giacomo; Faoro, Franco

    2006-05-01

    The wild tomato species Lycopersicon pimpinellifolium (currant tomato) was exposed to different O3 concentration, both in controlled environment fumigation facilities and in open-top chambers, to assess its sensitivity and to verify its potential as a bioindicator plant. Plants appeared particularly sensitive to O3 at an early stage of growth, responding with typical chlorotic spots within 24 h after exposure to a single pulse of 50 ppb for 3 h, and differentiating peculiar symptoms, such as reddish necrotic stipples, bronzing and extensive necrosis, depending on O3 concentration. Histo-cytochemical investigations with 3,3'-diaminobenzidine, to localize H2O2, and Evans blue, to detect dead cells, suggested that currant tomato sensitivity to O3 could be due to a deficiency in the anti-oxidant pools. The combination of these stainings proved to be useful, either to predict visible symptoms, early before their appearance, and to validate leaf ozone injury.

  13. The Potential Utility of High Resolution Ensemble Sensitivities During Weak Flow in Complex Terrain

    NASA Astrophysics Data System (ADS)

    Hacker, J.; Wile, S.

    2013-12-01

    Recent expansion in availability of re-locatable near-surface atmospheric observing sensors introduces the question of where placement maximizes gain in forecast accuracy. Here the potential for ensemble sensitivity analysis (ESA) is examined for high-resolution (Δx=4 km) predictions in complex terrain. The primary objective is to determine whether a mesoscale ESA applied at these scales is useful for identifying potential observing locations in weak flow. ESA can be inaccurate when the underlying assumptions of linear dynamics (and Gaussian statistics) are violated, or when the sensitivity cannot be robustly sampled. A case study of a fog event at the Salt Lake City airport (KSLC) provides a useful period for examining these issues, with the additional influence of complex terrain. A realistic upper-air observing network is used in perfect-model ensemble data assimilation experiments, providing the statistics for ESA. Results show that water vapor mixing ratios over KSLC are sensitive to temperature on the first model layer tens of km away, 6 h prior to verification and prior to the onset of fog. Sensitivity 12 h prior is weaker but leads to qualitatively similar results. Temperatures are shown to be a predictor of inversion strength in the Salt Lake basin; the ESA predicts southerly flow and strengthened inversions with warmer temperatures in a few locations. Simple linearity tests show that small perturbations do not lead to the expected forecast change, but larger perturbations do, suggesting that noise can dominate a small perturbation. Assimilating a perfect observation at the maximum sensitivity location produces forecasts more closely agreeing with the ESA. Sampling error evaluation show that similar conclusions can be reached with ensembles as small as 48 members, but smaller ensembles do not produce accurate sensitivity estimates.

  14. Evaluation of in silico tools to predict the skin sensitization potential of chemicals.

    PubMed

    Verheyen, G R; Braeken, E; Van Deun, K; Van Miert, S

    2017-01-01

    Public domain and commercial in silico tools were compared for their performance in predicting the skin sensitization potential of chemicals. The packages were either statistical based (Vega, CASE Ultra) or rule based (OECD Toolbox, Toxtree, Derek Nexus). In practice, several of these in silico tools are used in gap filling and read-across, but here their use was limited to make predictions based on presence/absence of structural features associated to sensitization. The top 400 ranking substances of the ATSDR 2011 Priority List of Hazardous Substances were selected as a starting point. Experimental information was identified for 160 chemically diverse substances (82 positive and 78 negative). The prediction for skin sensitization potential was compared with the experimental data. Rule-based tools perform slightly better, with accuracies ranging from 0.6 (OECD Toolbox) to 0.78 (Derek Nexus), compared with statistical tools that had accuracies ranging from 0.48 (Vega) to 0.73 (CASE Ultra - LLNA weak model). Combining models increased the performance, with positive and negative predictive values up to 80% and 84%, respectively. However, the number of substances that were predicted positive or negative for skin sensitization in both models was low. Adding more substances to the dataset will increase the confidence in the conclusions reached. The insights obtained in this evaluation are incorporated in a web database www.asopus.weebly.com that provides a potential end user context for the scope and performance of different in silico tools with respect to a common dataset of curated skin sensitization data.

  15. Sensitivity analysis of CLIMEX parameters in modelling potential distribution of Lantana camara L.

    PubMed

    Taylor, Subhashni; Kumar, Lalit

    2012-01-01

    A process-based niche model of L. camara L. (lantana), a highly invasive shrub species, was developed to estimate its potential distribution using CLIMEX. Model development was carried out using its native and invasive distribution and validation was carried out with the extensive Australian distribution. A good fit was observed, with 86.7% of herbarium specimens collected in Australia occurring within the suitable and highly suitable categories. A sensitivity analysis was conducted to identify the model parameters that had the most influence on lantana distribution. The changes in suitability were assessed by mapping the regions where the distribution changed with each parameter alteration. This allowed an assessment of where, within Australia, the modification of each parameter was having the most impact, particularly in terms of the suitable and highly suitable locations. The sensitivity of various parameters was also evaluated by calculating the changes in area within the suitable and highly suitable categories. The limiting low temperature (DV0), limiting high temperature (DV3) and limiting low soil moisture (SM0) showed highest sensitivity to change. The other model parameters were relatively insensitive to change. Highly sensitive parameters require extensive research and data collection to be fitted accurately in species distribution models. The results from this study can inform more cost effective development of species distribution models for lantana. Such models form an integral part of the management of invasive species and the results can be used to streamline data collection requirements for potential distribution modelling.

  16. Sensitivity Analysis of CLIMEX Parameters in Modelling Potential Distribution of Lantana camara L.

    PubMed Central

    Taylor, Subhashni; Kumar, Lalit

    2012-01-01

    A process-based niche model of L. camara L. (lantana), a highly invasive shrub species, was developed to estimate its potential distribution using CLIMEX. Model development was carried out using its native and invasive distribution and validation was carried out with the extensive Australian distribution. A good fit was observed, with 86.7% of herbarium specimens collected in Australia occurring within the suitable and highly suitable categories. A sensitivity analysis was conducted to identify the model parameters that had the most influence on lantana distribution. The changes in suitability were assessed by mapping the regions where the distribution changed with each parameter alteration. This allowed an assessment of where, within Australia, the modification of each parameter was having the most impact, particularly in terms of the suitable and highly suitable locations. The sensitivity of various parameters was also evaluated by calculating the changes in area within the suitable and highly suitable categories. The limiting low temperature (DV0), limiting high temperature (DV3) and limiting low soil moisture (SM0) showed highest sensitivity to change. The other model parameters were relatively insensitive to change. Highly sensitive parameters require extensive research and data collection to be fitted accurately in species distribution models. The results from this study can inform more cost effective development of species distribution models for lantana. Such models form an integral part of the management of invasive species and the results can be used to streamline data collection requirements for potential distribution modelling. PMID:22815881

  17. Auditory evoked potentials (AEP) methods for population-level assessment of hearing sensitivity in bottlenose dolphins

    NASA Astrophysics Data System (ADS)

    Houser, Dorian; Finneran, James

    2005-04-01

    A portable system for recording auditory evoked potentials (AEP) was developed to rapidly assess the hearing sensitivity of dolphins in air. The system utilizes a transducer embedded in a silicone suction cup to deliver amplitude modulated tones to the dolphin through the lower jaw. Frequencies tested range from 10-150 kHz and testing of both ears is completed within 90 min. AEP-determined thresholds from one subject were benchmarked against that subject's direct field behavioral audiogram to quantify variation between the two methods. To date, AEP audiograms have been obtained from over 30 bottlenose dolphins. Considerable individual variation in frequency-specific hearing sensitivity was observed. Some high-frequency hearing loss was observed in relatively young (early 20s) and old (35+ years) animals; conversely, age was not necessarily related to hearing loss as several animals greater than 40 years of age had good hearing sensitivity across the range of tested frequencies. Profound hearing loss typically occurred at higher frequencies. Decline in sensitivity was rapid in all cases and began between 50-60 kHz. Increased sample size of hearing sensitivity in dolphins suggest that the use of audiometric functions from single animals as representative of population level audiometry might be misleading.

  18. Microinjection of histone deacetylase inhibitor into the ventrolateral orbital cortex potentiates morphine induced behavioral sensitization.

    PubMed

    Wei, Lai; Zhu, Yuan-Mei; Zhang, Yu-Xiang; Liang, Feng; Barry, Devin M; Gao, Hong-Yu; Li, Tao; Huo, Fu-Quan; Yan, Chun-Xia

    2016-09-01

    Accumulating evidence indicates that epigenetic regulation, such as changes in histone modification in reward-related brain regions, contributes to the memory formation of addiction to opiates and psychostimulants. Our recent results suggested that the ventrolateral orbital cortex (VLO) is involved in the memories of stress and drug addiction. Since addiction and stress memories share some common pathways, the present study was designed to investigate the role of histone deacetylase (HDAC) activity in the VLO during morphine induced-behavioral sensitization. Rats received a single exposure to morphine for establishing the behavioral sensitization model. The effect of HDAC activity in the VLO in morphine induced-behavioral sensitization was examined by microinjection of HDAC inhibitor Trichostatin A (TSA). Furthermore, the protein expression levels of extracellular signal-regulated kinase (ERK) and phosphorylated ERK (p-ERK), histone H3 lysine 9 acetylation (aceH3K9) and brain-derived neurotrophic factor (BDNF) in the VLO in morphine-induced behavioral sensitization were examined. The results showed that the bilateral VLO lesions suppressed the expression phase, but not the developmental phase of morphine-induced behavioral sensitization. Microinjection of TSA into the VLO significantly increased both the development and expression phases. Moreover, the protein levels of p-ERK, aceH3K9 and BDNF except ERK in the VLO were significantly upregulated in morphine-treated rats in the expression phase. These effects were further strengthened by intra-VLO injection of TSA. Our findings suggest that HDAC activity in the VLO could potentiate morphine-induced behavioral sensitization. The upregulated expression of p-ERK, aceH3K9 and BDNF in the VLO might be the underlying mechanism of histone acetylation enhancing the morphine-induced behavioral sensitization. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Surveys for sensitivity to fibers and potential impacts from fiber induced failures

    NASA Technical Reports Server (NTRS)

    Butterfield, A. J.

    1979-01-01

    The surveys for sensitivities to fibers and potential impacts from fiber induced failures begins with a review of the survey work completed to date and then describes an impact study involving four industrial installations located in Virginia. The observations and results from both the surveys and the study provide guidelines for future efforts. The survey work was done with three broad objectives: (1) identify the pieces of potentially vulnerable equipment as candidates for test; (2) support the transfer function work by gaining an understanding of how fibers could get into a building; and (3) support the economic analysis by understanding what would happen if fibers precipitated a failure in an item of equipment.

  20. Variable maternal stress in rats alters locomotor activity, social behavior, and recognition memory in the adult offspring.

    PubMed

    Wilson, Christina A; Terry, Alvin V

    2013-03-01

    Rats repeatedly exposed to variable prenatal stress (PNS) exhibit behavioral signs that are similar to those manifested in several neuropsychiatric disorders such as deficits in attention and inhibitory control, and impairments in memory-related task performance. The purpose of the study described here was to conduct a comprehensive battery of tests to further characterize the behavioral phenotype of PNS rats as well as to evaluate the sensitivity of the model to therapeutic interventions (i.e., to compounds previously shown to have therapeutic potential in neuropsychiatric disorders). The results of this study indicated that PNS in rats is associated with: 1) increased locomotor activity and stereotypic behaviors, 2) elevated sensitivity to the psychostimulant amphetamine, 3) increased aggressive behaviors toward both adult and juvenile rats and 4) delay-dependent deficits in recognition memory. There was no evidence that PNS rats exhibited deficits in other areas of motor function/learning, sensorimotor gating, spatial learning and memory, social withdrawal, or anhedonia. In addition, the results revealed that the second generation antipsychotic risperidone attenuated amphetamine-related increases in locomotor activity in PNS rats; however, the effect was not sustained over time. Furthermore, deficits in recognition memory in PNS rats were attenuated by the norepinephrine reuptake inhibitor, atomoxetine, but not by the α7 nicotinic acetylcholine receptor partial agonist, GTS-21. This study supports the supposition that important phenomenological similarities exist between rats exposed to PNS and patients afflicted with neuropsychiatric disorders thus further establishing the face validity of the model for evaluating potential therapeutic interventions. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Myriophyllum aquaticum versus Lemna minor: sensitivity and recovery potential after exposure to atrazine.

    PubMed

    Teodorović, Ivana; Knežević, Varja; Tunić, Tanja; Cučak, Mićo; Lečić, Jelena Nikolić; Leovac, Anita; Tumbas, Ivana Ivančev

    2012-02-01

    The relative sensitivity and recovery potential of two aquatic macrophyte species, Lemna minor and Myriophyllum aquaticum, exposed to atrazine (concentration ranges 80-1,280 µg/L and 40-640 µg/L, respectively) were evaluated using slightly adapted standard protocol for Lemna spp.: relative growth rates (RGR) and yield of both plants were measured in 3-d-long intervals during the exposure and recovery phase. Myriophyllum aquaticum was also exposed to atrazine-spiked sediment (0.1-3.7 µg/g) in a water-free system. The results of M. aquaticum sediment contact tests showed that root- and shoot-based growth parameters are equally sensitive endpoints. In the water (sediment-free) test system, L. minor recovered after short (3 d) and longer exposure (7 d) to all atrazine concentrations after only a 5- to 6-d-long recovery phase. The recovery of M. aquaticum after short exposure was slower and less efficient: after 12 d of recovery phase the final biomass of plants exposed to 380 and 640 µg/L was below the initial values. The last interval RGR provides a good indication of plant recovery potential regardless of species growth strategy. If compared to L. minor, the difference in growth rate, sensitivity, lag phase, recovery potential from water-column substances, and also suitability for studies investigating the effect of sediment-bound pollutants advocates the use of M. aquaticum as an additional macrophyte species in risk assessment. Copyright © 2011 SETAC.

  2. Is skin penetration a determining factor in skin sensitization potential and potency? Refuting the notion of a LogKow threshold for skin sensitization.

    PubMed

    Fitzpatrick, Jeremy M; Roberts, David W; Patlewicz, Grace

    2017-01-01

    It is widely accepted that substances that cannot penetrate through the skin will not be sensitizers. LogKow and molecular weight (MW) have been used to set thresholds for sensitization potential. Highly hydrophilic substances e.g. LogKow ≤ 1 are expected not to penetrate effectively to induce sensitization. To investigate whether LogKow >1 is a true requirement for sensitization, a large dataset of substances that had been evaluated for their skin sensitization potential under Registration, Evaluation, Authorisation and restriction of CHemicals (REACH), together with available measured LogKow values was compiled using the OECD eChemPortal. The incidence of sensitizers relative to non-sensitizers above and below a LogKow of 1 was explored. Reaction chemistry principles were used to explain the sensitization observed for the subset of substances with a LogKow ≤0. 1482 substances were identified with skin sensitization data and measured LogKow values. 525 substances had a measured LogKow ≤ 1, 100 of those were sensitizers. There was no significant difference in the incidence of sensitizers above and below a LogKow of 1. Reaction chemistry principles that had been established for lower MW and more hydrophobic substances were found to be still valid in rationalizing the skin sensitizers with a LogKow ≤ 0. The LogKow threshold arises from the widespread misconception that the ability to efficiently penetrate the stratum corneum is a key determinant of sensitization potential and potency. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  3. Temperature sensitivity of microbial respiration, nitrogen mineralization, and potential soil enzyme activities in organic alpine soils

    NASA Astrophysics Data System (ADS)

    Koch, Oliver; Tscherko, Dagmar; Kandeler, Ellen

    2007-12-01

    Investigations focusing on the temperature sensitivity of microbial activity and nutrient turnover in soils improve our understanding of potential effects of global warming. This study investigates the temperature sensitivity of C mineralization, N mineralization, and potential enzyme activities involved in the C and N cycle (tyrosine amino-peptidase, leucine amino-peptidase, ß-glucosidase, ß-xylosidase, N-acetyl-ß-glucosaminidase). Four different study sites in the Austrian alpine zone were selected, and soils were sampled in three seasons (summer, autumn, and winter). A simple first-order exponential equation was used to calculate constant Q10 values for the C and N mineralization over the investigated temperature range (0-30°C). The Q10 values of the C mineralization (average 2.0) for all study sites were significantly higher than for the N mineralization (average 1.7). The Q10 values of both activities were significantly negatively related to a soil organic matter quality index calculated by the ratios of respiration to the organic soil carbon and mineralized N to the total soil nitrogen. The chemical soil properties or microbial biomass did not affect the Q10 values of C and N mineralization. Moreover, the Q10 values showed no distinct pattern according to sampling date, indicating that the substrate quality and other factors are more important. Using a flexible model function, the analysis of relative temperature sensitivity (RTS) showed that the temperature sensitivity of activities increased with decreasing temperature. The C and N mineralization and potential amino-peptidase activities (tyrosine and leucine) showed an almost constant temperature dependence over 0-30°C. In contrast, ß-glucosidase, ß-xylosidase, and N-acetyl-ß-glucosaminidase showed a distinctive increase in temperature sensitivity with decreasing temperature. Low temperature at the winter sampling date caused a greater increase in the RTS of all microbial activities than for the

  4. Effectiveness of automated locomotor training in patients with chronic incomplete spinal cord injury: a multicenter trial.

    PubMed

    Wirz, Markus; Zemon, David H; Rupp, Ruediger; Scheel, Anke; Colombo, Gery; Dietz, Volker; Hornby, T George

    2005-04-01

    To determine whether automated locomotor training with a driven-gait orthosis (DGO) can increase functional mobility in people with chronic, motor incomplete spinal cord injury (SCI). Repeated assessment of the same patients or single-case experimental A-B design. Research units of rehabilitation hospitals in Chicago; Heidelberg, Germany; and Basel and Zurich, Switzerland. Twenty patients with a chronic (>2 y postinjury), motor incomplete SCI, classified by the American Spinal Injury Association (ASIA) Impairment Scale with ASIA grades C (n=9) and D (n=11) injury. Most patients (n=16) were ambulatory before locomotor training. Locomotor training was provided using robotic-assisted, body-weight-supported treadmill training 3 to 5 times a week over 8 weeks. Single training sessions lasted up to 45 minutes of total walking time, with gait speed between .42 and .69 m/s and body-weight unloading as low as possible (mean +/- standard deviation, 37%+/-17%). Primary outcome measures included the 10-meter walk test, the 6-minute walk test, the Timed Up & Go test, and the Walking Index for Spinal Cord Injury-II tests. Secondary measures included lower-extremity motor scores and spastic motor behaviors to assess their potential contribution to changes in locomotor function. All subjects were tested before, during, and after training. Locomotor training using the DGO resulted in significant improvements in the subjects' gait velocity, endurance, and performance of functional tasks. There were no significant changes in the requirement of walking aids, orthoses, or external physical assistance. There was no correlation between improvements in walking speed or changes in muscle strength or spastic motor behaviors. Intensive locomotor training on a treadmill with the assistance of a DGO results in improved overground walking.

  5. Differential Effects of Inhaled Toluene on Locomotor Activity in Adolescent and Adult Rats

    PubMed Central

    Batis, Jeffery C.; Hannigan, John H.; Bowen, Scott E.

    2010-01-01

    Inhalant abuse is a world-wide public health concern among adolescents. Most preclinical studies have assessed inhalant effects in adult animals leaving unclear how behavioral effects differ in younger animals. We exposed adolescent (postnatal day [PN] 28) and adult (PN90) male rats to toluene using 1 of 3 exposure patterns. These patterns modeled those reported in toluene abuse in teens and varied concentration, number and length of exposures, as well as the inter-exposure interval. Animals were exposed repeatedly over 12 days to toluene concentrations of 0, 8,000 or 16,000 parts per million (ppm). Locomotor activity was quantified during toluene exposures and for 30 min following completion of the final daily toluene exposure. For each exposure pattern, there were significant toluene concentration-related increases and decreases in locomotor activity compared to the 0-ppm “air” controls at both ages. These changes depended upon when activity was measured – during or following exposure. Compared to adults, adolescents displayed greater locomotor activity on the first day and generally greater increases in activity over days than adults during toluene exposure. Adults displayed greater locomotor activity than adolescents in the “recovery” period following exposure on the first and subsequent days. Age group differences were clearest following the pattern of paced, brief (5-min) repeated binge exposures. The results suggest that locomotor behavior in rats during and following inhalation of high concentrations of toluene depends on age and the pattern of exposure. The results are consistent with dose-dependent shifts in sensitivity and sensitization or tolerance to repeated toluene in the adolescent animals compared to the adult animals. Alternate interpretations are possible and our interpretation is limited by the range of very high concentrations of toluene used. The results imply that both pharmacological and psychosocial factors contribute to the teen

  6. A case study for evaluating potential soil sensitivity in aridland systems.

    PubMed

    Peterman, Wendy L; Ferschweiler, Ken

    2016-04-01

    Globally, ecosystems are subjected to prolonged droughts and extreme heat events, leading to forest die-offs and dominance shifts in vegetation. Some scientists and managers view soil as the main resource to be considered in monitoring ecosystem responses to aridification. As the medium through which precipitation is received, stored, and redistributed for plant use, soil is an important factor in the sensitivity of ecosystems to a drying climate. This study presents a novel approach to evaluating where on a landscape soils may be most sensitive to drying, making them less resilient to disturbance, and where potential future vegetation changes could lead to such disturbance. The drying and devegetation of arid lands can increase wind erosion, contributing to aerosol and dust emissions. This has implications for air quality, human health, and water resources. This approach combines soil data with vegetation simulations, projecting future vegetation change, to create maps of potential areas of concern for soil sensitivity and dust production in a drying climate. Consistent with recent observations, the projections show shifts from grasslands and woodlands to shrublands in much of the southwestern region. An increase in forested area occurs, but shifts in the dominant types and spatial distribution of the forests also are seen. A net increase in desert ecosystems in the region and some changes in alpine and tundra ecosystems are seen. Approximately 124,000 km(2) of soils flagged as "sensitive" are projected to have vegetation change between 2041 and 2050, and 82,927 km(2) of soils may become sensitive because of future vegetation changes. These maps give managers a way to visualize and identify where soils and vegetation should be investigated and monitored for degradation in a drying climate, so restoration and mitigation strategies can be focused in these areas.

  7. A parallel cholinergic brainstem pathway for enhancing locomotor drive

    PubMed Central

    Smetana, Roy; Juvin, Laurent; Dubuc, Réjean; Alford, Simon

    2010-01-01

    The brainstem locomotor system is believed to be organized serially from the mesencephalic locomotor region (MLR) to reticulospinal neurons, which in turn, project to locomotor neurons in the spinal cord. In contrast, we now identify in lampreys, brainstem muscarinoceptive neurons receiving parallel inputs from the MLR and projecting back to reticulospinal cells to amplify and extend durations of locomotor output. These cells respond to muscarine with extended periods of excitation, receive direct muscarinic excitation from the MLR, and project glutamatergic excitation to reticulospinal neurons. Targeted block of muscarine receptors over these neurons profoundly reduces MLR-induced excitation of reticulospinal neurons and markedly slows MLR-evoked locomotion. Their presence forces us to rethink the organization of supraspinal locomotor control, to include a sustained feedforward loop that boosts locomotor output. PMID:20473293

  8. Light level impacts locomotor biomechanics in a secondarily diurnal gecko, Rhoptropus afer.

    PubMed

    Birn-Jeffery, Aleksandra V; Higham, Timothy E

    2016-11-15

    Locomotion through complex habitats relies on the continuous feedback from a number of sensory systems, including vision. Animals face a visual trade-off between acuity and light sensitivity that depends on light levels, which will dramatically impact the ability to process information and move quickly through a habitat, making ambient illumination an incredibly important ecological factor. Despite this, there is a paucity of data examining ambient light in the context of locomotor dynamics. There have been several independent transitions from the nocturnal ancestor to a diurnal activity pattern among geckos. We examined how ambient light level impacted the locomotor performance and high-speed three-dimensional kinematics of a secondarily diurnal, and cursorial, gecko (Rhoptropus afer) from Namibia. This species is active under foggy and sunny conditions, indicating that a range of ambient light conditions is experienced naturally. Locomotor speed was lowest in the 'no-light' condition compared with all other light intensities, occurring via a combination of shorter stride length and lower stride frequency. Additionally, the centre of mass was significantly lower, and the geckos were more sprawled, in the no-light condition relative to all of the higher light intensities. Locomotor behaviour is clearly sub-optimal under lower light conditions, suggesting that ecological conditions, such as very dense fog, might preclude the ability to run quickly during predator-prey interactions. The impact of ambient light on fitness should be explored further, especially in those groups that exhibit multiple transitions between diel activity patterns.

  9. Membrane Potential Measurements of Isolated Neurons Using a Voltage-Sensitive Dye

    PubMed Central

    Fairless, Richard; Beck, Andreas; Kravchenko, Mykola; Williams, Sarah K.; Wissenbach, Ulrich; Diem, Ricarda; Cavalié, Adolfo

    2013-01-01

    The ability to monitor changes in membrane potential is a useful tool for studying neuronal function, but there are only limited options available at present. Here, we have investigated the potential of a commercially available FLIPR membrane potential (FMP) dye, developed originally for high throughput screening using a plate reader, for imaging the membrane potential of cultured cells using an epifluorescence-based single cell imaging system. We found that the properties of the FMP dye make it highly suitable for such imaging since 1) its fluorescence displayed a high signal-to-noise ratio, 2) robust signals meant only minimal exposure times of around 5 ms were necessary, and 3) bidirectional changes in fluorescence were detectable resulting from hyper- or depolarising conditions, reaching equilibrium with a time constant of 4–8 s. Measurements were possible independently of whether membrane potential changes were induced by voltage clamping, or manipulating the ionic distribution of either Na+ or K+. Since FMP behaves as a charged molecule which accumulates in the cytosol, equations based on the Boltzmann distribution were developed determining that the apparent charge of FMP which represents a measure of the voltage sensitivity of the dye, is between −0.62 and −0.72. Finally, we demonstrated that FMP is suitable for use in a variety of neuronal cell types and detects membrane potential changes arising from spontaneous firing of action potentials and through stimulation with a variety of excitatory and inhibitory neurotransmitters. PMID:23516458

  10. Chemical reactivity and skin sensitization potential for benzaldehydes: can Schiff base formation explain everything?

    PubMed

    Natsch, Andreas; Gfeller, Hans; Haupt, Tina; Brunner, Gerhard

    2012-10-15

    Skin sensitizers chemically modify skin proteins rendering them immunogenic. Sensitizing chemicals have been divided into applicability domains according to their suspected reaction mechanism. The widely accepted Schiff base applicability domain covers aldehydes and ketones, and detailed structure-activity-modeling for this chemical group was presented. While Schiff base formation is the obvious reaction pathway for these chemicals, the in silico work was followed up by limited experimental work. It remains unclear whether hydrolytically labile Schiff bases can form sufficiently stable epitopes to trigger an immune response in the living organism with an excess of water being present. Here, we performed experimental studies on benzaldehydes of highly differing skin sensitization potential. Schiff base formation toward butylamine was evaluated in acetonitrile, and a detailed SAR study is presented. o-Hydroxybenzaldehydes such as salicylaldehyde and the oakmoss allergens atranol and chloratranol have a high propensity to form Schiff bases. The reactivity is highly reduced in p-hydroxy benzaldehydes such as the nonsensitizing vanillin with an intermediate reactivity for p-alkyl and p-methoxy-benzaldehydes. The work was followed up under more physiological conditions in the peptide reactivity assay with a lysine-containing heptapeptide. Under these conditions, Schiff base formation was only observable for the strong sensitizers atranol and chloratranol and for salicylaldehyde. Trapping experiments with NaBH₃CN showed that Schiff base formation occurred under these conditions also for some less sensitizing aldehydes, but the reaction is not favored in the absence of in situ reduction. Surprisingly, the Schiff bases of some weaker sensitizers apparently may react further to form stable peptide adducts. These were identified as the amides between the lysine residues and the corresponding acids. Adduct formation was paralleled by oxidative deamination of the parent

  11. Application of the KeratinoSens™ assay for assessing the skin sensitization potential of agrochemical active ingredients and formulations.

    PubMed

    Settivari, Raja S; Gehen, Sean C; Amado, Ricardo Acosta; Visconti, Nicolo R; Boverhof, Darrell R; Carney, Edward W

    2015-07-01

    Assessment of skin sensitization potential is an important component of the safety evaluation process for agrochemical products. Recently, non-animal approaches including the KeratinoSens™ assay have been developed for predicting skin sensitization potential. Assessing the utility of the KeratinoSens™ assay for use with multi-component mixtures such as agrochemical formulations has not been previously evaluated and is a significant need. This study was undertaken to evaluate the KeratinoSens™ assay prediction potential for agrochemical formulations. The assay was conducted for 8 agrochemical active ingredients (AIs) including 3 sensitizers (acetochlor, meptyldinocap, triclopyr), 5 non-sensitizers (aminopyralid, clopyralid, florasulam, methoxyfenozide, oxyfluorfen) and 10 formulations for which in vivo sensitization data were available. The KeratinoSens™ correctly predicted the sensitization potential of all the AIs. For agrochemical formulations it was necessary to modify the standard assay procedure whereby the formulation was assumed to have a common molecular weight. The resultant approach correctly predicted the sensitization potential for 3 of 4 sensitizing formulations and all 6 non-sensitizing formulations when compared to in vivo data. Only the meptyldinocap-containing formulation was misclassified, as a result of high cytotoxicity. These results demonstrate the promising utility of the KeratinoSens™ assay for evaluating the skin sensitization potential of agrochemical AIs and formulations.

  12. [High sensitivity cardiac troponin assays 2009: clinical potential, current practice and benefits, the future].

    PubMed

    Englis, M; Sochman, J; Pudil, R; Franeková, J; Jabor, A

    2009-11-01

    At present, determination of cardiac troponins (cTn) is the biomarker method of choice for diagnostics and risk stratification in patients with a myocardial injury. Past clinical practice had provided sound evidence that low cTn concentrations, measured with unacceptable imprecision by the currently used methods, hold important clinical, diagnostic and stratification potential. The new generation cTn assays, so called high-sensitivity assays, enable determination of very low cTn concentrations with satisfactory analytical precision and open the way to early identification of small but often prognostically important myocardial damage. Introduction of high-sensitivity cTn assays in practice is, however, associated with some difficulties: their superior diagnostic sensitivity to identify small injuries to myocardium is often linked to lower specificity, higher incidence of elevated cTn concentrations is frequently associated with less obvious clinical symptomatology (overdiagnosis), resulting in greater demand for further patient assessment (overcrowding), repeated analyses and trend monitoring of cTn fluctuation. These initial difficulties cannot lessen the by now indisputable, established benefit of high-sensitivity cTn assays that we briefly describe in the present paper.

  13. Laser-evoked potential habituation and central sensitization symptoms in childhood migraine.

    PubMed

    de Tommaso, Marina; Sciruicchio, Vittorio; Ricci, Katia; Montemurno, Anna; Gentile, Francesco; Vecchio, Eleonora; Barbaro, Maria Grazia Foschino; Simeoni, Michele; Goffredo, Marvita; Livrea, Paolo

    2016-04-01

    Few studies have addressed central sensitization symptoms and pain processing in childhood migraine. Our aims were to examine pain sensitivity and responses, including habituation, evoked by CO2 laser stimuli (laser-evoked potentials (LEPs)) in a cohort of children with migraine compared to non-migraine controls and to determine the correlation between LEP features and signs of central sensitization. Thirty-five patients 8-15 years of age with migraines without aura were evaluated during the inter-critical phase and were compared to 17 controls. LEPs were analyzed, and their main features were correlated with clinical symptoms including allodynia and pericranial tenderness. The laser-evoked pain threshold was lower and the N2P2 vertex complex amplitude was higher in children with migraines. Furthermore, habituation of vertex waves of LEPs clearly showed a tendency toward progressive amplitude enhancement in the migraine group. Acute allodynia and inter-critical pericranial tenderness correlated with trigeminal LEP features, particularly with the abnormal habituation pattern. Abnormalities of pain processing and symptoms of central sensitization appear to be characteristics of children with migraine. Reduced habituation and progressive amplification of cortical responses to laser stimuli indicate an overactive nociceptive system at the onset of migraine, and this hyperactivity may subtend allodynia and pericranial tenderness. Future prospective trials may aid in the early identification of clinical phenotypes that display a tendency to develop into the chronic form of migraine, warranting a timely therapeutic approach. © International Headache Society 2015.

  14. Sense and sensitivity: responsiveness to offspring signals varies with the parents' potential to breed again

    PubMed Central

    Thorogood, Rose; Ewen, John G.; Kilner, Rebecca M.

    2011-01-01

    How sensitive should parents be to the demands of their young? Offspring are under selection to seek more investment than is optimal for parents to supply, which makes parents vulnerable to losing future fitness by responding to manipulative displays. Yet, parents cannot afford to ignore begging and risk allocating resources inefficiently. Here, we show that parents may solve this problem by adjusting their sensitivity to begging behaviour in relation to their own likelihood of breeding again, a factor largely neglected in previous analyses of parent–offspring interactions. In two carotenoid-supplementation experiments on a New Zealand passerine, the hihi Notiomystis cincta, we supplemented adults to enhance their propensity to breed again, and supplemented entire broods to increase their mouth colour, thus enhancing their solicitation display. We found that adults that attempted two breeding attempts a season were largely insensitive to the experimentally carotenoid-rich gapes of their brood, whereas those that bred just once responded by increasing their rate of provisioning at the nest. Our results show that parents can strategically vary their sensitivity to begging in relation to their future reproductive potential. By restricting opportunities for offspring to influence provisioning decisions, parents greatly limit the potential for offspring to win parent–offspring conflict. PMID:21270035

  15. The potential for observation network design with mesoscale ensemble sensitivities in complex terrain

    NASA Astrophysics Data System (ADS)

    Chilcoat, K. H.; Hacker, J.; Doyle, J.

    2011-12-01

    Observation network design requires some framework for sensitivity studies. The goal is to place observations where they will reduce forecast error. We use uncertainty estimates from our best forecast models as an indicator of forecast error. The first step is then to find initial-state perturbations that reduce forecast uncertainty by minimizing a user-dependent norm. Adjoint models have helped meet this challenge for decades. An adjoint propagates a model state backward along a tangent linear approximation of a forecast model trajectory, and can therefore be used in conjunction with a forward propagator to minimize a cost function defined by forecast uncertainty. Within the limitations of model inadequacy and the tangent linear approximation, including diffusive and highly nonlinear phenomenon, adjoints can effectively identify initial-time perturbations yielding sensitivity in the forecast. More recently, ensemble sensitivities have emerged as a powerful alternative to adjoint models. Under the conditions of Gaussian statistics and an infinite ensemble, lagged covariances from an ensemble can be used equivalently to an adjoint model to give the least-squares minimization of a given cost function. One practical advantage is that costly development and maintenance of tangent linear and adjoint models are avoided. Ensemble sensitivities have been shown to be an effective alternative to adjoint models. They have been used successfully to diagnose predictors of forecast error in synoptic storms, extratropical transition, and developing hurricanes. Because they rely on lagged covariances from a finite-sized ensemble, they are subject to sampling error and spurious covariances. Their efficacy for high-resolution forecasts in mountainous environments has not been thoroughly explored. We present results from experiments designed to establish the potential for ensemble sensitivity computations with a high resolution mesoscale model (grid spacing 4 km) in complex terrain

  16. Lack of locomotor-cardiac coupling in trotting dogs.

    PubMed

    Simmons, A D; Carrier, D R; Farmer, C G; Gregersen, C S

    1997-10-01

    Coupling of locomotor and cardiac cycles has been suggested to facilitate effective arterial delivery and venous return during vigorous exercise. In an attempt to document locomotor-cardiac coupling, we ran five dogs on a motorized treadmill while monitoring heart activity with surface electrocardiogram electrodes and locomotor events with high-speed video and an accelerometer mounted on the dog's back. Analysis of the cardiac and locomotor frequencies revealed that heart rate was usually slightly greater than stride frequency. Hence the timing of the cardiac cycles varied with respect to the phase of the locomotor cycles, and therefore consistent coupling of the locomotor and cardiac cycles was not observed in any of the dogs. However, the period of the cardiac cycle sometimes varied in a rhythmic way that caused brief periods of transient coupling of the locomotor and cardiac cycles in three of the five dogs. These brief periods of coupling (5-20 heartbeats) occurred at approximately the same phase relationship in each of the three dogs. We hypothesize that the variation in cardiac period and the resulting transient coupling are a function of locomotor and ventilatory influences on venous return and/or ventricular ejection. Because venous return and ejection fraction are likely to vary in an unpredictable manner when animals run in a complex environment, we suggest that reflex control of heart rate will be important during locomotion and strict integer coupling of the locomotor and cardiac cycles is unlikely to evolve.

  17. Effects of consuming a diet high in fat and/or sugar on the locomotor effects of acute and repeated cocaine in male and female C57BL/6J mice

    PubMed Central

    Collins, Gregory T.; Chen, Yu; Tschumi, Chris; Rush, Elise L.; Mensah, Ayele; Koek, Wouter; France, Charles P.

    2015-01-01

    Drug abuse and obesity are serious public health problems. Dopamine plays a central role in mediating the reinforcing effects of drugs and food. Prolonged use of drugs is known to alter the function and/or sensitivity of many neurotransmitter systems, including dopamine, however, the impact of consuming foods high in fat and/or sugar is less clear. These studies characterized the locomotor effects of acute and repeated cocaine in male and female C57BL/6J mice consuming one of four diets: (1) standard chow + water; (2) standard chow + 10% sucrose solution; (3) high-fat chow + water; or (4) high-fat chow + 10% sucrose solution. The acute locomotor effects of cocaine (3.2–32.0 mg/kg) were evaluated four weeks after initiating dietary conditions; the effects of repeated cocaine administration were evaluated after 5, 6, 7, and 12 weeks. During acute tests, mice consuming a diet high in fat and/or sucrose exhibited greater locomotor responses to cocaine than mice consuming standard chow and water, regardless of sex. Although diet-induced enhancements persisted across repeated cocaine testing, locomotor sensitization developed more rapidly in females drinking sucrose (and consuming either standard or high-fat chow) than in females consuming standard chow and water. In addition to providing evidence that consuming a diet high in fat and/or sugar enhances abuse-related effects of cocaine in ways that might increase vulnerability to abuse cocaine, these studies identified a potentially important sex-related difference in the interaction between nutrition and cocaine effects, with the impacts of sucrose consumption being greater in females than in males. PMID:26237320

  18. Event-related potential correlates of the extraverts' sensitivity to valence changes in positive stimuli.

    PubMed

    Yuan, Jiajin; He, Yuanyuan; Lei, Yi; Yang, Jiemin; Li, Hong

    2009-08-05

    This study investigated whether the human sensitivity to valence intensity changes in positive stimuli varies with extraversion. Event-related potentials were recorded for highly positive, moderately positive, and neutral stimuli while participants (extraverts and nonextraverts) performed a standard/deviant categorization task, irrespective of the emotionality of deviants. The results of extraverts showed larger P2 and P3 amplitudes during highly positive condition than during moderately positive condition which, in turn, elicited larger P2 than neutral condition. Conversely, nonextraverts showed no differences at both P2 and P3 components. Thus, extraverts, unlike less extraverted individuals, are sensitive to valence changes in positive stimuli, which may be underlain by certain biogenetic mechanism.

  19. Assessment of phototoxicity, skin irritation, and sensitization potential of polystyrene and TiO2 nanoparticles

    NASA Astrophysics Data System (ADS)

    Park, Yoon-Hee; Jeong, Sang Hoon; Yi, Sang Min; Hyeok Choi, Byeong; Kim, Yu-Ri; Kim, In-Kyoung; Kim, Meyoung-Kon; Son, Sang Wook

    2011-07-01

    The human skin equivalent model (HSEM) is well known as an attractive alternative model for evaluation of dermal toxicity. However, only limited data are available on the usefulness of an HSEM for nanotoxicity testing. This study was designed to investigate cutaneous toxicity of polystyrene and TiO2 nanoparticles using cultured keratinocytes, an HSEM, and an animal model. In addition, we also evaluated the skin sensitization potential of nanoparticles using a local lymph node assay with incorporation of BrdU. Findings from the present study indicate that polystyrene and TiO2 nanoparticles do not induce phototoxicity, acute cutaneous irritation, or skin sensitization. Results from evaluation of the HSEMs correspond well with those from animal models. Our findings suggest that the HSEM might be a useful alternative model for evaluation of dermal nanotoxicity.

  20. Sensitivity of potential evapotranspiration to changes in climate variables for different Australian climatic zones

    NASA Astrophysics Data System (ADS)

    Guo, Danlu; Westra, Seth; Maier, Holger R.

    2017-04-01

    Assessing the factors that have an impact on potential evapotranspiration (PET) sensitivity to changes in different climate variables is critical to understanding the possible implications of climatic changes on the catchment water balance. Using a global sensitivity analysis, this study assessed the implications of baseline climate conditions on the sensitivity of PET to a large range of plausible changes in temperature (T), relative humidity (RH), solar radiation (Rs) and wind speed (uz). The analysis was conducted at 30 Australian locations representing different climatic zones, using the Penman-Monteith and Priestley-Taylor PET models. Results from both models suggest that the baseline climate can have a substantial impact on overall PET sensitivity. In particular, approximately 2-fold greater changes in PET were observed in cool-climate energy-limited locations compared to other locations in Australia, indicating the potential for elevated water loss as a result of increasing actual evapotranspiration (AET) in these locations. The two PET models consistently indicated temperature to be the most important variable for PET, but showed large differences in the relative importance of the remaining climate variables. In particular for the Penman-Monteith model, wind and relative humidity were the second-most important variables for dry and humid catchments, respectively, whereas for the Priestley-Taylor model solar radiation was the second-most important variable, with the greatest influence in warmer catchments. This information can be useful to inform the selection of suitable PET models to estimate future PET for different climate conditions, providing evidence on both the structural plausibility and input uncertainty for the alternative models.

  1. Nociceptive-Evoked Potentials Are Sensitive to Behaviorally Relevant Stimulus Displacements in Egocentric Coordinates

    PubMed Central

    Di Stefano, G.; Stubbs, M. T.; Djeugam, B.; Liang, M.

    2016-01-01

    Abstract Feature selection has been extensively studied in the context of goal-directed behavior, where it is heavily driven by top-down factors. A more primitive version of this function is the detection of bottom-up changes in stimulus features in the environment. Indeed, the nervous system is tuned to detect fast-rising, intense stimuli that are likely to reflect threats, such as nociceptive somatosensory stimuli. These stimuli elicit large brain potentials maximal at the scalp vertex. When elicited by nociceptive laser stimuli, these responses are labeled laser-evoked potentials (LEPs). Although it has been shown that changes in stimulus modality and increases in stimulus intensity evoke large LEPs, it has yet to be determined whether stimulus displacements affect the amplitude of the main LEP waves (N1, N2, and P2). Here, in three experiments, we identified a set of rules that the human nervous system obeys to identify changes in the spatial location of a nociceptive stimulus. We showed that the N2 wave is sensitive to: (1) large displacements between consecutive stimuli in egocentric, but not somatotopic coordinates; and (2) displacements that entail a behaviorally relevant change in the stimulus location. These findings indicate that nociceptive-evoked vertex potentials are sensitive to behaviorally relevant changes in the location of a nociceptive stimulus with respect to the body, and that the hand is a particularly behaviorally important site. PMID:27419217

  2. In vitro assessment of skin sensitization, photosensitization and phototoxicity potential of commercial glyphosate-containing formulations.

    PubMed

    de Ávila, Renato Ivan; Teixeira, Gabriel Campos; Veloso, Danillo Fabrini Maciel Costa; Moreira, Larissa Cleres; Lima, Eliana Martins; Valadares, Marize Campos

    2017-04-04

    This study evaluated the applicability of a modified Direct Peptide Reactivity Assay (DPRA) (OECD N° 442C, 2015) through the 10-fold reduction of reaction volume (micro-DPRA, mDPRA) for skin sensitization evaluation of six commercial glyphosate-containing formulations. In addition, another modification of DPRA was proposed by adding a UVA (5J/cm(2)) irradiation step, namely photo-mDPRA, to better characterize (photo)sensitizer materials. The phototoxicity profile of pesticides was also evaluated using the 3T3 Neutral Red Uptake Phototoxicity Test (3T3-NRU-PT) (OECD N° 432, 2004). The mDPRA could represent an environmentally acceptable test approach, since it reduces costs and organic waste. Peptide depletion was greater in photo-mDPRA and changed the reactivity class of each test material, in comparison to mDPRA. Thus, the association of mDPRA with photo-mDPRA was better for correctly characterizing human (photo)sensitizer substances and pesticides. In general, cysteine depletion was greater than that of lysine for all materials tested in both mDPRA and photo-mDPRA. Furthermore, while 3T3-NRU-PT is unable to predict (photo)sensitizers, it was capable of correctly identifying the phototoxic potential of the tested agrochemical formulations. In conclusion, mDPRA plus photo-mDPRA and 3T3-NRU-PT seem to be preliminary non-animal test batteries for skin (photo)sensitization/phototoxicity assessment of chemicals, agrochemical formulations and their ingredients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Effects of pinealectomy on the neuroendocrine reproductive system and locomotor activity in male European sea bass, Dicentrarchus labrax.

    PubMed

    Cowan, Mairi; Paullada-Salmerón, José A; López-Olmeda, José Fernando; Sánchez-Vázquez, Francisco Javier; Muñoz-Cueto, José A

    2017-02-08

    The seasonally changing photoperiod controls the timing of reproduction in most fish species, however, the transduction of this photoperiodic information to the reproductive axis is still unclear. This study explored the potential role of two candidate neuropeptide systems, gonadotropin-inhibitory hormone (Gnih) and kisspeptin, as mediators between the pineal organ (a principle transducer of photoperiodic information) and reproductive axis in male European sea bass, Dicentrarchus labrax. Two seven-day experiments of pinealectomy (Px) were performed, in March (end of reproductive season) and August (resting season). Effects of Px and season on the brain expression of gnih (sbgnih) and its receptor (sbgnihr), kisspeptins (kiss1, kiss2) and their receptors (kissr2, kissr3) and gonadotropin-releasing hormone (gnrh1, gnrh2, gnrh3) and the main brain receptor (gnrhr-II-2b) genes, plasma melatonin levels and locomotor activity rhythms were examined. Results showed that Px reduced night-time plasma melatonin levels. Gene expression analyses demonstrated a sensitivity of the Gnih system to Px in March, with a reduction in sbgnih in the mid-hindbrain, a region with bilateral connections to the pineal organ. In August, kiss2 levels increased in Px animals but not in controls. Significant differences in expression were observed for diencephalic sbgnih, sbgnihr, kissr3 and tegmental gnrh2 between seasons. Recordings of locomotor activity following surgery revealed a change from light-synchronised to free-running rhythmic behavior. Altogether, the Gnih and Kiss2 sensitivity to Px and seasonal differences observed for Gnih and its receptor, Gnrh2, and the receptor for Kiss2 (Kissr3), suggested they could be mediators involved in the relay between environment and seasonal reproduction.

  4. Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: locomotor activity, drug discrimination and self-administration.

    PubMed

    Meyer, A C; Horton, D B; Neugebauer, N M; Wooters, T E; Nickell, J R; Dwoskin, L P; Bardo, M T

    2011-09-01

    Tetrabenazine (TBZ), a benzoquinolizine derivative, binds with high affinity to the vesicular monoamine transporter-2 (VMAT2), inhibiting uptake of cytosolic monoamines. The current study aimed to provide preclinical evidence supporting the potential use of TBZ as a treatment for methamphetamine abuse. Effects of TBZ on function of the dopamine transporter (DAT) and serotonin transporter (SERT) in striatal and hippocampal synaptosomes, respectively, and on VMAT2 function in isolated striatal synaptic vesicles were determined. Effect of TBZ (acute, 0.1-3.0 mg/kg, s.c.; repeated, 1.0 mg/kg for 7 days) on locomotor activity in methamphetamine-sensitized rats was assessed. Ability of TBZ (0.1-3.0 mg/kg; s.c.) or vehicle to decrease the discriminative effect of methamphetamine also was determined. Ability of TBZ (acute, 0.1-1.0 mg/kg, s.c.; repeated, 0.1 or 1.0 mg/kg for 7 days) to specifically decrease methamphetamine self-administration was determined; for comparison, a separate group of rats was assessed for effects of TBZ on food-maintained responding. Results show that TBZ was 11-fold more potent inhibiting DAT than SERT, and 2.5-fold more potent inhibiting VMAT2 than DAT. Results from behavioral studies showed that the lowest dose of TBZ transiently increased methamphetamine self-administration, whereas higher TBZ doses decreased methamphetamine self-administration. Also, TBZ at high doses decreased methamphetamine locomotor sensitization and discriminative stimulus effects, as well as food-maintained responding. Thus, despite acting as a potent VMAT2 inhibitor, these preclinical results indicate that TBZ lacks behavioral specificity as an inhibitor of methamphetamine-induced reinforcement, diminishing its viability as a suitable treatment for methamphetamine abuse. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: Locomotor activity, drug discrimination and self-administration

    PubMed Central

    Meyer, AC; Horton, DB; Neugebauer, NM; Wooters, TE; Nickell, JR; Dwoskin, LP; Bardo, MT

    2013-01-01

    Tetrabenazine (TBZ), a benzoquinolizine derivative, binds with high affinity to the vesicular monoamine transporter-2 (VMAT2), inhibiting uptake of cytosolic monoamines. The current study aimed to provide preclinical evidence supporting the potential use of TBZ as a treatment for methamphetamine abuse. Effects of TBZ on function of the dopamine transporter (DAT) and serotonin transporter (SERT) in striatal and hippocampal synaptosomes, respectively, and on VMAT2 function in isolated striatal synaptic vesicles were determined. Effect of TBZ (acute, 0.1 - 3.0 mg/kg, s.c.; repeated, 1.0 mg/kg for 7 days) on locomotor activity in methamphetamine-sensitized rats was assessed. Ability of TBZ (0.1 -3.0 mg/kg; s.c.) or vehicle to decrease the discriminative effect of methamphetamine also was determined. Ability of TBZ (acute, 0.1 - 1.0 mg/kg, s.c.; repeated, 0.1 or 1.0 mg/kg for 7 days) to specifically decrease methamphetamine self-administration was determined; for comparison, a separate group of rats was assessed for effects of TBZ on food-maintained responding. Results show that TBZ was 11-fold more potent inhibiting DAT than SERT, and 2.5-fold more potent inhibiting VMAT2 than DAT. Results from behavioral studies showed that the lowest dose of TBZ transiently increased methamphetamine self-administration, whereas higher TBZ doses decreased methamphetamine self-administration. Also, TBZ at high doses decreased methamphetamine locomotor sensitization and discriminative stimulus effects, as well as food-maintained responding. Thus, despite acting as a potent VMAT2 inhibitor, these preclinical results indicate that TBZ lacks behavioral specificity as an inhibitor of methamphetamine-induced reinforcement, diminishing its viability as a suitable treatment for methamphetamine abuse. PMID:21669212

  6. Sensitivity of potential evaporation estimates to 100 years of climate variability

    NASA Astrophysics Data System (ADS)

    Bartholomeus, Ruud; Stagge, James; Tallaksen, Lena; Witte, Jan-Philip

    2015-04-01

    Evaporation from the vegetated surface is the largest loss term in many, if not the most, water balance studies on earth. As a consequence, an accurate representation of evaporation fluxes is required for appropriate quantification of surface runoff, the soil moisture budget, transpiration, recharge and groundwater processes. However, despite being a key component of the water balance, evaporation figures are usually associated with large uncertainties, as this term is difficult to measure or estimate by modeling. Many modeling frameworks have used the concept of potential evaporation, often estimated for different vegetation classes by multiplying the evaporation from a reference surface ('reference evaporation') with crop specific scaling factors ('crop factors'). Though this two-step potential evaporation approach undoubtedly has practical advantages, the empirical nature of both reference evaporation methods and crop factors limits its usability in extrapolations under non-stationary climatic conditions. We quantified the sensitivity of potential evaporation estimates for different vegetation classes using the two-step approach when calibrated using a non-stationary climate. We used the past century's time series of observed climate, containing non-stationary signals of multi-decadal atmospheric oscillations, global warming, and global dimming/brightening, to evaluate the sensitivity of potential evaporation estimates to the choice and length of the calibration period. We show that using empirical coefficients outside their calibration range may lead to systematic differences between process-based and empirical reference evaporation methods, and systematic errors in estimated potential evaporation components. Our hydrological models are to varying extent regression models, which limits their general applicability, and the estimation of potential evaporation is closely linked to climate variability. With our analysis, we want to raise awareness and to provide a

  7. Assessing potential impacts associated with contamination events in water distribution systems : a sensitivity analysis.

    SciTech Connect

    Davis, M. J.; Janke, R.; Taxon, T. N.

    2010-11-01

    An understanding of the nature of the adverse effects that could be associated with contamination events in water distribution systems is necessary for carrying out vulnerability analyses and designing contamination warning systems. This study examines the adverse effects of contamination events using models for 12 actual water systems that serve populations ranging from about 104 to over 106 persons. The measure of adverse effects that we use is the number of people who are exposed to a contaminant above some dose level due to ingestion of contaminated tap water. For this study the number of such people defines the impact associated with an event. We consider a wide range of dose levels in order to accommodate a wide range of potential contaminants. For a particular contaminant, dose level can be related to a health effects level. For example, a dose level could correspond to the median lethal dose, i.e., the dose that would be fatal to 50% of the exposed population. Highly toxic contaminants may be associated with a particular response at a very low dose level, whereas contaminants with low toxicity may only be associated with the same response at a much higher dose level. This report focuses on the sensitivity of impacts to five factors that either define the nature of a contamination event or involve assumptions that are used in assessing exposure to the contaminant: (1) duration of contaminant injection, (2) time of contaminant injection, (3) quantity or mass of contaminant injected, (4) population distribution in the water distribution system, and (5) the ingestion pattern of the potentially exposed population. For each of these factors, the sensitivities of impacts to injection location and contaminant toxicity are also examined. For all the factors considered, sensitivity tends to increase with dose level (i.e., decreasing toxicity) of the contaminant, with considerable inter-network variability. With the exception of the population distribution (factor 4

  8. Global bioenergy potentials from agricultural land in 2050: Sensitivity to climate change, diets and yields

    PubMed Central

    Haberl, Helmut; Erb, Karl-Heinz; Krausmann, Fridolin; Bondeau, Alberte; Lauk, Christian; Müller, Christoph; Plutzar, Christoph; Steinberger, Julia K.

    2011-01-01

    There is a growing recognition that the interrelations between agriculture, food, bioenergy, and climate change have to be better understood in order to derive more realistic estimates of future bioenergy potentials. This article estimates global bioenergy potentials in the year 2050, following a “food first” approach. It presents integrated food, livestock, agriculture, and bioenergy scenarios for the year 2050 based on a consistent representation of FAO projections of future agricultural development in a global biomass balance model. The model discerns 11 regions, 10 crop aggregates, 2 livestock aggregates, and 10 food aggregates. It incorporates detailed accounts of land use, global net primary production (NPP) and its human appropriation as well as socioeconomic biomass flow balances for the year 2000 that are modified according to a set of scenario assumptions to derive the biomass potential for 2050. We calculate the amount of biomass required to feed humans and livestock, considering losses between biomass supply and provision of final products. Based on this biomass balance as well as on global land-use data, we evaluate the potential to grow bioenergy crops and estimate the residue potentials from cropland (forestry is outside the scope of this study). We assess the sensitivity of the biomass potential to assumptions on diets, agricultural yields, cropland expansion and climate change. We use the dynamic global vegetation model LPJmL to evaluate possible impacts of changes in temperature, precipitation, and elevated CO2 on agricultural yields. We find that the gross (primary) bioenergy potential ranges from 64 to 161 EJ y−1, depending on climate impact, yields and diet, while the dependency on cropland expansion is weak. We conclude that food requirements for a growing world population, in particular feed required for livestock, strongly influence bioenergy potentials, and that integrated approaches are needed to optimize food and bioenergy supply

  9. Global bioenergy potentials from agricultural land in 2050: Sensitivity to climate change, diets and yields.

    PubMed

    Haberl, Helmut; Erb, Karl-Heinz; Krausmann, Fridolin; Bondeau, Alberte; Lauk, Christian; Müller, Christoph; Plutzar, Christoph; Steinberger, Julia K

    2011-12-01

    There is a growing recognition that the interrelations between agriculture, food, bioenergy, and climate change have to be better understood in order to derive more realistic estimates of future bioenergy potentials. This article estimates global bioenergy potentials in the year 2050, following a "food first" approach. It presents integrated food, livestock, agriculture, and bioenergy scenarios for the year 2050 based on a consistent representation of FAO projections of future agricultural development in a global biomass balance model. The model discerns 11 regions, 10 crop aggregates, 2 livestock aggregates, and 10 food aggregates. It incorporates detailed accounts of land use, global net primary production (NPP) and its human appropriation as well as socioeconomic biomass flow balances for the year 2000 that are modified according to a set of scenario assumptions to derive the biomass potential for 2050. We calculate the amount of biomass required to feed humans and livestock, considering losses between biomass supply and provision of final products. Based on this biomass balance as well as on global land-use data, we evaluate the potential to grow bioenergy crops and estimate the residue potentials from cropland (forestry is outside the scope of this study). We assess the sensitivity of the biomass potential to assumptions on diets, agricultural yields, cropland expansion and climate change. We use the dynamic global vegetation model LPJmL to evaluate possible impacts of changes in temperature, precipitation, and elevated CO(2) on agricultural yields. We find that the gross (primary) bioenergy potential ranges from 64 to 161 EJ y(-1), depending on climate impact, yields and diet, while the dependency on cropland expansion is weak. We conclude that food requirements for a growing world population, in particular feed required for livestock, strongly influence bioenergy potentials, and that integrated approaches are needed to optimize food and bioenergy supply.

  10. Cocaine-induced locomotor activity in rats selectively bred for low and high voluntary running behavior.

    PubMed

    Brown, Jacob D; Green, Caroline L; Arthur, Ian M; Booth, Frank W; Miller, Dennis K

    2015-02-01

    The rewarding effects of physical activity and abused drugs are caused by stimulation of similar brain pathways. Low (LVR) and high (HVR) voluntary running lines were developed by selectively breeding Wistar rats on running distance performance on postnatal days 28-34. We hypothesized that LVR rats would be more sensitive to the locomotor-activating effects of cocaine than HVR rats due to their lower motivation for wheel running. We investigated how selection for LVR or HVR behavior affects inherited activity responses: (a) open field activity levels, (b) habituation to an open field environment, and (c) the locomotor response to cocaine. Open field activity was measured for 80 min on three successive days (days 1-3). Data from the first 20 min were analyzed to determine novelty-induced locomotor activity (day 1) and the habituation to the environment (days 1-3). On day 3, rats were acclimated to the chamber for 20 min and then received saline or cocaine (10, 20, or 30 mg/kg) injection. Dopamine transporter (DAT) protein in the nucleus accumbens was measured via Western blot. Selecting for low and high voluntary running behavior co-selects for differences in inherent (HVR > LVR) and cocaine-induced (LVR > HVR) locomotor activity levels. The differences in the selected behavioral measures do not appear to correlate with DAT protein levels. LVR and HVR rats are an intriguing physical activity model for studying the interactions between genes related to the motivation to run, to use drugs of abuse, and to exhibit locomotor activity.

  11. Iridium Oxide Nanotube Electrodes for Highly Sensitive and Prolonged Intracellular Measurement of Action Potentials

    PubMed Central

    Lin, Ziliang Carter; Xie, Chong; Osakada, Yasuko; Cui, Yi; Cui, Bianxiao

    2014-01-01

    Intracellular recording of action potentials is important to understand electrically-excitable cells. Recently, vertical nanoelectrodes have been developed to achieve highly sensitive, minimally invasive, and large scale intracellular recording. It has been demonstrated that the vertical geometry is crucial for the enhanced signal detection. Here we develop nanoelectrodes made up of nanotubes of iridium oxide. When cardiomyocytes are cultured upon those nanotubes, the cell membrane not only wraps around the vertical tubes but also protrudes deep into the hollow center. We show that this geometry enhances cell-electrode coupling and results in measuring much larger intracellular action potentials. The nanotube electrodes afford much longer intracellular access and are minimally invasive, making it possible to achieve stable recording up to an hour in a single session and more than 8 days of consecutive daily recording. This study suggests that the electrode performance can be significantly improved by optimizing the electrode geometry. PMID:24487777

  12. The GABAB agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine.

    PubMed

    Bartoletti, M; Gubellini, C; Ricci, F; Gaiardi, M

    2004-09-01

    The purpose of the present study was to test the possible influence of baclofen, a GABAB agonist, on the long-term sensitisation to amphetamine in rats. As expected, chronic amphetamine treatment (1.5 mg/kg i.p. daily for 10 days) led to an increased locomotor response to amphetamine (0.75 mg/kg i.p.), when the animals were challenged 20 days after the end of repeated treatment. Baclofen (2 mg/kg i.p.), administered before the test session, did not significantly modify the spontaneous locomotor activity of rats, but decreased the normal and, to a greater extent, the sensitised locomotor response to amphetamine; thus baclofen prevented the expression of sensitisation to amphetamine. Moreover a previous chronic treatment with baclofen (2 mg/kg i.p. daily for 10 days) attenuated the amphetamine-induced locomotor activity in sensitised, but not in control animals. This effect was observed 20 days after the last baclofen administration. In conclusion, the present results demonstrate that GABAB receptors play an important role in the expression of the sensitised behavioural response to amphetamine and further support a potential role of GABAB agonists in the treatment of psychostimulant addiction.

  13. Low and High Locomotor Responsiveness to Cocaine Predicts Intravenous Cocaine Conditioned Place Preference in Male Sprague-Dawley Rats

    PubMed Central

    Allen, Richard M.; Everett, Carson V.; Nelson, Anna M.; Gulley, Joshua M.; Zahniser, Nancy R.

    2009-01-01

    Outbred, male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine’s ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice daily over four days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague-Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward. PMID:17250883

  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. On understanding the relationship between structure in the potential surface and observables in classical dynamics: A functional sensitivity analysis approach

    NASA Astrophysics Data System (ADS)

    Judson, Richard S.; Rabitz, Herschel

    1987-04-01

    The relationship between structure in the potential surface and classical mechanical observables is examined by means of functional sensitivity analysis. Functional sensitivities provide maps of the potential surface, highlighting those regions that play the greatest role in determining the behavior of observables. A set of differential equations for the sensitivities of the trajectory components are derived. These are then solved using a Green's function method. It is found that the sensitivities become singular at the trajectory turning points with the singularities going as η-3/2, with η being the distance from the nearest turning point. The sensitivities are zero outside of the energetically and dynamically allowed region of phase space. A second set of equations is derived from which the sensitivities of observables can be directly calculated. An adjoint Green's function technique is employed, providing an efficient method for numerically calculating these quantities. Sensitivity maps are presented for a simple collinear atom-diatom inelastic scattering problem and for two Henon-Heiles type Hamiltonians modeling intramolecular processes. It is found that the positions of the trajectory caustics in the bound state problem determine regions of the highest potential surface sensitivities. In the scattering problem (which is impulsive, so that ``sticky'' collisions did not occur), the positions of the turning points of the individual trajectory components determine the regions of high sensitivity. In both cases, these lines of singularities are superimposed on a rich background structure. Most interesting is the appearance of classical interference effects. The interference features in the sensitivity maps occur most noticeably where two or more lines of turning points cross. The important practical motivation for calculating the sensitivities derives from the fact that the potential is a function, implying that any direct attempt to understand how local

  16. Sensitizing potential of enzymatically cross-linked peanut proteins in a mouse model of peanut allergy.

    PubMed

    Radosavljevic, Jelena; Nordlund, Emilia; Mihajlovic, Luka; Krstic, Maja; Bohn, Torsten; Buchert, Johanna; Velickovic, Tanja Cirkovic; Smit, Joost

    2014-03-01

    The cross-linking of proteins by enzymes to form high-molecular-weight protein, aggregates can be used to tailor the technological or physiological functionality of food products. Aggregation of dietary proteins by food processing may promote allergic sensitization, but the effects of enzymatic cross-linking of dietary proteins on the allergenic potential of food are not known. In this study, the bioavailability and the sensitizing or tolerizing potential of peanut proteins (PE) cross-linked with microbial tyrosinase from Trichoderma reesei and mushroom tyrosinase from Agaricus bisporus, were investigated. The impact of cross-linking of PE on the in vitro bioavailability of fluorescein isothiocyanate-labeled peanut proteins was tested in a Caco-2 cell monolayer and by competitive ELISA. The in vivo allergenicity or capacity to induce oral tolerance in mice were measured by serum levels of PE-specific antibodies and T cell cytokine production after exposure to PE and cross-linked PE. Enzymatic processing of peanut proteins by the two tyrosinases increased the bioavailability of major peanut allergen Ara h 2, but did not significantly change the allergenic or tolerizing properties of peanut. Enzymatic treatment of peanut proteins yielded cross-linked proteins with preserved molecular and immunological features of peanut allergens. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Detection of potentially skin sensitizing hydroperoxides of linalool in fragranced products.

    PubMed

    Kern, Susanne; Dkhil, Hafida; Hendarsa, Prisca; Ellis, Graham; Natsch, Andreas

    2014-10-01

    On prolonged exposure to air, linalool can form sensitizing hydroperoxides. Positive hydroperoxide patch tests in dermatitis patients have frequently been reported, but their relevance has not been established. Owing to a lack of analytical methods and data, it is unclear from which sources the public might be exposed to sufficient quantities of hydroperoxides for induction of sensitization to occur. To address this knowledge gap, we developed analytical methods and performed stability studies for fine fragrances and deodorants/antiperspirants. In parallel, products recalled from consumers were analysed to investigate exposure to products used in everyday life. Liquid chromatography-mass spectrometry with high mass resolution was found to be optimal for the selective and sensitive detection of the organic hydroperoxide in the complex product matrix. Linalool hydroperoxide was detected in natural linalool, but the amount was not elevated by storage in a perfume formulation exposed to air. No indication of hydroperoxide formation in fine fragrances was found in stability studies. Aged fine fragrances recalled from consumers contained a geometric mean linalool concentration of 1,888 μg/g and, corrected for matrix effects, linalool hydroperoxide at a concentration of around 14 μg/g. In antiperspirants, we detected no oxidation products. In conclusion, very low levels of linalool hydroperoxide in fragranced products may originate from raw materials, but we found no evidence for oxidation during storage of products. The levels detected are orders of magnitude below the levels inducing sensitization in experimental animals, and these results therefore do not substantiate a causal link between potential hydroperoxide formation in cosmetics and positive results of patch tests.

  18. The GOES-R Advanced Baseline Imager: polarization sensitivity and potential impacts

    NASA Astrophysics Data System (ADS)

    Pearlman, Aaron J.; Cao, Changyong; Wu, Xiangqian

    2015-09-01

    In contrast to the National Oceanic and Atmospheric Administration's (NOAA's) current geostationary imagers for operational weather forecasting, the next generation imager, the Advanced Baseline Imager (ABI) aboard the Geostationary Operational Environmental Satellite R-Series (GOES-R), will have six reflective solar bands - five more than currently available. These bands will be used for applications such as aerosol retrievals, which are influenced by polarization effects. These effects are determined by two factors: instrument polarization sensitivity and the polarization states of the observations. The former is measured as part of the pre-launch testing program performed by the instrument vendor. We analyzed the results of the pre-launch polarization sensitivity measurements of the 0.47 μm and 0.64 μm channels and used them in conjunction with simulated scene polarization states to estimate potential on-orbit radiometric impacts. The pre-launch test setups involved illuminating the ABI with an integrating sphere through either one or two polarizers. The measurement with one (rotating) polarizer yields the degree of linear polarization of ABI, and the measurements using two polarizers (one rotating and one fixed) characterized the non-ideal properties of the polarizer. To estimate the radiometric performance impacts from the instrument polarization sensitivity, we simulated polarized scenes using a radiative transfer code and accounted for the instrument polarization sensitivity over its field of regard. The results show the variation in the polarization impacts over the day and by regions of the full disk can reach up to 3.2% for the 0.47μm channel and 4.8% for the 0.64μm channel. Geostationary orbiters like the ABI give the unique opportunity to show these impacts throughout the day compared to low earth orbiters, which are more limited to certain times of day. This work may enhance the ability to diagnose anomalies on-orbit.

  19. Potential evaporation estimation through an unstressed surface energy balance and its sensitivity to climate change

    NASA Astrophysics Data System (ADS)

    Barella-Ortiz, A.; Polcher, J.; Tuzet, A.; Laval, K.

    2013-06-01

    Potential evaporation (ETP) is a basic input for hydrological and agronomic models, as well as a key variable in most actual evaporation estimations. It has been approached through several diffusive and energy balance methods, out of which the Penman-Monteith equation is recommended as the standard one. In order to deal with the diffusive approach, ETP must be estimated at a sub-diurnal frequency, as currently done in land surface models (LSM). This study presents an improved method, developed in the ORCHIDEE LSM, which consists in estimating ETP through an unstressed surface energy balance (USEB method). The results confirm the quality of the estimation which is currently implemented in the model (Milly, 1992). ETP has also been estimated using a reference equation (computed at a daily time step) provided by the Food and Agriculture Organization (FAO). First, a comparison for a reference period under current climate conditions, shows that both formulations differ, specially in arid areas. However, they supply similar values when FAO's assumption of neutral stability conditions is relaxed, by replacing FAO's aerodynamic resistance by the model's one. Furthermore, if the vapour pressure deficit (VPD) estimated for FAO's equation, is substituted by ORCHIDEE's VPD or its humidity gradient, the daily mean estimate is further improved. In a second step, ETP's sensitivity to climate change is assessed comparing trends in both formulations for the 21st Century. It is found that the USEB method shows a higher sensitivity. Both VPD and the model's humidity gradient, as well as the aerodynamic resistance have been identified as key parameters in governing ETP trends. Finally, the sensitivity study is extended to three empirical approximations based on temperature, net radiation and mass transfer (Hargreaves, Priestley-Taylor and Rohwer, respectively). The sensitivity of these methods is compared to the USEB method's one to test if simplified equations are able to reproduce

  20. Estradiol Sensitizes the Transient Receptor Potential Vanilloid 1 Receptor in Pain Responses.

    PubMed

    Payrits, Maja; Sághy, Éva; Cseko, Kata; Pohóczky, Krisztina; Bölcskei, Kata; Ernszt, Dávid; Barabás, Klaudia; Szolcsányi, János; Ábrahám, István M; Helyes, Zsuzsanna; Szoke, Éva

    2017-10-01

    Sex differences exist in chronic pain pathologies, and gonadal estradiol (E2) alters the pain sensation. The nocisensor transient receptor potential vanilloid 1 (TRPV1) receptor plays a critical role in triggering pain. Here we examined the impact of E2 on the function of TRPV1 receptor in mice sensory neurons in vitro and in vivo. Both mechano- and thermonociceptive thresholds of the plantar surface of the paw of female mice were significantly lower in proestrus compared with the estrus phase. These thresholds were higher in ovariectomized (OVX) mice and significantly lower in sham-operated mice in proestrus compared with the sham-operated mice in estrus phase. This difference was absent in TRPV1 receptor-deficient mice. Furthermore, E2 potentiated the TRPV1 receptor activation-induced mechanical hyperalgesia in OVX mice. Long pretreatment (14 hours) with E2 induced a significant increase in TRPV1 receptor messenger RNA expression and abolished the capsaicin-induced TRPV1 receptor desensitization in primary sensory neurons. The short E2 incubation (10 minutes) also prevented the desensitization, which reverted after coadministration of E2 and the tropomyosin-related kinase A (TrkA) receptor inhibitor. Our study provides in vivo and in vitro evidence for E2-induced TRPV1 receptor upregulation and sensitization mediated by TrkAR via E2-induced genomic and nongenomic mechanisms. The sensitization and upregulation of TRPV1 receptor by E2 in sensory neurons may explain the greater pain sensitivity in female mice. Copyright © 2017 Endocrine Society.

  1. [Discovery of potential ATP-sensitive potassium channel openers with potential hypotensive activity from Chinese herbs based on molecular simulation].

    PubMed

    Li, Yong; Jiang, Lu-di; Chen, Xi; He, Yu-Su; Li, Gong-Yu; Zhang, Yan-Ling

    2016-01-01

    In this research, a combined method of ligand-based pharmacophore (LBP), structure-based pharmacophore (SBP), and molecular docking was applied for virtual screening potential ATP-sensitive potassium channel (KATP) openers from Chinese herbs. LBP models were generated by 3D-QSAR pharmacophore(hypogen) program, based on the training set composed of 48 KATP agonists. The best LBP model consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one hydrophobic feature, one aromatic ring and five excluded volumes. Besides, the correlation coefficient of training set and test set, N, and CAI value of the model were 0.876 4, 0.705 8, 3.304, and 2.616 respectively. Meanwhile, SBP models were also generated based on a 3D structure of KATP (PMID: PM0079770). The best SBP model consisted of six hydrogen-bond acceptors, eight hydrogen-bond donors, seven hydrophobic features and eighteen excluded volumes. The corresponding N and CAI value were 2.200 and 2.017. Then, the best LBP model and SBP model were applied to identify potential KATP openers from Traditional Chinese Medicine Database(TCMD), respectively. 349 hits were obtained after analyzed by drug-likeness rules. Moreover, 12 compounds with high docking scores were reserved after molecular docking evaluation. Interestingly, part of the results had been verified as hypotensive active ingredients by literatures. Therefore, this study uncovers a specific target effect contained in TCMD, and provides candidates for new KATP openers' research. Copyright© by the Chinese Pharmaceutical Association.

  2. Locomotor behaviour of Blattella germanica modified by DEET.

    PubMed

    Sfara, Valeria; Mougabure-Cueto, Gastón A; Zerba, Eduardo N; Alzogaray, Raúl A

    2013-01-01

    N,N-diethyl-3-methylbenzamide (DEET) is the active principle of most insect repellents used worldwide. However, its toxicity on insects has not been widely studied. The aim of this work is to study the effects of DEET on the locomotor activity of Blattella germanica. DEET has a dose-dependent repellent activity on B. germanica. Locomotor activity was significantly lower when insects were pre-exposed to 700 µg/cm(2) of DEET for 20 or 30 minutes, but it did not change when pre-exposure was shorter. Locomotor activity of insects that were pre-exposed to 2.000 µg/cm(2) of DEET for 10 minutes was significantly lower than the movement registered in controls. No differences were observed when insects were pre-exposed to lower concentrations of DEET. A 30-minute pre-exposure to 700 µg/cm(2) of DEET caused a significant decrease in locomotor activity. Movement was totally recovered 24 h later. The locomotor activity measured during the exposure to different concentrations of DEET remained unchanged. Insects with decreased locomotor activity were repelled to the same extent than control insects by the same concentration of DEET. We demonstrated that the repellency and modification of locomotor activity elicited by DEET are non-associated phenomena. We also suggested that the reduction in locomotor activity indicates toxicity of DEET, probably to insect nervous system.

  3. Locomotor Behaviour of Blattella germanica Modified by DEET

    PubMed Central

    Sfara, Valeria; Mougabure-Cueto, Gastón A.; Zerba, Eduardo N.; Alzogaray, Raúl A.

    2013-01-01

    N,N-diethyl-3-methylbenzamide (DEET) is the active principle of most insect repellents used worldwide. However, its toxicity on insects has not been widely studied. The aim of this work is to study the effects of DEET on the locomotor activity of Blattella germanica. DEET has a dose-dependent repellent activity on B. germanica. Locomotor activity was significantly lower when insects were pre-exposed to 700 µg/cm2 of DEET for 20 or 30 minutes, but it did not change when pre-exposure was shorter. Locomotor activity of insects that were pre-exposed to 2.000 µg/cm2 of DEET for 10 minutes was significantly lower than the movement registered in controls. No differences were observed when insects were pre-exposed to lower concentrations of DEET. A 30-minute pre-exposure to 700 µg/cm2 of DEET caused a significant decrease in locomotor activity. Movement was totally recovered 24 h later. The locomotor activity measured during the exposure to different concentrations of DEET remained unchanged. Insects with decreased locomotor activity were repelled to the same extent than control insects by the same concentration of DEET. We demonstrated that the repellency and modification of locomotor activity elicited by DEET are non-associated phenomena. We also suggested that the reduction in locomotor activity indicates toxicity of DEET, probably to insect nervous system. PMID:24376701

  4. Evaluation of furfuryl alcohol sensitization potential following dermal and pulmonary exposure: enhancement of airway responsiveness.

    PubMed

    Franko, Jennifer; Jackson, Laurel G; Hubbs, Ann; Kashon, Michael; Meade, B J; Anderson, Stacey E

    2012-01-01

    Furfuryl alcohol is considered by the U.S. Environmental Protection Agency to be a high volume production chemical, with over 1 million pounds produced annually. Due to its high production volume and its numerous industrial and consumer uses, there is considerable potential for work-related exposure, as well as exposure to the general population, through pulmonary, oral, and dermal routes of exposure. Human exposure data report a high incidence of asthma in foundry mold workers exposed to furan resins, suggesting potential immunologic effects. Although furfuryl alcohol was nominated and evaluated for its carcinogenic potential by the National Toxicology Program, studies evaluating its immunotoxicity are lacking. The studies presented here evaluated the immunotoxic potential of furfuryl alcohol following exposure by the dermal and pulmonary routes using a murine model. When tested in a combined irritancy local lymph node assay, furfuryl alcohol was identified to be an irritant and mild sensitizer (EC3 = 25.6%). Pulmonary exposure to 2% furfuryl alcohol resulted in enhanced airway hyperreactivity, eosinophilic infiltration into the lungs, and enhanced cytokine production (IL-4, IL-5, and interferon-γ) by ex vivo stimulated lung-associated draining lymphoid cells. Airway hyperreactivity and eosinophilic lung infiltration were augmented by prior dermal exposure to furfuryl alcohol. These results suggest that furfuryl alcohol may play a role in the development of allergic airway disease and encourage the need for additional investigation.

  5. Pelvic Breadth and Locomotor Kinematics in Human Evolution.

    PubMed

    Gruss, Laura Tobias; Gruss, Richard; Schmitt, Daniel

    2017-04-01

    A broad pelvis is characteristic of most, if not all, pre-modern hominins. In at least some early australopithecines, most notably the female Australopithecus afarensis specimen known as "Lucy," it is very broad and coupled with very short lower limbs. In 1991, Rak suggested that Lucy's pelvic anatomy improved locomotor efficiency by increasing stride length through rotation of the wide pelvis in the axial plane. Compared to lengthening strides by increasing flexion and extension at the hips, this mechanism could avoid potentially costly excessive vertical oscillations of the body's center of mass (COM). Here, we test this hypothesis. We examined 3D kinematics of walking at various speeds in 26 adult subjects to address the following questions: Do individuals with wider pelves take longer strides, and do they use a smaller degree of hip flexion and extension? Is pelvic rotation greater in individuals with shorter legs, and those with narrower pelves? Our results support Rak's hypothesis. Subjects with wider pelves do take longer strides for a given velocity, and for a given stride length they flex and extend their hips less, suggesting a smoother pathway of the COM. Individuals with shorter legs do use more pelvic rotation when walking, but pelvic breadth was not related to pelvic rotation. These results suggest that a broad pelvis could benefit any bipedal hominin, but especially a short-legged australopithecine such as Lucy, by improving locomotor efficiency, particularly when carrying an infant or traveling in a foraging group with individuals of varying sizes. Anat Rec, 300:739-751, 2017. © 2017 Wiley Periodicals, Inc.

  6. Transition from ethanol-induced sensitization to tolerance across early and late infancy in the rat.

    PubMed

    Castello, Stefania; D'Aloisio, Genesis; Arias, Carlos; Molina, Juan Carlos

    Drugs of abuse, as cocaine or amphetamine, induce locomotor sensitization during infancy and adulthood of the rat. This effect during the preweanling period is observed only after a short interval of time between training and testing. We recently reported short-term locomotor sensitization induced by ethanol in pups chronically exposed to the drug during the second postnatal week of life. The present series of experiments was designed to explore the persistence of the sensitization effect across the preweanling period. Pups were chronically exposed to ethanol in five consecutive days during the second or the third postnatal weeks, and their locomotor activity was evaluated in an open field 3, 8 or 15days later. Our results showed that, contrarily to what has been observed with other drugs during infancy, sensitization to ethanol persisted at least 8days in rats exposed to the drug during the second postnatal week. Surprisingly, in older pups, the same procedure induced tolerance instead sensitization. This ontogenetic model offers a potentially interesting tool for studying within the same species, how tolerance and sensitization are interrelated, and how these effects affect ethanol-mediated reinforcement and ethanol intake during ontogeny.

  7. Loss of cocaine locomotor response in Pitx3-deficient mice lacking a nigrostriatal pathway.

    PubMed

    Beeler, Jeff A; Cao, Zhen Fang Huang; Kheirbek, Mazen A; Zhuang, Xiaoxi

    2009-04-01

    Both the dorsal and ventral striatum have been demonstrated to have a critical role in reinforcement learning and addiction. Dissecting the specific function of these striatal compartments and their associated nigrostriatal and mesoaccumbens dopamine pathways, however, has proved difficult. Previous studies using lesions to isolate the contribution of nigrostriatal and mesoaccumbens dopamine in mediating the locomotor and reinforcing effects of psychostimulant drugs have yielded inconsistent and inconclusive results. Using a naturally occurring mutant mouse line, aphakia, that lacks a nigrostriatal dopamine pathway but retains an intact mesoaccumbens pathway, we show that the locomotor activating effects of cocaine, including locomotor sensitization, are dependent on an intact nigrostriatal dopamine projection. In contrast, cocaine reinforcement, as measured by conditioned place preference and cocaine sensitization of sucrose preference, is intact in these mice. In light of the well-established role of the nucleus accumbens in mediating the effects of psychostimulants, these data suggest that the nigrostriatal pathway can act as a critical effector mechanism for the nucleus accumbens highlighting the importance of intrastriatal connectivity and providing insight into the functional architecture of the striatum.

  8. Integrated Locomotor Function Tests for Countermeasure Evaluation

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Mulavara, A. P.; Peters, B. T.; Cohen, H. S.; Landsness, E. C.; Black, F. O.

    2005-01-01

    Following spaceflight crewmembers experience locomotor dysfunction due to inflight adaptive alterations in sensorimotor function. Countermeasures designed to mitigate these postflight gait alterations need to be assessed with a new generation of tests that evaluate the interaction of various sensorimotor sub-systems central to locomotor control. The goal of the present study was to develop new functional tests of locomotor control that could be used to test the efficacy of countermeasures. These tests were designed to simultaneously examine the function of multiple sensorimotor systems underlying the control of locomotion and be operationally relevant to the astronaut population. Traditionally, gaze stabilization has been studied almost exclusively in seated subjects performing target acquisition tasks requiring only the involvement of coordinated eye-head movements. However, activities like walking involve full-body movement and require coordination between lower limbs and the eye-head-trunk complex to achieve stabilized gaze during locomotion. Therefore the first goal of this study was to determine how the multiple, interdependent, full-body sensorimotor gaze stabilization subsystems are functionally coordinated during locomotion. In an earlier study we investigated how alteration in gaze tasking changes full-body locomotor control strategies. Subjects walked on a treadmill and either focused on a central point target or read numeral characters. We measured: temporal parameters of gait, full body sagittal plane segmental kinematics of the head, trunk, thigh, shank and foot, accelerations along the vertical axis at the head and the shank, and the vertical forces acting on the support surface. In comparison to the point target fixation condition, the results of the number reading task showed that compensatory head pitch movements increased, peak head acceleration was reduced and knee flexion at heel-strike was increased. In a more recent study we investigated the

  9. Locomotor training: experiencing the changing body.

    PubMed

    Hannold, Elizabeth M; Young, Mary Ellen; Rittman, Maude R; Bowden, Mark G; Behrman, Andrea L

    2006-01-01

    This study examined the experiences of persons with incomplete spinal cord injury who participated in loco-motor training (LT). LT is an emerging rehabilitation intervention for enhancing the recovery of walking in persons with central nervous system disorders. Multiple interviews and field observations provided data from eight participants, including four veterans. Findings indicate that experiences of bodily changes were prevalent among participants. Themes included (1) experiencing impaired or absent proprioception, (2) struggling for bodily control, and (3) experiencing emergent bodily sensations. Themes 1 and 2 reflected bodily disruption as a result of spinal cord injury and were challenging to participants as they attempted to reconnect the body and self through LT. Theme 3 reflected bodily sensations (burning, soreness) that were seen as positive signs of recovery and resulted in hope and motivation. Understanding how LT participants experience bodily changes may enable therapists to develop improved participant-centered intervention approaches.

  10. Sensitive bromine-based screening of potential toxic furanoids in Dioscorea bulbifera L.

    PubMed

    Zhang, Zhengyu; Lin, Dongju; Li, Weiwei; Gao, Huiyuan; Peng, Ying; Zheng, Jiang

    2017-07-01

    Numerous furanoids have been reported to be toxic, and many of them were found in herbal medicines. Toxicities of furanoids are suggested to result from the generation of cis-enedials via biotransformation. The detection of the electrophilic metabolic intermediates is a challenge. Earlier, we developed a selective approach to screen potential toxic furanoids, through which we found two major furanoids, diosbulbin B and 8-epidiosbulbin E acetate, in Dioscorea bulbifera L., a known furanoid-containing and hepatotoxic herbal medicine. In the present study, we improved the approach to analyze furanoids in D. bulbifera L., which allowed us to detect additional six potential furanoids, including diosbulbin A, diosbulbin D, diosbulbin E, diosbulbin F, diosbulbin M, and diosbulbin D glycoside. The achievements of this study enhanced the sensitivity to screen potential toxic furanoids through elevating S/N values by approximately 3 times. This will facilitate the understanding of mechanisms of toxic actions of D. bulbifera L. and other furanoid-containing toxic herbal medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. KSper, a pH-sensitive K+ current that controls sperm membrane potential

    PubMed Central

    Navarro, Betsy; Kirichok, Yuriy; Clapham, David E.

    2007-01-01

    Mature mammalian spermatozoa are quiescent in the male reproductive tract. Upon ejaculation and during their transit through the female reproductive tract, they undergo changes that enable them to fertilize the egg. During this process of capacitation, they acquire progressive motility, develop hyperactivated motility, and are readied for the acrosome reaction. All of these processes are regulated by intracellular pH. In the female reproductive tract, the spermatozoan cytoplasm alkalinizes, which in turn activates a Ca2+-selective current (ICatSper) required for hyperactivated motility. Here, we show that alkalinization also has a dramatic effect on membrane potential, producing a rapid hyperpolarization. This hyperpolarization is primarily mediated by a weakly outwardly rectifying K+ current (IKSper) originating from the principal piece of the sperm flagellum. Alkalinization activates the pHi-sensitive IKSper, setting the membrane potential to negative potentials where Ca2+ entry via ICatSper is maximized. IKSper is one of two dominant ion currents of capacitated sperm cells. PMID:17460039

  12. Semicarbazide-sensitive amine oxidase substrates potentiate hydralazine hypotension: possible role of hydrogen peroxide.

    PubMed

    Vidrio, Horacio; Medina, Martha; González-Romo, Pilar; Lorenzana-Jiménez, Marte; Díaz-Arista, Patricia; Baeza, Alejandro

    2003-11-01

    The relation between inhibition of semicarbazide-sensitive amine oxidase (SSAO) and vasodilation by hydralazine (HYD) was evaluated in chloralose/urethane-anesthetized rats pretreated with various substrates of the enzyme and subsequently administered a threshold hypotensive dose of the vasodilator. The SSAO substrates benzylamine, phenethylamine, and methylamine potentiate the hypotensive response to HYD. Methylamine, which was studied in greater detail because of its status as a possible endogenous SSAO substrate, does not influence the response to the reference vasodilator pinacidil; it does enhance HYD relaxation in aortic rings obtained from pretreated rats. Experiments designed to identify the product of SSAO activity responsible for potentiation by methylamine suggest involvement of hydrogen peroxide (H2O2), as evidenced by the findings that such potentiation is abolished by additional pretreatment with the H2O2-metabolizing enzyme catalase, and that the plasma concentration of H2O2 is increased by methylamine and decreased by HYD. These results are interpreted as a substantiation of the relation between the known SSAO inhibitory effect of HYD and its vasodilator activity. Pretreatment with the SSAO substrates would increase production of H2O2 in vascular smooth muscle and thus magnify the influence of this vasoconstrictor agent on vascular tone. In these conditions, the decrease in H2O2 production and hence in vascular tone caused by SSAO inhibition by HYD would also be magnified. It is speculated that inhibition of vascular SSAO could represent a novel mechanism of vasodilation.

  13. The influence of locomotor rehabilitation on module quality and post-stroke hemiparetic walking performance.

    PubMed

    Routson, Rebecca L; Clark, David J; Bowden, Mark G; Kautz, Steven A; Neptune, Richard R

    2013-07-01

    Recent studies have suggested the biomechanical subtasks of walking can be produced by a reduced set of co-excited muscles or modules. Individuals post-stroke often exhibit poor inter-muscular coordination characterized by poor timing and merging of modules that are normally independent in healthy individuals. However, whether locomotor therapy can influence module composition and timing and whether these improvements lead to improved walking performance is unclear. The goal of this study was to examine the influence of a locomotor rehabilitation therapy on module composition and timing and post-stroke hemiparetic walking performance. Twenty-seven post-stroke hemiparetic subjects participated in a 12-week locomotor intervention incorporating treadmill training with body weight support and manual trainers accompanied by training overground walking. Electromyography (EMG), kinematic and ground reaction force data were collected from subjects both pre- and post-therapy and from 19 age-matched healthy controls walking on an instrumented treadmill at their self-selected speed. Non-negative matrix factorization was used to identify the module composition and timing from the EMG data. Module timing and composition, and various measures of walking performance were compared pre- and post-therapy. In subjects with four modules pre- and post-therapy, locomotor training resulted in improved timing of the ankle plantarflexor module and a more extended paretic leg angle that allowed the subjects to walk faster and with more symmetrical propulsion. In addition, subjects with three modules pre-therapy increased their number of modules and improved walking performance post-therapy. Thus, locomotor training has the potential to influence module composition and timing, which can lead to improvements walking performance. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. The Influence of Locomotor Rehabilitation on Module Quality and Post-Stroke Hemiparetic Walking Performance

    PubMed Central

    Routson, Rebecca L.; Clark, David J.; Bowden, Mark G.; Kautz, Steven A.; Neptune, Richard R.

    2013-01-01

    Recent studies have suggested the biomechanical subtasks of walking can be produced by a reduced set of co-excited muscles or modules. Individuals post-stroke often exhibit poor inter-muscular coordination characterized by poor timing and merging of modules that are normally independent in healthy individuals. However, whether locomotor therapy can influence module composition and timing and whether these improvements lead to improved walking performance is unclear. The goal of this study was to examine the influence of a locomotor rehabilitation therapy on module composition and timing and post-stroke hemiparetic walking performance. Twenty-eight post-stroke hemiparetic subjects participated in a 12-week locomotor intervention incorporating treadmill training with body weight support and manual trainers accompanied by training overground walking. Electromyography (EMG), kinematic and ground reaction force data were collected from subjects both pre- and post-therapy and from 19 age-matched healthy controls walking on an instrumented treadmill at their self-selected speed. Non-negative matrix factorization was used to identify the module composition and timing from the EMG data. Module timing and composition, and various measures of walking performance were compared pre- and post-therapy. In subjects with four modules pre- and post-therapy, locomotor training resulted in improved timing of the ankle plantarflexor module and a more extended paretic leg angle that allowed the subjects to walk faster and with more symmetrical propulsion. In addition, subjects with three modules pre-therapy increased their number of modules and improved walking performance post-therapy. Thus, locomotor training has the potential to influence module composition and timing, which can lead to improvements walking performance. PMID:23489952

  15. Functional Reorganization of the Locomotor Network in Parkinson Patients with Freezing of Gait

    PubMed Central

    Fling, Brett W.; Cohen, Rajal G.; Mancini, Martina; Carpenter, Samuel D.; Fair, Damien A.; Nutt, John G.; Horak, Fay B.

    2014-01-01

    Freezing of gait (FoG) is a transient inability to initiate or maintain stepping that often accompanies advanced Parkinson’s disease (PD) and significantly impairs mobility. The current study uses a multimodal neuroimaging approach to assess differences in the functional and structural locomotor neural network in PD patients with and without FoG and relates these findings to measures of FoG severity. Twenty-six PD patients and fifteen age-matched controls underwent resting-state functional magnetic resonance imaging and diffusion tensor imaging along with self-reported and clinical assessments of FoG. After stringent movement correction, fifteen PD patients and fourteen control participants were available for analysis. We assessed functional connectivity strength between the supplementary motor area (SMA) and the following locomotor hubs: 1) subthalamic nucleus (STN), 2) mesencephalic and 3) cerebellar locomotor region (MLR and CLR, respectively) within each hemisphere. Additionally, we quantified structural connectivity strength between locomotor hubs and assessed relationships with metrics of FoG. FoG+ patients showed greater functional connectivity between the SMA and bilateral MLR and between the SMA and left CLR compared to both FoG− and controls. Importantly, greater functional connectivity between the SMA and MLR was positively correlated with i) clinical, ii) self-reported and iii) objective ratings of freezing severity in FoG+, potentially reflecting a maladaptive neural compensation. The current findings demonstrate a re-organization of functional communication within the locomotor network in FoG+ patients whereby the higher-order motor cortex (SMA) responsible for gait initiation communicates with the MLR and CLR to a greater extent than in FoG− patients and controls. The observed pattern of altered connectivity in FoG+ may indicate a failed attempt by the CNS to compensate for the loss of connectivity between the STN and SMA and may reflect a loss

  16. Sensitivity analysis and parameter estimation for distributed hydrological modeling: potential of variational methods

    NASA Astrophysics Data System (ADS)

    Castaings, W.; Dartus, D.; Le Dimet, F.-X.; Saulnier, G.-M.

    2009-04-01

    Variational methods are widely used for the analysis and control of computationally intensive spatially distributed systems. In particular, the adjoint state method enables a very efficient calculation of the derivatives of an objective function (response function to be analysed or cost function to be optimised) with respect to model inputs. In this contribution, it is shown that the potential of variational methods for distributed catchment scale hydrology should be considered. A distributed flash flood model, coupling kinematic wave overland flow and Green Ampt infiltration, is applied to a small catchment of the Thoré basin and used as a relatively simple (synthetic observations) but didactic application case. It is shown that forward and adjoint sensitivity analysis provide a local but extensive insight on the relation between the assigned model parameters and the simulated hydrological response. Spatially distributed parameter sensitivities can be obtained for a very modest calculation effort (~6 times the computing time of a single model run) and the singular value decomposition (SVD) of the Jacobian matrix provides an interesting perspective for the analysis of the rainfall-runoff relation. For the estimation of model parameters, adjoint-based derivatives were found exceedingly efficient in driving a bound-constrained quasi-Newton algorithm. The reference parameter set is retrieved independently from the optimization initial condition when the very common dimension reduction strategy (i.e. scalar multipliers) is adopted. Furthermore, the sensitivity analysis results suggest that most of the variability in this high-dimensional parameter space can be captured with a few orthogonal directions. A parametrization based on the SVD leading singular vectors was found very promising but should be combined with another regularization strategy in order to prevent overfitting.

  17. Clemastine Potentiates the Human P2X7 Receptor by Sensitizing It to Lower ATP Concentrations*

    PubMed Central

    Nörenberg, Wolfgang; Hempel, Christoph; Urban, Nicole; Sobottka, Helga; Illes, Peter; Schaefer, Michael

    2011-01-01

    P2X7 receptors have emerged as potential drug targets for the treatment of medical conditions such as e.g. rheumatoid arthritis and neuropathic pain. To assess the impact of pharmaceuticals on P2X7, we screened a compound library comprising approved or clinically tested drugs and identified several compounds that augment the ATP-triggered P2X7 activity in a stably transfected HEK293 cell line. Of these, clemastine markedly sensitized Ca2+ entry through P2X7 to lower ATP concentrations. Extracellularly but not intracellularly applied clemastine rapidly and reversibly augmented P2X7-mediated whole-cell currents evoked by non-saturating ATP concentrations. Clemastine also accelerated the ATP-induced pore formation and Yo-Pro-1 uptake, increased the fractional NMDG+ permeability, and stabilized the open channel conformation of P2X7. Thus, clemastine is an extracellularly binding allosteric modulator of P2X7 that sensitizes P2X7 to lower ATP concentrations and facilitates its pore dilation. The activity of clemastine on native P2X7 receptors, Ca2+ entry, and whole-cell currents was confirmed in human monocyte-derived macrophages. Similar effects were observed in murine bone marrow-derived macrophages. Consistent with the data on recombinant P2X7, clemastine augmented the ATP-induced cation entry and Yo-Pro-1 uptake. In accordance with the observation that P2X7 controls the cytokine release from LPS-primed macrophages, we found that clemastine augmented the IL-1β release from LPS-primed human macrophages. Collectively, these data point to a sensitization of the recombinantly or natively expressed human P2X7 receptor toward its physiological activator, ATP, possibly leading to a modulation of macrophage-dependent immune responses. PMID:21262970

  18. Evidence That GABA Mediates Dopaminergic and Serotonergic Pathways Associated with Locomotor Activity in Juvenile Chinook Salmon (Oncorhynchus tshawytscha)

    USGS Publications Warehouse

    Clements, S.; Schreck, C.B.

    2004-01-01

    The authors examined the control of locomotor activity in juvenile salmon (Oncorhynchus tshawytscha) by manipulating 3 neurotransmitter systems-gamma-amino-n-butyric acid (GABA), dopamine, and serotonin-as well as the neuropeptide corticotropin releasing hormone (CRH). Intracerebroventricular (ICV) injections of CRH and the GABAAagonist muscimol stimulated locomotor activity. The effect of muscimol was attenuated by administration of a dopamine receptor antagonist, haloperidol. Conversely, the administration of a dopamine uptake inhibitor (4???,4??? -difluoro-3-alpha-[diphenylmethoxy] tropane hydrochloride [DUI]) potentiated the effect of muscimol. They found no evidence that CRH-induced hyperactivity is mediated by dopaminergic systems following concurrent injections of haloperidol or DUI with CRH. Administration of muscimol either had no effect or attenuated the locomotor response to concurrent injections of CRH and fluoxetine, whereas the GABAA antagonist bicuculline methiodide potentiated the effect of CRH and fluoxetine.

  19. Behavioral sensitization and cross-sensitization between methylphenidate amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in female SD rats.

    PubMed

    Yang, Pamela B; Atkins, Kristal D; Dafny, Nachum

    2011-07-01

    The psychostimulants amphetamine and methylphenidate (MPD/Ritalin) are the drugs most often used to treat attention deficit hyperactivity disorder (ADHD). In addition, students of all ages take these drugs to improve academic performance but also abuse them for pleasurable enhancement. In addition, other psychostimulants such as 3,4-methylenedioxymethamphetamine (MDMA/ecstasy) are used/abused for similar objectives. One of the experimental markers for the potential of a drug to produce dependence is its ability to induce behavioral sensitization and cross sensitization with other drugs of abuse. The objective of this study is to use identical experimental protocols and behavioral assays to compare in female rats the effects of amphetamine, MPD and MDMA on locomotor activity and to determine if they induce behavioral sensitization and/or cross sensitization with each other. The main findings of this study are as follows: (1) acute amphetamine, MPD and MDMA all elicited increases in locomotor activity; (2) chronic administration of an intermediate dose of amphetamine or MPD elicited behavioral sensitization; (3) chronic administration of MDMA elicited behavioral sensitization in some animals and behavioral tolerance in others; (4) cross sensitization between MPD and amphetamine was observed; and (5) MDMA did not show either cross sensitization or cross tolerance with amphetamine. In conclusion, these results suggest that MDMA acts by different mechanisms compared to MPD and amphetamine. Copyright © 2011. Published by Elsevier B.V.

  20. Behavioral sensitization and cross-sensitization between methylphenidate amphetamine, and 3-4, methylenedioxymethamphetamine (MDMA) in female SD rats

    PubMed Central

    Yang, Pamela B.; Atkins, Kristal D.; Dafny, Nachum

    2014-01-01

    The psychostimulants amphetamine and methylphenidate (MPD / Ritalin) are the drugs most often used to treat attention deficit hyperactivity disorder (ADHD). In addition, students of all ages take these drugs to improve academic performance but also abuse them for pleasurable enhancement. In addition, other psychostimulants such 3,4 methylenedioxymethamphetamine (MDMA / ecstasy) are used / abused for similar objectives. One of the experimental markers for the potential of a drug to produce dependence is its ability to induce behavioral sensitization and cross sensitization with other drugs of abuse. The objective of this study is to use identical experimental protocols and behavioral assays to compare in female rats the effects of amphetamine, MPD and MDMA on locomotor activity and to determine if they induce behavioral sensitization and/or cross sensitization with each other. The main findings of this study are 1. Acute amphetamine, MPD and MDMA all elicited increases in locomotor activity. 2. Chronic administration of an intermediate dose of amphetamine or MPD elicited behavioral sensitization. 3. Chronic administration of MDMA elicited behavioral sensitization in some animals and behavioral tolerance in others. 4. Cross sensitization between MPD and amphetamine was observed. 5. MDMA did not show either cross sensitization or cross tolerance with amphetamine. In conclusion, these results suggest that MDMA act by different mechanisms compared to MPD and amphetamine. PMID:21549116

  1. The potential role of postsynaptic phospholipase C activity in synaptic facilitation and behavioral sensitization in Aplysia.

    PubMed

    Fulton, Daniel; Condro, Michael C; Pearce, Kaycey; Glanzman, David L

    2008-07-01

    Previous findings indicate that synaptic facilitation, a cellular mechanism underlying sensitization of the siphon withdrawal response (SWR) in Aplysia, depends on a cascade of postsynaptic events, including activation of inositol triphosphate (IP3) receptors and release of Ca2+ from postsynaptic intracellular stores. These findings suggest that phospholipase C (PLC), the enzyme that catalyzes IP3 formation, may play an important role in postsynaptic signaling during facilitation and learning in Aplysia. Using the PLC inhibitor U73122, we found that PLC activity is required for synaptic facilitation following a 10-min treatment with 5-HT, as measured at 20 min after 5-HT washout. Prior work has indicated that facilitation at this time is supported primarily by postsynaptic processes. To determine whether postsynaptic PLC activity is involved in 5-HT-mediated facilitatory actions, we examined the effect of U73122 on enhancement of the response of motor neurons isolated in cell culture to glutamate, the sensory neuron transmitter. A 10-min application of 5-HT induced persistent (>40 min) enhancement of glutamate-evoked potentials (Glu-EPs) recorded from isolated motor neurons, and this enhancement was blocked by U73122. Finally, we showed that injecting U73122 into intact animals before behavioral training impaired intermediate-term sensitization, indicating that PLC activity contributes to this form of nonassociative learning.

  2. Effect of MOG Sensitization on Somatosensory Evoked Potential in Lewis Rats

    PubMed Central

    All, Angelo H.; Walczak, Piotr; Agrawal, Gracee; Gorelik, Michael; Lee, Christopher; Thakor, Nitish V.; Bulte, Jeff W.M.; Kerr, Douglas A.

    2009-01-01

    Myelin oligodendrocyte glycoprotein (MOG) is commonly used as an immunogen to induce an immune response against endogenous myelin, thereby modeling multiple sclerosis in rodents. When MOG is combined with complete Freund’s adjuvant (CFA), multifocal, multiphasic disease ensues; whereas when MOG is combined with incomplete Freund’s adjuvant (IFA), clinical disease is usually absent. MOG-IFA immunized animals can be induced to have neurological disease after intraspinal injections of cytokines and ethidium bromide (EtBr). In this study, we investigated whether MOG-IFA immunized rats exhibited subclinical injury as defined by Somatosensory Evoked Potential (SEP) recordings. The titration of Anti-MOG-125 antibodies showed robust peripheral mounting of immune response against myelin in MOG-immunized rats. However the SEP measures showed no significant change over time. Upon injecting cytokine-EtBr in the spinal cord after MOG sensitization, the SEP recordings showed reduced amplitude and prolonged latency, suggestive of axonal injury and demyelination in the dorsal column, respectively. These findings were later confirmed using T2-weighted MRI and histological hematoxilin-eosin stain of the spinal cord. This report establishes that MOG-IFA immunization alone does not alter neuronal conduction in SEP-related neural-pathways and that longitudinal in-vivo SSEP recordings provide a sensitive read-out for focal myelitis (MOG-IFA & intraspinal cytokine-EtBr) in rats. PMID:19423134

  3. Effect of MOG sensitization on somatosensory evoked potential in Lewis rats

    PubMed Central

    All, Angelo H.; Walczak, Piotr; Agrawal, Gracee; Gorelik, Michael; Lee, Christopher; Thakor, Nitish V.; Bulte, Jeff W.M.; Kerr, Douglas A.

    2011-01-01

    Myelin oligodendrocyte glycoprotein (MOG) is commonly used as an immunogen to induce an immune response against endogenous myelin, thereby modeling multiple sclerosis in rodents. When MOG is combined with complete Freund's adjuvant (CFA), multifocal, multiphasic disease ensues; whereas when MOG is combined with incomplete Freund's adjuvant (IFA), clinical disease is usually absent. MOG–IFA immunized animals can be induced to have neurological disease after intraspinal injections of cytokines and ethidium bromide (EtBr). In this study, we investigated whether MOG–IFA immunized rats exhibited subclinical injury as defined by somatosensory evoked potential (SEP) recordings. The titration of anti-MOG-125 antibodies showed robust peripheral mounting of immune response against myelin in MOG-immunized rats. However the SEP measures showed no significant change over time. Upon injecting cytokine–EtBr in the spinal cord after MOG sensitization, the SEP recordings showed reduced amplitude and prolonged latency, suggestive of axonal injury and demyelination in the dorsal column, respectively. These findings were later confirmed using T2-weighted MRI and histological hematoxylin–eosin stain of the spinal cord. This report establishes that MOG–IFA immunization alone does not alter neuronal conduction in SEP-related neural-pathways and that longitudinal in-vivo SEP recordings provide a sensitive read-out for focal myelitis (MOG–IFA and intraspinal cytokine–EtBr) in rats. PMID:20508959

  4. Sensitivity to structure in action sequences: An infant event-related potential study.

    PubMed

    Monroy, Claire D; Gerson, Sarah A; Domínguez-Martínez, Estefanía; Kaduk, Katharina; Hunnius, Sabine; Reid, Vincent

    2017-05-06

    Infants are sensitive to structure and patterns within continuous streams of sensory input. This sensitivity relies on statistical learning, the ability to detect predictable regularities in spatial and temporal sequences. Recent evidence has shown that infants can detect statistical regularities in action sequences they observe, but little is known about the neural process that give rise to this ability. In the current experiment, we combined electroencephalography (EEG) with eye-tracking to identify electrophysiological markers that indicate whether 8-11-month-old infants detect violations to learned regularities in action sequences, and to relate these markers to behavioral measures of anticipation during learning. In a learning phase, infants observed an actor performing a sequence featuring two deterministic pairs embedded within an otherwise random sequence. Thus, the first action of each pair was predictive of what would occur next. One of the pairs caused an action-effect, whereas the second did not. In a subsequent test phase, infants observed another sequence that included deviant pairs, violating the previously observed action pairs. Event-related potential (ERP) responses were analyzed and compared between the deviant and the original action pairs. Findings reveal that infants demonstrated a greater Negative central (Nc) ERP response to the deviant actions for the pair that caused the action-effect, which was consistent with their visual anticipations during the learning phase. Findings are discussed in terms of the neural and behavioral processes underlying perception and learning of structured action sequences. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Effect of MOG sensitization on somatosensory evoked potential in Lewis rats.

    PubMed

    All, Angelo H; Walczak, Piotr; Agrawal, Gracee; Gorelik, Michael; Lee, Christopher; Thakor, Nitish V; Bulte, Jeff W M; Kerr, Douglas A

    2009-09-15

    Myelin oligodendrocyte glycoprotein (MOG) is commonly used as an immunogen to induce an immune response against endogenous myelin, thereby modeling multiple sclerosis in rodents. When MOG is combined with complete Freund's adjuvant (CFA), multifocal, multiphasic disease ensues; whereas when MOG is combined with incomplete Freund's adjuvant (IFA), clinical disease is usually absent. MOG-IFA immunized animals can be induced to have neurological disease after intraspinal injections of cytokines and ethidium bromide (EtBr). In this study, we investigated whether MOG-IFA immunized rats exhibited subclinical injury as defined by somatosensory evoked potential (SEP) recordings. The titration of anti-MOG-125 antibodies showed robust peripheral mounting of immune response against myelin in MOG-immunized rats. However the SEP measures showed no significant change over time. Upon injecting cytokine-EtBr in the spinal cord after MOG sensitization, the SEP recordings showed reduced amplitude and prolonged latency, suggestive of axonal injury and demyelination in the dorsal column, respectively. These findings were later confirmed using T2-weighted MRI and histological hematoxylin-eosin stain of the spinal cord. This report establishes that MOG-IFA immunization alone does not alter neuronal conduction in SEP-related neural-pathways and that longitudinal in-vivo SEP recordings provide a sensitive read-out for focal myelitis (MOG-IFA and intraspinal cytokine-EtBr) in rats.

  6. Seismogenic Potential of Anhydrite-Carbonate Fault Gouge Sensitive to Pore Fluid Composition.

    NASA Astrophysics Data System (ADS)

    Hunfeld, L. B.; Niemeijer, A. R.; Spiers, C. J.

    2016-12-01

    Anhydrite-carbonate fault gouges show rapid changes in the velocity dependence of friction with temperature that are directly relevant to understanding both induced and natural seismic rupture in formations of this composition. This sensitivity to temperature raises questions about the controlling deformation mechanisms and whether these might be affected by pore fluid composition. We performed direct shear experiments on simulated fault gouge prepared from anhydrite-carbonate caprock supplied from the seismogenic Groningen gas field (by gas-producer NAM), varying pore fluid salinity, pH, and gas/brine ratio. We investigated temperatures in the range 50-150 °C at 40 MPa effective normal stress and sliding velocities of 0.1-10 mu/s. Results showed frictional strength was unaffected by pore brine chemistry and temperature, but increased from 0.64 to 0.74 in methane- and air-saturated samples. However, the rate-dependence of friction was highly sensitive to all variables investigated, showing velocity-weakening behaviour at low pore fluid salinity, at high pore fluid pH, when (partially) dry, and at high temperature (150°C). These results imply increased seismic potential for anhydrite-carbonate fault rocks at depths >3-5 km, especially compared to clastic gouges which show velocity-strengthening under similar conditions. The controlling mechanisms remain unresolved but fluid-rock interaction clearly plays a key role.

  7. Contrast sensitivity, ocular blood flow and their potential role in assessing ischaemic retinal disease.

    PubMed

    Shoshani, Yochai Z; Harris, Alon; Rusia, Deepam; Spaeth, George L; Siesky, Brent; Pollack, Ayala; Wirostko, Barbara

    2011-08-01

    To examine the definition, evaluation methodology, association to ocular blood flow and potential clinical value of contrast sensitivity (CS) testing in clinical and research settings, focusing in patients with ischemic retinal disease. A review of the medical literature focusing on CS and ocular blood flow in ischemic retinal disease. CS may be more sensitive than other methods at detecting subtle defects or improvements in primarily central retinal ganglion cell function early on in a disease process. CS testing attempts to provide spatial detection differences which are not directly assessed with standard visual acuity chart testing. Analyzing all studies that have assessed both CS change and ocular blood flow, it is apparent that both choroidal circulation and retinal circulation may have an important role in influencing CS. The concept that CS is directly influenced by ocular blood flow is supported by reviewing the studies involving both. Although the studies in the literature have not established a direct cause and effect relationship per se, the literature review makes it logical to assume that changes in retinal and choroidal blood flow influence CS. This raises the possibility that a subjective visual characteristic, specifically CS, may be able to be evaluated more objectively by studying blood flow. It appears appropriate to study the relationship between blood flow and CS more extensively to develop improved ways of measuring various aspects of blood flow to the eye and to best quantify early changes in visual function. © 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.

  8. Iridium oxide nanotube electrodes for sensitive and prolonged intracellular measurement of action potentials.

    PubMed

    Lin, Ziliang Carter; Xie, Chong; Osakada, Yasuko; Cui, Yi; Cui, Bianxiao

    2014-01-01

    Intracellular recording of action potentials is important to understand electrically-excitable cells. Recently, vertical nanoelectrodes have been developed to achieve highly sensitive, minimally invasive and large-scale intracellular recording. It has been demonstrated that the vertical geometry is crucial for the enhanced signal detection. Here we develop nanoelectrodes of a new geometry, namely nanotubes of iridium oxide. When cardiomyocytes are cultured upon those nanotubes, the cell membrane not only wraps around the vertical tubes but also protrudes deep into the hollow centre. We show that this nanotube geometry enhances cell-electrode coupling and results in larger signals than solid nanoelectrodes. The nanotube electrodes also afford much longer intracellular access and are minimally invasive, making it possible to achieve stable recording up to an hour in a single session and more than 8 days of consecutive daily recording. This study suggests that the nanoelectrode performance can be significantly improved by optimizing the electrode geometry.

  9. Sensitive linear response of an electron-hole superfluid in a periodic potential

    NASA Astrophysics Data System (ADS)

    Berman, Oleg L.; Kezerashvili, Roman Ya.; Lozovik, Yurii E.; Ziegler, Klaus

    2017-08-01

    We consider excitons in a two-dimensional periodic potential and study the linear response of the excitonic superfluid to an electromagnetic wave at low and high densities. It turns out that the static structure factor for small wavevectors is very sensitive to a change of density and temperature. It is a consequence of the fact that thermal fluctuations play a crucial role at small wavevectors, since exchanging the order of the two limits, zero temperature and vanishing wavevector, leads to different results for the structure factor. This effect could be used for high accuracy measurements in the superfluid exciton phase, which might be realized by a gated electron-hole gas, for instance, in coupled quantum wells or double layer materials. The transition of the exciton system from the superfluid state to a non-superfluid state and its manifestation by light scattering are discussed.

  10. Heat shock response regulates insulin sensitivity and glucose homeostasis: pathophysiological impact and therapeutic potential.

    PubMed

    Kondo, Tatsuya; Koga, Saori; Matsuyama, Rina; Miyagawa, Katsutoshi; Goto, Rieko; Kai, Hirofumi; Araki, Eiichi

    2011-07-01

    A large and increasing number of people in all over the world suffer from obesity, metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Attenuation of the heat shock response (HSR), which was originally identified as a cellular defense mechanism, is one of the key factors involved in the deterioration of metabolic abnormalities. On the other hand, activating the HSR increases heat shock protein 72 (HSP72) expression and improves insulin resistance and glucose homeostasis in rodents and humans, possibly by inhibiting the activation of stress kinases such as c-jun terminal kinase (JNK) and inhibitor of kappa B kinase β (IKKβ). These approaches may also reduce inflammatory cytokine production and prevent the onset of atherogenic complications. This review focuses on the physiological effects of HSR in regulating insulin sensitivity and hyperglycemia, and the potential to target the HSR system for the treatment of MS and T2DM, as well as other cellular stress-related diseases.

  11. IATA for skin sensitization potential – 1 out of 2 or 2 out of 3? (ESCD meeting)

    EPA Science Inventory

    To meet EU regulatory requirements and to avoid or minimize animal testing, there is a need for non-animal methods to assess skin sensitization potential. Given the complexity of the skin sensitization endpoint, there is an expectation that integrated testing and assessment appro...

  12. IATA for skin sensitization potential – 1 out of 2 or 2 out of 3? (ASCCT meeting)

    EPA Science Inventory

    To meet EU regulatory requirements and to avoid or minimize animal testing, there is a need for non-animal methods to assess skin sensitization potential. Given the complexity of the skin sensitization endpoint, there is an expectation that integrated testing and assessment appro...

  13. Dermal sensitization potential of ja-2 solid propellant in guinea pigs. Report for 4 April-9 May 1986

    SciTech Connect

    Lewis, C.M.; Brown, L.D.; Korte, D.W.

    1989-11-01

    JA-2 Solid Propellant was evaluated for its potential to produce dermal sensitization in male guinea pigs. The Buehler test, which utilizes repeated closed patch inductions with the test compound, was used for this evaluation. No evidence that JA-2 Solid Propellant induced sensitization was obtained in the study.

  14. Sensitivity of the projected hydroclimatic environment of the Delaware River basin to formulation of potential evapotranspiration

    USGS Publications Warehouse

    Williamson, Tanja N.; Nystrom, Elizabeth A.; Milly, Paul C.D.

    2016-01-01

    The Delaware River Basin (DRB) encompasses approximately 0.4 % of the area of the United States (U.S.), but supplies water to 5 % of the population. We studied three forested tributaries to quantify the potential climate-driven change in hydrologic budget for two 25-year time periods centered on 2030 and 2060, focusing on sensitivity to the method of estimating potential evapotranspiration (PET) change. Hydrology was simulated using the Water Availability Tool for Environmental Resources (Williamson et al. 2015). Climate-change scenarios for four Coupled Model Intercomparison Project Phase 5 (CMIP5) global climate models (GCMs) and two Representative Concentration Pathways (RCPs) were used to derive monthly change factors for temperature (T), precipitation (PPT), and PET according to the energy-based method of Priestley and Taylor (1972). Hydrologic simulations indicate a general increase in annual (especially winter) streamflow (Q) as early as 2030 across the DRB, with a larger increase by 2060. This increase in Q is the result of (1) higher winter PPT, which outweighs an annual actual evapotranspiration (AET) increase and (2) (for winter) a major shift away from storage of PPT as snow pack. However, when PET change is evaluated instead using the simpler T-based method of Hamon (1963), the increases in Q are small or even negative. In fact, the change of Q depends as much on PET method as on time period or RCP. This large sensitivity and associated uncertainty underscore the importance of exercising caution in the selection of a PET method for use in climate-change analyses.

  15. Mechanisms of transient receptor potential vanilloid 1 activation and sensitization by allyl isothiocyanate.

    PubMed

    Gees, Maarten; Alpizar, Yeranddy A; Boonen, Brett; Sanchez, Alicia; Everaerts, Wouter; Segal, Andrei; Xue, Fenqin; Janssens, Annelies; Owsianik, Grzegorz; Nilius, Bernd; Voets, Thomas; Talavera, Karel

    2013-09-01

    Allyl isothiocyanate (AITC; aka, mustard oil) is a powerful irritant produced by Brassica plants as a defensive trait against herbivores and confers pungency to mustard and wasabi. AITC is widely used experimentally as an inducer of acute pain and neurogenic inflammation, which are largely mediated by the activation of nociceptive cation channels transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 (TRPV1). Although it is generally accepted that electrophilic agents activate these channels through covalent modification of cytosolic cysteine residues, the mechanism underlying TRPV1 activation by AITC remains unknown. Here we show that, surprisingly, AITC-induced activation of TRPV1 does not require interaction with cysteine residues, but is largely dependent on S513, a residue that is involved in capsaicin binding. Furthermore, AITC acts in a membrane-delimited manner and induces a shift of the voltage dependence of activation toward negative voltages, which is reminiscent of capsaicin effects. These data indicate that AITC acts through reversible interactions with the capsaicin binding site. In addition, we show that TRPV1 is a locus for cross-sensitization between AITC and acidosis in nociceptive neurons. Furthermore, we show that residue F660, which is known to determine the stimulation by low pH in human TRPV1, is also essential for the cross-sensitization of the effects of AITC and low pH. Taken together, these findings demonstrate that not all reactive electrophiles stimulate TRPV1 via cysteine modification and help understanding the molecular bases underlying the surprisingly large role of this channel as mediator of the algesic properties of AITC.

  16. Brain potentials evoked by intraepidermal electrical stimuli reflect the central sensitization of nociceptive pathways

    PubMed Central

    Lee, M. C.; O'Neill, J.; Dickenson, A. H.; Iannetti, G. D.

    2016-01-01

    Central sensitization (CS), the increased sensitivity of the central nervous system to somatosensory inputs, accounts for secondary hyperalgesia, a typical sign of several painful clinical conditions. Brain potentials elicited by mechanical punctate stimulation using flat-tip probes can provide neural correlates of CS, but their signal-to-noise ratio is limited by poor synchronization of the afferent nociceptive input. Additionally, mechanical punctate stimulation does not activate nociceptors exclusively. In contrast, low-intensity intraepidermal electrical stimulation (IES) allows selective activation of type II Aδ-mechano-heat nociceptors (II-AMHs) and elicits reproducible brain potentials. However, it is unclear whether hyperalgesia from IES occurs and coexists with secondary mechanical punctate hyperalgesia, and whether the magnitude of the electroencephalographic (EEG) responses evoked by IES within the hyperalgesic area is increased. To address these questions, we explored the modulation of the psychophysical and EEG responses to IES by intraepidermal injection of capsaicin in healthy human subjects. We obtained three main results. First, the intensity of the sensation elicited by IES was significantly increased in participants who developed robust mechanical punctate hyperalgesia after capsaicin injection (i.e., responders), indicating that hyperalgesia from IES coexists with punctate mechanical hyperalgesia. Second, the N2 peak magnitude of the EEG responses elicited by IES was significantly increased after the intraepidermal injection of capsaicin in responders only. Third, a receiver-operator characteristics analysis showed that the N2 peak amplitude is clearly predictive of the presence of CS. These findings suggest that the EEG responses elicited by IES reflect secondary hyperalgesia and therefore represent an objective correlate of CS. PMID:27098022

  17. Disparities in potentially avoidable emergency department (ED) care: ED visits for ambulatory care sensitive conditions.

    PubMed

    Johnson, Pamela Jo; Ghildayal, Neha; Ward, Andrew C; Westgard, Bjorn C; Boland, Lori L; Hokanson, Jon S

    2012-12-01

    Hospital care for ambulatory care sensitive conditions (ACSC) is potentially avoidable and often viewed as an indicator of suboptimal primary care. However, potentially preventable encounters with the health care system also occur in emergency department (ED) settings. We examined ED visits to identify subpopulations with disproportionate use of EDs for ACSC care. We analyzed data from the 2007-2009 National Hospital Ambulatory Medical Care Survey for 78,114 ED visits by adults aged 18 and older. Outcomes were ACSC visits determined from the primary ED diagnosis. We constructed analytic groups aligned with Agency for Healthcare Research and Quality's priority populations. Multivariate logistic regression was used to estimate the odds of all-cause, acute, and chronic ACSC visits. We used Stata SE survey techniques to account for the complex survey design. Overall, 8.4% of ED visits were for ACSC, representing over 8 million potentially avoidable ED visits annually. ACSC visits were more likely to result in hospitalization than non-ACSC visits (34.4% vs. 14.0%, P<0.001). Multivariate models revealed significant disparities in ACSC visits to the ED by race/ethnicity, insurance status, age group, and socioeconomic status, although patterns differed for acute and chronic ACSC. Disproportionately higher use of EDs for ACSC care exists for many priority populations and across a broader range of priority populations than previously documented. These differences constitute disparities in potentially avoidable ED visits for ACSC. To avoid exacerbating disparities, health policy efforts to minimize economic inefficiencies in health care delivery by limiting ED visits for ACSC should first address their determinants.

  18. Locomotor activation by theacrine, a purine alkaloid structurally similar to caffeine: involvement of adenosine and dopamine receptors.

    PubMed

    Feduccia, Allison A; Wang, Yuanyuan; Simms, Jeffrey A; Yi, Henry Y; Li, Rui; Bjeldanes, Leonard; Ye, Chuangxing; Bartlett, Selena E

    2012-08-01

    Purine compounds, such as caffeine, have many health-promoting properties and have proven to be beneficial in treating a number of different conditions. Theacrine, a purine alkaloid structurally similar to caffeine and abundantly present in Camellia kucha, has recently become of interest as a potential therapeutic compound. In the present study, theacrine was tested using a rodent behavioral model to investigate the effects of the drug on locomotor activity. Long Evans rats were injected with theacrine (24 or 48 mg/kg, i.p.) and activity levels were measured. Results showed that the highest dose of theacrine (48 mg/kg, i.p.) significantly increased locomotor activity compared to control animals and activity remained elevated throughout the duration of the session. To test for the involvement of adenosine receptors underlying theacrine's motor-activating properties, rats were administered a cocktail of the adenosine A₁ agonist, N⁶-cyclopentyladenosine (CPA; 0.1 mg/kg, i.p.) and A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.2 mg/kg, i.p.). Pre-treatment with theacrine significantly attenuated the motor depression induced by the adenosine receptor agonists, indicating that theacrine is likely acting as an adenosine receptor antagonist. Next, we examined the role of DA D₁ and D₂ receptor antagonism on theacrine-induced hyperlocomotion. Both antagonists, D₁R SCH23390 (0.1 or 0.05 mg/kg, i.p.) and D₂R eticlopride (0.1 mg/kg, i.p.), significantly reduced theacrine-stimulated activity indicating that this behavioral response, at least in part, is mediated by DA receptors. In order to investigate the brain region where theacrine may be acting, the drug (10 or 20 μg) was infused bilaterally into nucleus accumbens (NAc). Theacrine enhanced activity levels in a dose-dependent manner, implicating a role of the NAc in modulating theacrine's effects on locomotion. In addition, theacrine did not induce locomotor

  19. Grammatical sensitivity: its origins and potential contribution to early word reading skill.

    PubMed

    Bowey, Judith A

    2005-04-01

    A three-phase longitudinal study examined the origins of grammatical sensitivity and its usefulness as a predictor of early word-level reading. At about 4 years of age, children were given a range of language and cognitive tests. One year later, the children were given a further series of language and cognitive tests, this time including grammatical sensitivity, phonological sensitivity, and nonword repetition. Another year later, word-level reading achievement was assessed. Overall, grammatical sensitivity and phonological sensitivity were more firmly grounded in earlier language ability than in cognitive ability. Phonological sensitivity and nonword repetition showed reliable predictive associations with subsequent word reading skills. Grammatical sensitivity did not.

  20. Potential evaporation estimation through an unstressed surface-energy balance and its sensitivity to climate change

    NASA Astrophysics Data System (ADS)

    Barella-Ortiz, A.; Polcher, J.; Tuzet, A.; Laval, K.

    2013-11-01

    Potential evaporation (ETP) is a basic input for many hydrological and agronomic models, as well as a key variable in most actual evaporation estimations. It has been approached through several diffusive and energy balance methods, out of which the Penman-Monteith equation is recommended as the standard one. In order to deal with the diffusive approach, ETP must be estimated at a sub-diurnal frequency, as currently done in land surface models (LSMs). This study presents an improved method, developed in the ORCHIDEE LSM, which consists of estimating ETP through an unstressed surface-energy balance (USEB method). The results confirm the quality of the estimation which is currently implemented in the model (Milly, 1992). The ETP underlying the reference evaporation proposed by the Food and Agriculture Organization, FAO, (computed at a daily time step) has also been analysed and compared. First, a comparison for a reference period under current climate conditions shows that USEB and FAO's ETP estimations differ, especially in arid areas. However, they produce similar values when the FAO's assumption of neutral stability conditions is relaxed, by replacing FAO's aerodynamic resistance by that of the model's. Furthermore, if the vapour pressure deficit (VPD) estimated for the FAO's equation, is substituted by ORCHIDEE's VPD or its humidity gradient, the agreement between the daily mean estimates of ETP is further improved. In a second step, ETP's sensitivity to climate change is assessed by comparing trends in these formulations for the 21st century. It is found that the USEB method shows a higher sensitivity than the FAO's. Both VPD and the model's humidity gradient, as well as the aerodynamic resistance have been identified as key parameters in governing ETP trends. Finally, the sensitivity study is extended to two empirical approximations based on net radiation and mass transfer (Priestley-Taylor and Rohwer, respectively). The sensitivity of these ETP estimates is

  1. Assessment of sensitization potential of monoterpenes using the rat popliteal lymph node assay.

    PubMed

    Friedrich, Karen; Delgado, Isabella F; Santos, Laísa M F; Paumgartten, Francisco J R

    2007-08-01

    The popliteal lymph node assay (PLNA) has been proposed as a screening test for detecting chemicals with potential of inducing allergic and auto-immune-like reactions in humans. In the present study, we used the rat PLNA to evaluate the immuno-sensitizing potential of 10 monoterpenes found in the essential oils of a variety of aromatic, edible and medicinal plants. The primary or direct PLNA was performed with the monoterpenes, and chlorpromazine (CPZ) and barbital were used as positive and negative controls, respectively. Female, 7-8 week-old Wistar rats were injected subcutaneously (50 microL) with the test substance (0.5, 2.5 or 5mg) into the right hind footpad while the contralateral footpad was injected with the vehicle (DMSO) alone. Weight (WI) and cellularity (CI) indices for draining PLNs were determined 7 days after treatment. PLNA was positive (WI >or= 2 and CI >or= 5) for CPZ, citral, alpha-terpinene, beta-myrcene and (-)-alpha-pinene, and negative for barbital, DMSO, (-)-menthol, 1,8-cineole, (+/-) citronellal, (+)-limonene, (+/-) camphor and terpineol. A secondary PLNA, a T-cell priming test, was carried out with the four substances that had been positive in the primary assay. Six weeks after being locally primed with 5 mg/paw, rats were sc injected into the same footpad with a dose (0.5 mg/paw) of the substance that had been previously found to be insufficient to cause a positive response. WI and CI were then calculated 4 and 7 days after the second injection. CPZ was also positive in the secondary assay thereby confirming that it is a sensitizing agent. Citral, alpha-terpinene, beta-myrcene and (-)-alpha-pinene, however, were negative in the secondary assay. In summary, citral, alpha-terpinene, beta-myrcene and (-)-alpha-pinene induced a clear immuno-stimulatory response due to their irritant properties but no monoterpene proved to be a sensitizing agent in the PLNA.

  2. Locomotor Profiling from Rodents to the Clinic and Back Again.

    PubMed

    Young, Jared W; Minassian, Arpi; Geyer, Mark A

    The quantification of unconditioned motoric activity is one of the oldest and most commonly utilized tools in behavioral studies. Although typically measured in reference to psychiatric disorders, e.g., amphetamine-induced hyperactivity used as a model of schizophrenia, bipolar disorder (BD), and Tourette's syndrome, the motoric behavior of psychiatric patients had not been quantified similarly to rodents until recently. The rodent behavioral pattern monitor (BPM) was reverse-translated for use in humans, providing the quantification of not only motoric activity but also the locomotor exploratory profile of various psychiatric populations. This measurement includes the quantification of specific exploration and locomotor patterns. As an example, patients with BD, schizophrenia, and those with history of methamphetamine dependence exhibited unique locomotor profiles. It was subsequently determined that reducing dopamine transporter function selectively recreated the locomotor profile of BD mania patients and not any other patient population. Hence, multivariate locomotor profiling offers a first-step approach toward understanding the neural mechanism(s) underlying abnormal behavior in patients with psychiatric disorders. Advances in wearable technology will undoubtedly enable similar multivariate assessments of exploratory and locomotor behavior in "real-world" contexts. Furthermore, trans-diagnostic studies of locomotor activity profiles will inform about essential brain-based functions that cut across diagnostic nosologies.

  3. Anxiety sensitivity and intolerance of uncertainty as potential risk factors for cyberchondria.

    PubMed

    Norr, Aaron M; Albanese, Brian J; Oglesby, Mary E; Allan, Nicholas P; Schmidt, Norman B

    2015-03-15

    Online medical information seeking has become an increasingly common behavior. Despite the benefits of easily accessible medical information on the Internet, researchers have identified a vicious cycle of increased physical health concerns and online medical information seeking known as "cyberchondria". Despite proposed theoretical models of cyberchondria, there is a dearth of research investigating risk factors for the development of cyberchondria. Two potential risk factors are anxiety sensitivity (AS) and intolerance of uncertainty (IU). The current study investigated the relationships among AS, IU, and cyberchondria in a large community sample. Participants (N=526) completed self-report questionnaires via online crowdsourcing. Structural equation models utilizing latent variables revealed a significant unique positive relationship between AS, as well as the IU Inhibitory lower-order factor, and cyberchondria, controlling for the effects of health anxiety. Additionally, results revealed a significant unique relationship between the IU Inhibitory factor and mistrust of medical professionals, a proposed cyberchondria-relevant construct. The cross-sectional data in the current study do not offer a true test of AS and IU as risk factors. However, establishing these unique relationships is an important step forward in the literature. The results of the current study suggest the potential importance of both AS and IU in the development of cyberchondria. Future research is needed to establish the temporal precedence of elevated AS and/or IU to determine if they are true risk factors or simply correlates of cyberchondria. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Mechanism of response of potential-sensitive dyes studied by time-resolved fluorescence

    PubMed Central

    Das, Tapan K.; Periasamy, N.; Krishnamoorthy, G.

    1993-01-01

    The mechanism of response of two potential-sensitive dyes, diOC2(5) (3,3′-diethyloxadicarbocyanine iodide) and oxonol V (bis-[3-phenyl-5-oxoisoxazol-4-yl]pentamethine oxonol), were studied by using steady-state and time-resolved fluorescence techniques. The lipid concentration dependence of the Δψ (membrane potential)-induced change in total fluorescence intensity was quite different for these two dyes. Time-resolved fluorescence measurements showed that the fluorescence decay of these dyes in membranes could be resolved into at least three exponentials. Δψ-induced changes in the levels of these three populations were also measured under a variety of conditions. In the case of diOC2(5) an inside negative Δψ increased the levels of the bound forms. This shows that diOC2(5) responds to Δψ mainly by an “on-off” mechanism whereby Δψ perturbs the membrane-water partition coefficient of the dye. The Δψ-induced changes approached zero when the dye was totally membrane bound. In contrast, the Δψ-induced response of oxonol V increased with increased membrane binding. An inside negative Δψ decreased the level of the bound form with a longer lifetime. This shows that the mechanism of response of oxonol V is a Δψ-induced shift in the equilibrium between bound forms of the dye. PMID:19431883

  5. Cystatin C: a possible sensitive marker for detecting potential kidney injury after computed tomography coronary angiography.

    PubMed

    Takeuchi, Toyonari; Isobe, Satoshi; Sato, Kimihide; Kato, Mariko I; Kasai, Naho N; Ohyama, Hisato; Yoshikawa, Daiji; Ishii, Hideki; Matsubara, Tatsuaki; Murohara, Toyoaki

    2011-01-01

    Cystatin C (CyC) has recently been recognized as a sensitive marker for potential renal dysfunction. We investigated the role of CyC for evaluating potential kidney injury after computed tomography coronary angiography (CTCA). The CyC, serum creatinine (sCr), estimated glomerular filtration rate (eGFR), and blood urea nitrogen (BUN) levels were evaluated before and 1 day and 1 week after the procedure in 140 patients with preserved renal function referred for CTCA. The amount of unrestricted oral fluid intake was measured for 24 hours after CTCA. The relationship between the amount of oral fluid intake and the changes in each renal marker was compared. A strong correlation was observed between oral fluid volume and the changes in CyC (r = -0.80, P < 0.0001) as well as the changes in sCr (r = -0.54, P < 0.0001) and eGFR (r = 0.57, P < 0.0001), but a weak correlation was observed between oral fluid volume and the changes in BUN (r = -0.22, P = 0.03). A progressive rise in a mean level of CyC was observed. The percentage of diabetic history was greater (73% vs 40%, P < 0.001) and oral fluid volume was lower (1142 mL vs 2114 mL, P < 0.0001) in patients with a rise in CyC but without one in sCr than in those showing a rise in neither CyC nor sCr at 1 day postprocedure. Seventy-four (80%) of 92 patients with a rise in CyC at 1 day postprocedure showed a recovery to the baseline sCr levels at 1 week postprocedure, but only 26 (28%) showed a recovery to the baseline CyC levels at 1 week. Cystatin C is a more sensitive marker than sCr in evaluating the effects of oral fluid volume on renal function and in detecting potential kidney injury, especially in diabetic patients after CTCA.

  6. Comparison of toluene-induced locomotor activity in Four Mouse Strains

    PubMed Central

    Bowen, Scott E; Kimar, Sarah; Irtenkauf, Susan

    2010-01-01

    The mechanisms by which abused inhalants exert their neurobehavioral effects are only partially understood. In research with other drugs of abuse, specific inbred mouse strains have been useful in exploring genetic loci important to variation in behavioral reactions to these drugs. In the present investigation, mice from three inbred strains (Balb/cByj, C57BL/6J and DBA/2J) and one outbred strain (Swiss Webster) were studied for their acute and chronic sensitivity to toluene-induced changes in locomotor activity. Mice were exposed to toluene (0, 100, 2000, 8000, 10000 ppm) for 30 min in static exposure chambers equipped with activity monitors. In the acute condition, concentrations of toluene <8000 ppm increased ambulatory distance while the concentrations of ≥8000 ppm induced temporally biphasic effects with initial increases in activity followed by hypoactivity. Between-group differences in absolute locomotor activity levels were evident. The inbred Balb/cByj and DBA/2J strains as well as the outbred Swiss Webster strain of mice showed greater increases in activity after an acute challenge exposure to 2000 ppm than the inbred C57BL/6J strain. The same animals were then exposed 30 min/day to 8000 ppm toluene for 14 consecutive days. Re-determination of responses to 2000-ppm challenge exposures revealed that sensitization developed in locomotor activity and that the DBA/2J strain showed the greatest increase in sensitivity. These baseline differences in acute sensitivity and the differential shifts in sensitivity after repeated exposures among the inbred mouse strains suggest a genetic basis for the behavioral effects to toluene. The results support the notion that like for other drugs of abuse, using various strains of mice may be useful for investigating mechanisms that underlie risk for inhalant abuse. PMID:20138905

  7. Regionalisation of climate change sensitive forest development types for potential afforestation areas.

    PubMed

    Witt, Anke; Fürst, Christine; Frank, Susanne; Koschke, Lars; Makeschin, Franz

    2013-09-01

    This paper describes how to use sectoral planning information from forestry to predict and up-scale information on Climate Change sensitive forest development types for potential afforestation areas. The method was developed and applied in the frame of the project RegioPower with focus on the case study region 'Oberes Elbtal-Osterzgebirge'. The data for our study was taken from forest management planning at level of the Federal State of Saxony, Germany. Here, a silvicultural system is implemented, which describes best practices to develop our actual forests into Climate Change adapted forest development types. That includes the selection of drought resistant tree species, a broad range of tree species mixtures per eligible forest development type and the tending, harvesting and regeneration strategies to be applied. This information however, exists only for forest areas and not for areas which could be potentially afforested. The eligibility of the forest development types within the actual forest areas depends on site information, such as nutrient potential, exposition and hydrological soil parameters. The regionalisation of the forest development types to landscape scale had to be based on topographical parameters from the digital elevation model and hydrological soil parameters from soil mapping. In result, we could provide maps for regional planning and decision making with spatially explicit information on the eligible forest development types based on forest management planning information. These maps form a valuable input for testing and optimising afforestation areas with regard to improving the ability of our case study region to mitigate Climate Change effects such as water erosion or drought.

  8. Cross-species sensitivity to a novel androgen receptor agonist of potential environmental concern, spironolactone.

    PubMed

    LaLone, Carlie A; Villeneuve, Daniel L; Cavallin, Jenna E; Kahl, Michael D; Durhan, Elizabeth J; Makynen, Elizabeth A; Jensen, Kathleen M; Stevens, Kyle E; Severson, Megan N; Blanksma, Chad A; Flynn, Kevin M; Hartig, Philip C; Woodard, Jonne S; Berninger, Jason P; Norberg-King, Teresa J; Johnson, Rodney D; Ankley, Gerald T

    2013-11-01

    Spironolactone is a pharmaceutical that in humans is used to treat conditions like hirsutism, various dermatologic afflictions, and female-pattern hair loss through antagonism of the androgen receptor. Although not routinely monitored in the environment, spironolactone has been detected downstream of a pharmaceutical manufacturer, indicating a potential for exposure of aquatic species. Furthermore, spironolactone has been reported to cause masculinization of female western mosquitofish, a response indicative of androgen receptor activation. Predictive methods to identify homologous proteins to the human and western mosquitofish androgen receptor suggest that vertebrates would be more susceptible to adverse effects mediated by chemicals like spironolactone that target the androgen receptor compared with invertebrate species that lack a relevant homolog. In addition, an adverse outcome pathway previously developed for activation of the androgen receptor suggests that androgen mimics can lead to reproductive toxicity in fish. To assess this, 21-d reproduction studies were conducted with 2 fish species, fathead minnow and Japanese medaka, and the invertebrate Daphnia magna. Spironolactone significantly reduced the fecundity of medaka and fathead minnows at 50 μg/L, whereas daphnia reproduction was not affected by concentrations as large as 500 μg/L. Phenotypic masculinization of females of both fish species was observed at 5 μg/L as evidenced by formation of tubercles in fathead minnows and papillary processes in Japanese medaka. Effects in fish occurred at concentrations below those reported in the environment. These results demonstrate how a priori knowledge of an adverse outcome pathway and the conservation of a key molecular target across vertebrates can be utilized to identify potential chemicals of concern in terms of monitoring and highlight potentially sensitive species and endpoints for testing.

  9. Potential hazards of fenvalerate in massive pollution influence the apoptosis sensitivity.

    PubMed

    Cui, Zheng-Guo; Jin, Yu-Jie; Sun, Lu; Zakki, Shahbaz Ahmad; Li, Meng-Ling; Feng, Qian-Wen; Kondo, Takashi; Ogawa, Ryohei; Inadera, Hidekuni

    2017-09-26

    Fenvalerate (Fen), a synthetic pyrethroid insecticide, is widely used in agricultural, domestic and veterinary applications. Fen induces abnormal cell proliferation and apoptosis, which are linked to its hazardous effects. However, this view is controversial and the underlying molecular mechanisms remain elusive. In the present study, the effects of Fen on cadmium (Cd)-induced apoptosis and the associated molecular mechanisms were investigated in human myeloid leukemia U937 cells. U937 cells were treated with 50 μm cadmium chloride (CdCl2 ) with or without Fen pretreatment at 1-50 μm. Apoptosis was evaluated by externalization of phosphatidylserine on the plasma membrane. The expression levels of apoptosis-related proteins, including Bcl-2 family members were determined by western blot analysis. The results revealed that pretreatment with Fen at 20 μm for 12 hours significantly inhibited Cd-induced apoptosis. Decreased expression of pro-apoptotic Bcl-2 family proteins (Noxa and Bid) and increased expression of anti-apoptotic proteins (Bcl-xL, Mcl-1 and XIAP) were observed after combined treatment with Fen and CdCl2 . Phosphorylation of ERK and AKT was increased, while phosphorylation of JNK was decreased by the combined treatment, compared with CdCl2 treatment alone. In conclusion, Fen decreased apoptotic sensitivity induced by Cd in U937 cells. This effect was associated with activation of ERK and AKT, suppression of JNK and changes in expression of Bcl-2 family proteins and XIAP. The present findings suggest a potential influence of Fen on Cd toxicity via suppression of apoptosis. Fen decreased apoptotic sensitivity induced by Cd, and thus it may contribute carcinogenic risk and influence on cancer therapy. Copyright © 2017 John Wiley & Sons, Ltd.

  10. Evidence for Novel Pharmacological Sensitivities of Transient Receptor Potential (TRP) Channels in Schistosoma mansoni

    PubMed Central

    Bais, Swarna; Churgin, Matthew A.; Fang-Yen, Christopher; Greenberg, Robert M.

    2015-01-01

    Schistosomiasis, caused by parasitic flatworms of the genus Schistosoma, is a neglected tropical disease affecting hundreds of millions globally. Praziquantel (PZQ), the only drug currently available for treatment and control, is largely ineffective against juvenile worms, and reports of PZQ resistance lend added urgency to the need for development of new therapeutics. Ion channels, which underlie electrical excitability in cells, are validated targets for many current anthelmintics. Transient receptor potential (TRP) channels are a large family of non-selective cation channels. TRP channels play key roles in sensory transduction and other critical functions, yet the properties of these channels have remained essentially unexplored in parasitic helminths. TRP channels fall into several (7–8) subfamilies, including TRPA and TRPV. Though schistosomes contain genes predicted to encode representatives of most of the TRP channel subfamilies, they do not appear to have genes for any TRPV channels. Nonetheless, we find that the TRPV1-selective activators capsaicin and resiniferatoxin (RTX) induce dramatic hyperactivity in adult worms; capsaicin also increases motility in schistosomula. SB 366719, a highly-selective TRPV1 antagonist, blocks the capsaicin-induced hyperactivity in adults. Mammalian TRPA1 is not activated by capsaicin, yet knockdown of the single predicted TRPA1-like gene (SmTRPA) in S. mansoni effectively abolishes capsaicin-induced responses in adult worms, suggesting that SmTRPA is required for capsaicin sensitivity in these parasites. Based on these results, we hypothesize that some schistosome TRP channels have novel pharmacological sensitivities that can be targeted to disrupt normal parasite neuromuscular function. These results also have implications for understanding the phylogeny of metazoan TRP channels and may help identify novel targets for new or repurposed therapeutics. PMID:26655809

  11. [The new technologies of kinesiotherapy for the rehabilitation of the patients suffering from the post-stroke locomotor disorders].

    PubMed

    Gusarova, S A; Styazhkina, E M; Gurkina, M V; Chesnikova, E I; Sycheva, A Yu

    2016-01-01

    This paper was designed to report the results of the application of two therapeutic modalities for the rehabilitation of 44 patients presenting with post-stroke locomotor disorders in the form of spastic hemiparesis. The patients allocated to the main group were treated with the use of the new kinesiotherapeutic methods including cryomassage and the Armeo robotic complex. The patients of the control group had to perform traditional therapeutic physical exercises in combination with classical massage and remedial gymnastics. It is concluded that the application of the combination of the modern kinesiotherapeutic factors exerting the positive corrective influence on different aspects of the locomotor deficiency in the upper extremities and the psychoemotional status of the patients has advantages over traditional physical exercise therapy in terms of clinical efficiency because it enhances the rehabilitative potential for these patients with serious locomotor problems.

  12. Locomotor Activity and Body Temperature Patterns over a Temperature Gradient in the Highveld Mole-Rat (Cryptomys hottentotus pretoriae).

    PubMed

    Haupt, Meghan; Bennett, Nigel C; Oosthuizen, Maria K

    2017-01-01

    African mole-rats are strictly subterranean mammals that live in extensive burrow systems. High humidity levels in the burrows prevent mole-rats from thermoregulating using evaporative cooling. However, the relatively stable environment of the burrows promotes moderate temperatures and small daily temperature fluctuations. Mole-rats therefore display a relatively wide range of thermoregulation abilities. Some species cannot maintain their body temperatures at a constant level, whereas others employ behavioural thermoregulation. Here we test the effect of ambient temperature on locomotor activity and body temperature, and the relationship between the two parameters, in the highveld mole-rat. We exposed mole-rats to a 12L:12D and a DD light cycle at ambient temperatures of 30°C, 25°C and 20°C while locomotor activity and body temperature were measured simultaneously. In addition, we investigated the endogenous rhythms of locomotor activity and body temperature at different ambient temperatures. Mole-rats displayed nocturnal activity at all three ambient temperatures and were most active at 20°C, but least active at 30°C. Body temperature was highest at 30°C and lowest at 20°C, and the daily cycle was highly correlated with locomotor activity. We show that the mole-rats have endogenous rhythms for both locomotor activity and body temperature. However, the endogenous body temperature rhythm appears to be less robust compared to the locomotor activity rhythm. Female mole-rats appear to be more sensitive to temperature changes than males, increased heterothermy is evident at lower ambient temperatures, whilst males show smaller variation in their body temperatures with changing ambient temperatures. Mole-rats may rely more heavily on behavioural thermoregulation as it is more energy efficient in an already challenging environment.

  13. Motor and locomotor responses to systemic amphetamine in three lines of selectively bred Long-Evans rats.

    PubMed

    Brudzynski, Stefan M; Gibson, Brittany; Silkstone, Michael; Burgdorf, Jeffrey; Kroes, Roger A; Moskal, Joseph R; Panksepp, Jaak

    2011-11-01

    The goal of the study was to measure spontaneous and amphetamine-induced motor and locomotor activity in three selectively bred lines of male Long-Evans rats. The number of 50 kHz ultrasonic vocalizations (USVs) emitted in response to heterospecific play with human hand ("tickling") had been measured daily in these lines of rats from 21 to 24 days of age, as a criterion for dividing them into high vocalizing line, low vocalizing line, and random breeding and testing lines. This study sought to determine whether selection of rats based on their affective social-vocalizations also had effects on their locomotor performance and sensitivity to amphetamine. In this study adult animals from the 25th generation (with no further selection) were tested. The results showed that rats, which were selectively bred to emit high numbers of 50 kHz vocalizations, also exhibited elevated levels of spontaneous locomotor activity. After systemic injection of d-amphetamine (1.5mg/kg), the level of motor and locomotor activity significantly increased further in all the lines as compared to saline controls. The horizontal and vertical activities and the distance covered by rats of the high line, both at the baseline and after amphetamine challenge, were significantly higher than those of the low line animals in absolute scores but not as proportion of relevant saline controls. Since appetitive 50 kHz USVs and locomotor activity are both dependent on the activity of the dopamine system, it is concluded that selection of rats based on the expression of their positive emotional state is also selecting other features than vocalization, namely locomotor behavior. This may help explain why these animals are relatively resistant to depressogenic manipulations.

  14. Locomotor Activity and Body Temperature Patterns over a Temperature Gradient in the Highveld Mole-Rat (Cryptomys hottentotus pretoriae)

    PubMed Central

    Haupt, Meghan; Bennett, Nigel C.

    2017-01-01

    African mole-rats are strictly subterranean mammals that live in extensive burrow systems. High humidity levels in the burrows prevent mole-rats from thermoregulating using evaporative cooling. However, the relatively stable environment of the burrows promotes moderate temperatures and small daily temperature fluctuations. Mole-rats therefore display a relatively wide range of thermoregulation abilities. Some species cannot maintain their body temperatures at a constant level, whereas others employ behavioural thermoregulation. Here we test the effect of ambient temperature on locomotor activity and body temperature, and the relationship between the two parameters, in the highveld mole-rat. We exposed mole-rats to a 12L:12D and a DD light cycle at ambient temperatures of 30°C, 25°C and 20°C while locomotor activity and body temperature were measured simultaneously. In addition, we investigated the endogenous rhythms of locomotor activity and body temperature at different ambient temperatures. Mole-rats displayed nocturnal activity at all three ambient temperatures and were most active at 20°C, but least active at 30°C. Body temperature was highest at 30°C and lowest at 20°C, and the daily cycle was highly correlated with locomotor activity. We show that the mole-rats have endogenous rhythms for both locomotor activity and body temperature. However, the endogenous body temperature rhythm appears to be less robust compared to the locomotor activity rhythm. Female mole-rats appear to be more sensitive to temperature changes than males, increased heterothermy is evident at lower ambient temperatures, whilst males show smaller variation in their body temperatures with changing ambient temperatures. Mole-rats may rely more heavily on behavioural thermoregulation as it is more energy efficient in an already challenging environment. PMID:28072840

  15. Potential natural sensitizers extracted from the skin of Canarium odontophyllum fruits for dye-sensitized solar cells.

    PubMed

    Lim, Andery; Kumara, N T R N; Tan, Ai Ling; Mirza, Aminul Huq; Chandrakanthi, R L N; Petra, Mohammad Iskandar; Ming, Lim Chee; Senadeera, G K R; Ekanayake, Piyasiri

    2015-03-05

    Possibility of use of dye extract from skin samples of a seasonal, indigenous fruit from Borneo, namely Canarium odontophyllum, in dye sensitized solar cells (DSSCs) are explored. Three main groups of flavonoid pigments are detected and these pigments exhibit different UV-vis absorption properties, and hence showing different light harvesting capabilities. When applied in DSSCs. The detected pigment constituents of the extract consist of aurone (maritimein), anthocyanidin (pelargonidin) and anthocyanidin (cyanidin derivatives). When tested in DSSC, the highest conversion efficiency of 1.43% is exhibited by cyanidin derivatives, and this is followed by conversion efficiencies of 0.51% and 0.79% for aurone and pelargonidin, respectively. It is shown that individual pigments, like cyanidin derivatives and pelargonidin, exhibit higher power conversion efficiency when compared to that of C.odontophyllum skin pigment mixture (with a conversion efficiency of only 0.68%). The results indicate a possibility of masking effects of the pigments when used as a mixture. The acidification of C.odontophyllum skin pigments with concentrated hydrochloric acid improves the conversion efficiency of the mixture from 0.68% to 0.99%. The discussion in this paper will draw data and observations from the variation in absorption and adsorption properties, the HOMO-LUMO levels, the energy band gaps and the functional group compositions of the detected flavonoids.

  16. Potential natural sensitizers extracted from the skin of Canarium odontophyllum fruits for dye-sensitized solar cells

    NASA Astrophysics Data System (ADS)

    Lim, Andery; Kumara, N. T. R. N.; Tan, Ai Ling; Mirza, Aminul Huq; Chandrakanthi, R. L. N.; Petra, Mohammad Iskandar; Ming, Lim Chee; Senadeera, G. K. R.; Ekanayake, Piyasiri

    2015-03-01

    Possibility of use of dye extract from skin samples of a seasonal, indigenous fruit from Borneo, namely Canarium odontophyllum, in dye sensitized solar cells (DSSCs) are explored. Three main groups of flavonoid pigments are detected and these pigments exhibit different UV-vis absorption properties, and hence showing different light harvesting capabilities. When applied in DSSCs. The detected pigment constituents of the extract consist of aurone (maritimein), anthocyanidin (pelargonidin) and anthocyanidin (cyanidin derivatives). When tested in DSSC, the highest conversion efficiency of 1.43% is exhibited by cyanidin derivatives, and this is followed by conversion efficiencies of 0.51% and 0.79% for aurone and pelargonidin, respectively. It is shown that individual pigments, like cyanidin derivatives and pelargonidin, exhibit higher power conversion efficiency when compared to that of C.odontophyllum skin pigment mixture (with a conversion efficiency of only 0.68%). The results indicate a possibility of masking effects of the pigments when used as a mixture. The acidification of C.odontophyllum skin pigments with concentrated hydrochloric acid improves the conversion efficiency of the mixture from 0.68% to 0.99%. The discussion in this paper will draw data and observations from the variation in absorption and adsorption properties, the HOMO-LUMO levels, the energy band gaps and the functional group compositions of the detected flavonoids.

  17. Reliability review of the remote tool delivery system locomotor

    SciTech Connect

    Chesser, J.B.

    1999-04-01

    The locomotor being built by RedZone Robotics is designed to serve as a remote tool delivery (RID) system for waste retrieval, tank cleaning, viewing, and inspection inside the high-level waste tanks 8D-1 and 8D-2 at West Valley Nuclear Services (WVNS). The RTD systm is to be deployed through a tank riser. The locomotor portion of the RTD system is designed to be inserted into the tank and is to be capable of moving around the tank by supporting itself and moving on the tank internal structural columns. The locomotor will serve as a mounting platform for a dexterous manipulator arm. The complete RTD system consists of the locomotor, dexterous manipulator arm, cameras, lights, cables, hoses, cable/hose management system, power supply, and operator control station.

  18. Transient receptor potential (TRP) A1 activated currents in TRPV1 and cholecystokinin-sensitive cranial visceral afferent neurons.

    PubMed

    Choi, Myung-Jin; Jin, Zhenhua; Park, Yong Seek; Rhee, Young Kyoung; Jin, Young-Ho

    2011-04-06

    Culinary use of the pungent spices has potential health benefits including a reduction in food intake. Pungent spices often contain ingredients that activate members of the transient receptor potential (TRP) family A1 and evoke pain from capsaicin-sensitive somatosensory neurons. TRPA1 channel have also been identified on cranial visceral afferent neurons but their distribution and functional contributions are poorly understood. Visceral vagal neurons transduce mechanical and chemical signals from peripheral organs to the nucleus tractus solitarii. Many capsaicin-sensitive vagal afferents participate in peripheral satiety signaling that includes cholecystokinin (CCK) sensitive neurons. To assess signaling, the TRPA1 selective agonist allyl isothiocyanate (AITC) was tested together with CCK and capsaicin (200nM), a TRPV1 specific agonist. In isolated nodose neurons, AITC (0.05-0.2mM) evoked concentration-dependent inward currents in 38% of the tested neurons. The TRPA1 specific antagonist HC-030031 (10μM) blocked AITC responses. TRPA1 responses were mixed across neurons that were capsaicin-sensitive and -insensitive. However CCK evoked inward currents only on capsaicin-sensitive neurons and 28% of the CCK-sensitive neurons expressed TRPA1. Our results indicate that TRPA1 is co-expressed with TRPV1 in CCK-sensitive nodose neurons. The findings indicate a potential mechanism by which spices can act within cranial visceral afferent pathways mediating satiety and contribute to the reduction of the food intake associated with spiced diets.

  19. Apamin Sensitive Potassium Current Modulates Action Potential Duration Restitution and Arrhythmogenesis of Failing Rabbit Ventricles

    PubMed Central

    Hsieh, Yu-Cheng; Chang, Po-Cheng; Hsueh, Chia-Hsiang; Lee, Young Soo; Shen, Changyu; Weiss, James N.; Chen, Zhenhui; Ai, Tomohiko; Lin, Shien-Fong; Chen, Peng-Sheng

    2013-01-01

    Background Apamin-sensitive K currents (IKAS) are upregulated in heart failure (HF). We hypothesize that apamin can flatten action potential duration restitution (APDR) curve and reduce ventricular fibrillation (VF) duration in failing ventricles. Methods and Results We simultaneously mapped membrane potential and intracellular Ca (Cai) in 7 rabbits hearts with pacing-induced HF and in 7 normal hearts. A dynamic pacing protocol was used to determine APDR at baseline and after apamin (100 nM) infusion. Apamin did not change APD80 in normal ventricles, but prolonged APD80 in failing ventricles at either long (≥300 ms) or short (≤170 ms) pacing cycle length (PCL), but not at intermediate PCL. The maximal slope of APDR curve was 2.03 [95% CI, 1.73 to 2.32] in failing ventricles and 1.26 [95% CI, 1.13 to 1.40] in normal ventricles at baseline (p=0.002). After apamin administration, the maximal slope of APDR in failing ventricles decreased to 1.43 [95% CI, 1.01 to 1.84] (p=0.018) whereas no significant changes were observed in normal ventricles. During VF in failing ventricles, the number of phase singularities (baseline vs apamin, 4.0 vs 2.5), dominant frequency (13.0 Hz vs 10.0 Hz), and VF duration (160 s vs 80 s) were all significantly (p<0.05) decreased by apamin. Conclusions Apamin prolongs APD at long and short, but not at intermediate PCL in failing ventricles. IKAS upregulation may be antiarrhythmic by preserving the repolarization reserve at slow heart rate, but is proarrhythmic by steepening the slope of APDR curve which promotes the generation and maintenance of VF. PMID:23420832

  20. Apamin-sensitive potassium current modulates action potential duration restitution and arrhythmogenesis of failing rabbit ventricles.

    PubMed

    Hsieh, Yu-Cheng; Chang, Po-Cheng; Hsueh, Chia-Hsiang; Lee, Young Soo; Shen, Changyu; Weiss, James N; Chen, Zhenhui; Ai, Tomohiko; Lin, Shien-Fong; Chen, Peng-Sheng

    2013-04-01

    Apamin-sensitive K currents (I(KAS)) are upregulated in heart failure. We hypothesize that apamin can flatten action potential duration restitution (APDR) curve and can reduce ventricular fibrillation duration in failing ventricles. We simultaneously mapped membrane potential and intracellular Ca (Ca(i)) in 7 rabbit hearts with pacing-induced heart failure and in 7 normal hearts. A dynamic pacing protocol was used to determine APDR at baseline and after apamin (100 nmol/L) infusion. Apamin did not change APD(80) in normal ventricles, but prolonged APD(80) in failing ventricles at either long (≥300 ms) or short (≤170 ms) pacing cycle length, but not at intermediate pacing cycle length. The maximal slope of APDR curve was 2.03 (95% confidence interval, 1.73-2.32) in failing ventricles and 1.26 (95% confidence interval, 1.13-1.40) in normal ventricles at baseline (P=0.002). After apamin administration, the maximal slope of APDR in failing ventricles decreased to 1.43 (95% confidence interval, 1.01-1.84; P=0.018), whereas no significant changes were observed in normal ventricles. During ventricular fibrillation in failing ventricles, the number of phase singularities (baseline versus apamin, 4.0 versus 2.5), dominant frequency (13.0 versus 10.0 Hz), and ventricular fibrillation duration (160 versus 80 s) were all significantly (P<0.05) decreased by apamin. Apamin prolongs APD at long and short, but not at intermediate pacing cycle length in failing ventricles. I(KAS) upregulation may be antiarrhythmic by preserving the repolarization reserve at slow heart rate, but is proarrhythmic by steepening the slope of APDR curve, which promotes the generation and maintenance of ventricular fibrillation.

  1. Evidence for a Role of Orexin/Hypocretin System in Vestibular Lesion-Induced Locomotor Abnormalities in Rats

    PubMed Central

    Pan, Leilei; Qi, Ruirui; Wang, Junqin; Zhou, Wei; Liu, Jiluo; Cai, Yiling

    2016-01-01

    Vestibular damage can induce locomotor abnormalities in both animals and humans. Rodents with bilateral vestibular loss showed vestibular deficits syndrome such as circling, opisthotonus as well as locomotor and exploratory hyperactivity. Previous studies have investigated the changes in the dopamine system after vestibular loss, but the results are inconsistent and inconclusive. Numerous evidences indicate that the orexin system is implicated in central motor control. We hypothesized that orexin may be potentially involved in vestibular loss-induced motor disorders. In this study, we examined the effects of arsanilate- or 3,3′-iminodipropionitrile (IDPN)-induced vestibular lesion (AVL or IVL) on the orexin-A (OXA) labeling in rat hypothalamus using immunohistochemistry. The vestibular lesion-induced locomotor abnormalities were recorded and verified using a histamine H4 receptor antagonist JNJ7777120 (20 mg/kg, i.p.). The effects of the orexin receptor type 1 antagonist SB334867 (16 μg, i.c.v.) on these behavior responses were also investigated. At 72 h post-AVL and IVL, animals exhibited vestibular deficit syndrome and locomotor hyperactivity in the home cages. These responses were significantly alleviated by JNJ7777120 which also eliminated AVL-induced increases in exploratory behavior in an open field. The numbers of OXA-labeled neurons in the hypothalamus were significantly increased in the AVL animals at 72 h post-AVL and in the IVL animals at 24, 48, and 72 h post-IVL. SB334867 significantly attenuated the vestibular deficit syndrome and locomotor hyperactivity at 72 h post-AVL and IVL. It also decreased exploratory behavior in the AVL animals. These results suggested that the alteration of OXA expression might contribute to locomotor abnormalities after acute vestibular lesion. The orexin receptors might be the potential therapeutic targets for vestibular disorders. PMID:27507932

  2. The locomotor anatomy of Australopithecus afarensis.

    PubMed

    Stern, J T; Susman, R L

    1983-03-01

    The postcranial skeleton of Australopithecus afarensis from the Hadar Formation, Ethiopia, and the footprints from the Laetoli Beds of northern Tanzania, are analyzed with the goal of determining (1) the extent to which this ancient hominid practiced forms of locomotion other than terrestrial bipedality, and (2) whether or not the terrestrial bipedalism of A. afarensis was notably different from that of modern humans. It is demonstrated that A. afarensis possessed anatomic characteristics that indicate a significant adaptation for movement in the trees. Other structural features point to a mode of terrestrial bipedality that involved less extension at the hip and knee than occurs in modern humans, and only limited transfer of weight onto the medial part of the ball of the foot, but such conclusions remain more tentative than that asserting substantive arboreality. A comparison of the specimens representing smaller individuals, presumably female, to those of larger individuals, presumably male, suggests sexual differences in locomotor behavior linked to marked size dimorphism. The males were probably less arboreal and engaged more frequently in terrestrial bipedalism. In our opinion, A. afarensis from Hadar is very close to what can be called a "missing link." We speculate that earlier representatives of the A. afarensis lineage will present not a combination of arboreal and bipedal traits, but rather the anatomy of a generalized ape.

  3. Locomotor sequence learning in visually guided walking.

    PubMed

    Choi, Julia T; Jensen, Peter; Nielsen, Jens Bo

    2016-04-01

    Voluntary limb modifications must be integrated with basic walking patterns during visually guided walking. In this study we tested whether voluntary gait modifications can become more automatic with practice. We challenged walking control by presenting visual stepping targets that instructed subjects to modify step length from one trial to the next. Our sequence learning paradigm is derived from the serial reaction-time (SRT) task that has been used in upper limb studies. Both random and ordered sequences of step lengths were used to measure sequence-specific and sequence-nonspecific learning during walking. In addition, we determined how age (i.e., healthy young adults vs. children) and biomechanical factors (i.e., walking speed) affected the rate and magnitude of locomotor sequence learning. The results showed that healthy young adults (age 24 ± 5 yr,n= 20) could learn a specific sequence of step lengths over 300 training steps. Younger children (age 6-10 yr,n= 8) had lower baseline performance, but their magnitude and rate of sequence learning were the same compared with those of older children (11-16 yr,n= 10) and healthy adults. In addition, learning capacity may be more limited at faster walking speeds. To our knowledge, this is the first study to demonstrate that spatial sequence learning can be integrated with a highly automatic task such as walking. These findings suggest that adults and children use implicit knowledge about the sequence to plan and execute leg movement during visually guided walking.

  4. Locomotor-respiratory coupling during wheelchair propulsion.

    PubMed

    MacDonald, M L; Kirby, R L; Nugent, S T; MacLeod, D A

    1992-04-01

    Visceral movement due to impact loading is believed to play a role in the locomotor-respiratory coupling (LRC) that has been detected in a number of mammalian species. In the bird and bat species in which LRC has been described, the effect of the wing muscles on the timing of respiration appears to be a dominant influence. To test the hypothesis that LRC occurs in humans propelling wheelchairs (where there is no impact loading and the arms are used for locomotion), we studied 10 wheelchair athletes on a motorized treadmill at three speeds. Each subject's data were analyzed by spectral analysis (based on the fast Fourier transform), which detected apparent LRC (rates within 1% of a single-digit integer ratio) in 12 (40%) of the 30 test settings. However, a control analysis, in which each subject's arm-thrust rates were compared with another subject's breathing rates, revealed apparent (but false) coupling in 8 (27%), not significantly less often (using the chi 2 test). These findings appear to refute the hypothesis that LRC occurs during wheelchair propulsion. These data are consistent with the theory that the visceral piston is important to LRC and suggest that rhythmic arm movements are insufficient to induce the phenomenon in this setting.

  5. Telemetered in vivo strain analysis of locomotor mechanics of brachiating gibbons.

    PubMed

    Swartz, S M; Bertram, J E; Biewener, A A

    1989-11-16

    The slender elongated form that is characteristic of the forelimb long bones of gibbons (Hylobates) has long been attributed to their functional adaptation to habitual armswinging locomotion, although potential selective advantages of this morphology for brachiation have yet to be demonstrated. If the forces exerted on the limb skeleton during brachiation indeed differ greatly from those of other locomotor modes, then the changes in skeletal loading accompanying a shift in locomotor behaviour could favour alterations in skeletal morphology in brachiating lineages. In vivo skeletal strain patterns recorded by using radiotelemetry during brachiation indicate that the forelimb bones of the gibbon are loaded in substantial tension and show reduced bending and compression in comparison with those of other mammals. We suggest that this unique loading regime could have contributed to the evolution of the distinctive morphology of hylobatid limbs.

  6. Modeling skin sensitization potential of mechanistically hard-to-be-classified aniline and phenol compounds with quantum mechanistic properties.

    PubMed

    Ouyang, Qin; Wang, Lirong; Mu, Ying; Xie, Xiang-Qun

    2014-12-24

    Advanced structure-activity relationship (SAR) modeling can be used as an alternative tool for identification of skin sensitizers and in improvement of the medical diagnosis and more effective practical measures to reduce the causative chemical exposures. It can also circumvent ethical concern of using animals in toxicological tests, and reduce time and cost. Compounds with aniline or phenol moieties represent two large classes of frequently skin sensitizing chemicals but exhibiting very variable, and difficult to predict, potency. The mechanisms of action are not well-understood. A group of mechanistically hard-to-be-classified aniline and phenol chemicals were collected. An in silico model was established by statistical analysis of quantum descriptors for the determination of the relationship between their chemical structures and skin sensitization potential. The sensitization mechanisms were investigated based on the features of the established model. Then the model was utilized to analyze a subset of FDA approved drugs containing aniline and/or phenol groups for prediction of their skin sensitization potential. A linear discriminant model using the energy of the highest occupied molecular orbital (ϵHOMO) as the descriptor yielded high prediction accuracy. The contribution of ϵHOMO as a major determinant may suggest that autoxidation or free radical binding could be involved. The model was further applied to predict allergic potential of a subset of FDA approved drugs containing aniline and/or phenol moiety. The predictions imply that similar mechanisms (autoxidation or free radical binding) may also play a role in the skin sensitization caused by these drugs. An accurate and simple quantum mechanistic model has been developed to predict the skin sensitization potential of mechanistically hard-to-be-classified aniline and phenol chemicals. The model could be useful for the skin sensitization potential predictions of a subset of FDA approved drugs.

  7. Aversive startle potentiation and fear pathology: Mediating role of threat sensitivity and moderating impact of depression.

    PubMed

    Yancey, James R; Vaidyanathan, Uma; Patrick, Christopher J

    2015-11-01

    Enhanced startle reactivity during exposure to unpleasant cues (aversive startle potentiation; ASP) appears in the RDoC matrix as a physiological index of acute threat response. Increased ASP has been linked to focal fear disorders and to scale measures of dispositional fearfulness (i.e., threat sensitivity; THT+). However, some studies have reported reduced ASP for fear pathology accompanied by major depressive disorder (MDD) or pervasive distress. The current study evaluated whether (a) THT+ as indexed by reported dispositional fearfulness mediates the relationship between fear disorders (when unaccompanied by depression) and ASP, and (b) depression moderates relations of THT+ and fear disorders with ASP. Fear disorder participants without MDD showed enhanced ASP whereas those with MDD (or other distress conditions) showed evidence of reduced ASP. Continuous THT+ scores also predicted ASP, and this association: (a) was likewise moderated by depression/distress, and (b) accounted for the relationship between ASP and fear pathology without MDD. These findings point to a role for the RDoC construct of acute threat, operationalized dispositionally, in enhanced ASP shown by individuals with fear pathology unaccompanied by distress pathology.

  8. Chemical reactivity trends of ergotamine and butenolide from electrostatic potentials and charge sensitivities

    SciTech Connect

    Mrozek, J.; Michalak, A.

    1995-12-05

    A set of reactivity indices, including maps of the electrostatic potential and local and condensed Fukui function (FF) indices in the atomic resolution, are reported for two vasoconstricting mycotoxins: butenolide and ergotamine; both the finite difference approach of Parr and Yan as well as charge sensitivity analysis, determining the charge responses via the inversion of the hardness tensor, have been used to generate the FF data. These two routes of arriving at the atomic FF indices provide an opportunity to evaluate the available parametrizations of the semiempirical NDDO-type of methods which have been used to determine the input charge distribution; namely, the best parametrization should generate consistent FF predictions resulting from both approaches. For butenolide, the MNDO parametrization was found to fulfill this consistency requirement. The chemical reactivity information has been used to trace possible similarities in reactivity trends of the butenolide molecule and the related fragment of ergotamine, toward hypothetical nucleophilic, electrophilic, and radical attacks. These predictions have been compared to experimental data available for other unsaturated lactones. 13 refs., 18 figs., 1 tab.

  9. Spatial representation in the social interaction potential metric: an analysis of scale and parameter sensitivity

    NASA Astrophysics Data System (ADS)

    Li, Xiao; Farber, Steven

    2016-10-01

    The social interaction potential (SIP) metric measures urban structural constraints on social interaction opportunities of a metropolitan region based on the time geographic concept of joint accessibility. Previous implementations of the metric used an interaction surface based on census tracts and the locations of their centroids. This has been shown to be a shortcoming, as the metric strongly depends on the scale of the zoning system in the region, making it difficult to compare the SIP metric between metropolitan regions. This research explores the role of spatial representation in the SIP metric and identifies a suitable grid-based representation that allows for comparison between regions while retaining cost-effectiveness with respect to computational burden. We also report on findings from an extensive sensitivity analysis investigating the SIP metric's input parameters such as a travel flow congestion factor and the length of the allowable time budget for social activities. The results provide new insights on the role of the modifiable areal unit problem in the computation of time geographic measures of accessibility.

  10. Effects of grating spatial orientation on visual evoked potentials and contrast sensitivity in multiple sclerosis.

    PubMed

    Logi, F; Pellegrinetti, A; Bonfiglio, L; Baglini, O; Siciliano, G; Ludice, A; Sartucci, F

    2001-02-01

    Previous studies suggest a delay of pattern visual evoked potentials (PVEPs) in multiple sclerosis (MS) depending on grating orientation. We examined a group of 14 patients with definite MS recording PVEPs to vertical and horizontal grating and analysing latency and amplitude of P60, N70 and P100 waves. We evaluated contrast sensitivity (CS) to dark and bright bars of several spatial frequencies (SF). The aim was to evaluate the diagnostic value of evoked responses and CS in revealing involvement of cortical structures. PVEPs to 1 degrees cycle/degree (c/d) vertical bars were abnormal in 25% for P60, in 32% for N70 and in 36%, for P100; in 25%, 36% and 42% respectively at 4 c/d; as regards horizontal bars at 1 c/d we found alterations of P60, N70 and P100 in 11%, 19% and 27% respectively; at 4 c/d in 19%, 27%) and 35%. CS resulted more abnormal for vertical grating, with a maximum impairment for 3.7 c/d SF. We may conclude that the use of vertical grating in clinical routine is more reliable both for PVEPs and CS testing; in addition CS can be abnormal even with normal PVEPs: this could mean an early impairment of CS and provide useful indications about a subclinical involvement of visual cortex.

  11. Bone-Targeted Acid-Sensitive Doxorubicin Conjugate Micelles as Potential Osteosarcoma Therapeutics

    PubMed Central

    2015-01-01

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic d-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data. PMID:25291150

  12. An 'Early Warning System' for the prevention of dredging potential impacts on sensitive areas

    NASA Astrophysics Data System (ADS)

    Piermattei, Viviana; Martellucci, Riccardo; Pierattini, Alberto; Bonamano, Simone; Paladini de Mendoza, Francesco; Albani, Marta; Stefanì, Chiara; Madonia, Alice; Fersini, Giorgio; Marcelli, Marco

    2016-04-01

    Coastal marine ecosystems are increasingly subject to multiple pressures and stressors produced by the effects of human activities. Intense and frequent disturbances which affect marine environment can derive from dredging activity, which is a fundamental management for most ports and harbours. The potential environmental effects of dredging procedures are generally due to the excavation of material from the sea bottom and the relocation elsewhere for disposal, overflow from the dredger and loss of material from pipelines during transport. Depending on the location and the intensity of these activities the marine environment, particularly sensitive areas, may be affected by dredging. The main environmental effects can be associated with suspended sediments and increases in turbidity into the water column, which can have adverse effects on marine animals and plants by reducing light penetration and by physical disturbance. For this reason it is fundamental to implement a real time monitoring system to control and prevent negative effects, enabling a rapid response to adverse water quality conditions and a fast activation of mitigation procedures, in agreement with all the reference authorities. In this work we present the development of an innovative 'Early Warning System' based on fixed stations, ad hoc in situ surveys and forecasting models, which was applied to a dredging activity carried out in the Gulf of Gaeta (Latium, Italy). It represents an extension of the C-CEMS (Civitavecchia Coastal Environmental Monitoring System) network, which is operative in the Tyrrhenian sea since 2005.

  13. A preliminary investigation of the potential mechanical sensitivity of vertical comb drives

    NASA Astrophysics Data System (ADS)

    Gallagher, E.; Moussa, W.

    2014-10-01

    This article describes a preliminary step taken in investigating the potential of vertical comb drives to be used as force-compensation mechanisms in interfacial force microscopes, by exploring the lower limit of the stiffness of the springs the comb drives can be fabricated with. The stiffness of their springs will affect the sensitivity of the microscope. Six vertical comb drives were fabricated for this study; the dimensions of their spring beams were chosen with the intention of giving them stiffnesses of three different orders of magnitude. During fabrication it was found that etching the tops of some of the teeth down to create the vertical offset between the combs can be done using only photoresist to mask the rest of the teeth. The stiffnesses of the fabricated springs were estimated by applying loads to them and measuring their resulting deflections. Weights were applied to the two comb drives with the stiffest springs. Voltages were also applied to them so as to determine the force-voltage relationship for their comb design. Since the other four comb drives had the same comb design, the stiffnesses of their springs could be estimated from the displacements of their movable combs when voltages were applied to them.

  14. Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics.

    PubMed

    Low, Stewart A; Yang, Jiyuan; Kopeček, Jindřich

    2014-11-19

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic D-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data.

  15. The anatomy and physiology of the locomotor system.

    PubMed

    Farley, Alistair; McLafferty, Ella; Hendry, Charles

    Mobilisation is one of the activities of living. The term locomotor system refers to those body tissues and organs responsible for movement. Nurses and healthcare workers should be familiar with the body structures that enable mobilisation to assist those in their care with this activity. This article outlines the structure and function of the locomotor system, including the skeleton, joints, muscles and muscle attachments. Two common bone disorders, osteoporosis and osteoarthritis, are also considered.

  16. Locomotor requirements for bipedal locomotion: a Delphi survey.

    PubMed

    Hedman, Lois Deming; Morris, David M; Graham, Cecilia L; Brown, Cynthia J; Ford, Matthew P; Ingram, Debbie A; Hilliard, Marjorie J; Salzman, Alice J

    2014-01-01

    Bipedal locomotor control requirements may be useful as classifications for walking dysfunction because they go beyond gait analysis to address all issues contributing to walking dysfunction. The objective of this study was to determine whether locomotor experts could achieve consensus about the requirements for bipedal locomotion. Locomotor experts from physical therapy and other related professions participated in an electronic mail Delphi survey. Experts recommended additions, deletions, rewording, and merges for 15 proposed locomotor requirements in round 1. In rounds 2 and 3, panelists commented on and rated the validity, mutual exclusiveness, and understandability of each requirement. Consensus was defined a priori as: (1) 75% or more panelists agree or strongly agree that a requirement is valid, mutually exclusive, and understandable in round 3; (2) no difference between round 2 and 3 ratings with kappa coefficients ≥.60; and (3) a reduction in panelists who commented and convergence of comments between rounds 1 and 3. Content analysis and nonparametric statistics were used. Fifty-eight panelists reached full consensus on 5 locomotor requirements (Initiation, Termination, Anticipatory Dynamic Balance, Multi-Task Capacity, and Walking Confidence) and partial consensus for 7 other requirements. There were no significant differences in ratings between rounds 2 and 3, and there was a decrease in the percentage of panelists who commented between rounds 1 and 3. The study's 6-month time frame may have contributed to panelist attrition. Locomotor experts achieved consensus on several bipedal locomotor requirements. With validation, these requirements can provide the framework for a clinically feasible and systematic diagnostic tool for physical therapists to categorize locomotor problems and standardize intervention for walking dysfunction.

  17. Effects of acute and repeated administration of N-methyl-D-aspartate (NMDA) into the ventral tegmental area: locomotor activating effects of NMDA and cocaine.

    PubMed

    Schenk, S; Partridge, B

    1997-09-26

    Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-D-aspartate (NMDA) (0.6, 1.25 or 2.5 microg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.

  18. C57BL/6J MICE EXHIBIT REDUCED DOPAMINE D3 RECEPTOR-MEDIATED LOCOMOTOR-INHIBITORY FUNCTION RELATIVE TO DBA/2J MICE

    PubMed Central

    McNAMARA, R. K.; LEVANT, B.; TAYLOR, B.; AHLBRAND, R.; LIU, Y.; SULLIVAN, J. R.; STANFORD, K.; RICHTAND, N. M.

    2007-01-01

    Previous reports have identified greater sensitivity to the locomotor-stimulating, sensitizing, and reinforcing effects of amphetamine in inbred C57BL/6J mice relative to inbred DBA/2J mice. The dopamine D3 receptor (D3R) plays an inhibitory role in the regulation of rodent locomotor activity, and exerts inhibitory opposition to D1 receptor (D1R)-mediated signaling. Based on these observations, we investigated D3R expression and D3R-mediated locomotor-inhibitory function, as well as D1R binding and D1R-mediated locomotor-stimulating function, in C57BL/6J and DBA/2J mice. C57BL/6J mice exhibited lower D3R binding density (−32%) in the ventral striatum (nucleus accumbens/islands of Calleja), lower D3R mRNA expression (−26%) in the substantia nigra/ventral tegmentum, and greater D3R mRNA expression (+40%) in the hippocampus, relative to DBA/2J mice. There were no strain differences in DR3 mRNA expression in the ventral striatum or prefrontal cortex, nor were there differences in D1R binding in the ventral striatum. Behaviorally, C57BL/6J mice were less sensitive to the locomotor-inhibitory effect of the D3R agonist PD128907 (10 μg/kg), and more sensitive to the locomotor-stimulating effects of novelty, amphetamine (1 mg/kg), and the D1R-like agonist ±-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8,-diol hydrochloride (SKF38393) (5–20 mg/kg) than DBA/2J mice. While the selective D3R antagonist N-(4-[4-{2,3-dichlorphenyl}-1 piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904) (0.01–1.0 mg/kg) augmented novelty-, amphetamine-, and SKF38393-induced locomotor activity in DBA/2J mice, it reduced novelty-induced locomotor activity in C57BL/6J mice. Collectively, these results demonstrate that C57BL/6J mice exhibit less D3R-mediated inhibitory function relative to DBA/2J mice, and suggest that reduced D3R-mediated inhibitory function may contribute to heightened sensitivity to the locomotor-stimulating effects of amphetamine in the C57BL/6J mouse strain

  19. Locomotor adaptation and locomotor adaptive learning in Parkinson's disease and normal aging.

    PubMed

    Roemmich, Ryan T; Nocera, Joe R; Stegemöller, Elizabeth L; Hassan, Anhar; Okun, Michael S; Hass, Chris J

    2014-02-01

    Locomotor adaptation enables safe, efficient navigation among changing environments. We investigated how healthy young (HYA) and older (HOA) adults and persons with Parkinson's disease (PD) adapt to walking on a split-belt treadmill, retain adapted gait parameters during re-adaptation, and store aftereffects to conventional treadmill walking. Thirteen PD, fifteen HYA, and fifteen HOA walked on a split-belt treadmill for ten minutes with one leg twice as fast as the other. Participants later re-adapted to the same conditions to assess retention of the split-belt gait pattern. After re-adaptation, we assessed aftereffects of this pattern during conventional treadmill walking. Persons with PD exhibited step length asymmetry throughout many adaptation and adaptive learning conditions. Early adaptation was similar across groups, though HYA and HOA continued to adapt into late adaptation while PD did not. Despite pervasive step length asymmetry among conditions which were symmetric in HYA and HOA, persons with PD demonstrated significant step length aftereffects during conventional treadmill walking after split-belt walking. Though they may exhibit a default asymmetry under various walking conditions, persons with PD can adapt and store new walking patterns. Locomotor adaptation therapy may be effective in ameliorating asymmetric gait deficits in persons with PD. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  20. Damage caused during hypoxia and reoxygenation in the locomotor muscle of the crab Neohelice granulata (Decapoda: Varunidae).

    PubMed

    Geihs, Márcio Alberto; Vargas, Marcelo Alves; Nery, Luiz Eduardo Maia

    2014-06-01

    The aim of this work was to determine whether different durations of severe hypoxia (0.5 mg O2 L(-1)) followed by reoxygenation cause damage to the locomotor muscle of the crab Neohelice granulata. We evaluated reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential, and aerobic fiber area of the locomotor muscle after different periods of hypoxia (1, 4, or 10h) followed by 30 or 120 min of reoxygenation. Additionally, changes in cell volume, mitochondrial dysfunction, and infiltration of hemocytes were evaluated after hypoxia and a subsequent 2, 24, or 48 h of reoxygenation. After hypoxia, neither ROS nor LPO increased. However, mitochondrial membrane potential and aerobic fiber area decreased in a time-dependent manner. After reoxygenation, the ROS and LPO levels increased and mitochondrial membrane potential decreased, but these quickly recovered in crabs exposed to 4h of hypoxia. On the other hand, alterations of mitochondria resulted in morphological changes in aerobic fibers, which required more time to recover during reoxygenation after 10h of hypoxia. The locomotor muscles of the crab N. granulata suffer damage after hypoxia and reoxygenation. The intensity of this damage is dependent on the duration of hypoxia. In all experimental situations analyzed, the locomotor muscle of this crab was capable of recovery.

  1. NALOXONE BLOCKS ETHANOL-MEDIATED APPETITIVE CONDITIONING AND LOCOMOTOR ACTIVATION IN ADOLESCENT RATS

    PubMed Central

    Pautassi, Ricardo Marcos; Nizhnikov, Michael E.; Acevedo, María Belén; Spear, Norman E.

    2010-01-01

    Age-related differences in ethanol sensitivity could put adolescents at risk for developing alcohol-related problems. Little information exists, however, about adolescent sensitivity to ethanol's appetitive effects and the neurobiological mechanisms underlying ethanol reinforcement during this developmental stage. The present study assessed the role of the opioid system in adolescent rats in an appetitive second-order schedule of ethanol reinforcement and ethanol-induced locomotor stimulation. On postnatal day 32 (PD32), animals were pretreated with the general opioid antagonist naloxone (0.0, 0.75, 1.50, or 2.5 mg/kg) and then given pairings of ethanol (0.0 or 2.0 g/kg, intragastrically) with intraoral pulses of water (conditioned stimulus 1 [CS1], first-order conditioning phase). CS1 delivery occurred 30–45 min after ethanol administration when the effect of ethanol was assumed to be appetitive. On PD33, adolescents were exposed to CS1 (second-order conditioning phase) while in a chamber featuring distinctive exteroceptive cues (CS2). Preference for CS2 was then tested. Adolescents given CS1-ethanol pairings exhibited greater preference for CS2 than controls, indicating ethanol-mediated reinforcement, but only when not pretreated with naloxone. Blood alcohol levels during conditioning were not altered by naloxone. Experiment 2 revealed that ethanol induced locomotor activation soon after administration, and naloxone dose-dependently suppressed this stimulating effect. The present study indicates that adolescent rats are sensitive to ethanol's reinforcing and locomotor-stimulating effects. Both effects of ethanol appear to be mediated by endogenous opioid system activation. PMID:20708642

  2. Naloxone blocks ethanol-mediated appetitive conditioning and locomotor activation in adolescent rats.

    PubMed

    Pautassi, Ricardo Marcos; Nizhnikov, Michael E; Acevedo, María Belén; Spear, Norman E

    2011-01-01

    Age-related differences in ethanol sensitivity could put adolescents at risk for developing alcohol-related problems. Little information exists, however, about adolescent sensitivity to ethanol's appetitive effects and the neurobiological mechanisms underlying ethanol reinforcement during this developmental stage. The present study assessed the role of the opioid system in adolescent rats in an appetitive second-order schedule of ethanol reinforcement and ethanol-induced locomotor stimulation. On postnatal day 32 (PD32), animals were pretreated with the general opioid antagonist naloxone (0.0, 0.75, 1.50, or 2.5 mg/kg) and then given pairings of ethanol (0.0 or 2.0 g/kg, intragastrically) with intraoral pulses of water (conditioned stimulus 1 [CS₁], first-order conditioning phase). CS₁ delivery occurred 30-45 min after ethanol administration when the effect of ethanol was assumed to be appetitive. On PD33, adolescents were exposed to CS₁ (second-order conditioning phase) while in a chamber featuring distinctive exteroceptive cues (CS₂). Preference for CS₂ was then tested. Adolescents given CS₁-ethanol pairings exhibited greater preference for CS₂ than controls, indicating ethanol-mediated reinforcement, but only when not pretreated with naloxone. Blood alcohol levels during conditioning were not altered by naloxone. Experiment 2 revealed that ethanol-induced locomotor activation soon after administration, and naloxone dose-dependently suppressed this stimulating effect. The present study indicates that adolescent rats are sensitive to ethanol's reinforcing and locomotor-stimulating effects. Both effects of ethanol appear to be mediated by endogenous opioid system activation.

  3. Mercury-sensitive water channels as possible sensors of water potentials in pollen.

    PubMed

    Shachar-Hill, Bruria; Hill, Adrian E; Powell, Janet; Skepper, Jeremy N; Shachar-Hill, Yair

    2013-11-01

    The growing pollen tube is central to plant reproduction and is a long-standing model for cellular tip growth in biology. Rapid osmotically driven growth is maintained under variable conditions, which requires osmosensing and regulation. This study explores the mechanism of water entry and the potential role of osmosensory regulation in maintaining pollen growth. The osmotic permeability of the plasmalemma of Lilium pollen tubes was measured from plasmolysis rates to be 1.32±0.31×10(-3) cm s(-1). Mercuric ions reduce this permeability by 65%. Simulations using an osmotic model of pollen tube growth predict that an osmosensor at the cell membrane controls pectin deposition at the cell tip; inhibiting the sensor is predicted to cause tip bursting due to cell wall thinning. It was found that adding mercury to growing pollen tubes caused such a bursting of the tips. The model indicates that lowering the osmotic permeability per se does not lead to bursting but rather to thickening of the tip. The time course of induced bursting showed no time lag and was independent of mercury concentration, compatible with a surface site of action. The submaximal bursting response to intermediate mercuric ion concentration was independent of the concentration of calcium ions, showing that bursting is not due to a competitive inhibition of calcium binding or entry. Bursting with the same time course was also shown by cells growing on potassium-free media, indicating that potassium channels (implicated in mechanosensing) are not involved in the bursting response. The possible involvement of mercury-sensitive water channels as osmosensors and current knowledge of these in pollen cells are discussed.

  4. Transforming potential and matrix stiffness co-regulate confinement sensitivity of tumor cell migration

    PubMed Central

    Pathak, Amit

    2013-01-01

    It is now well established that tumor cell invasion through tissue is strongly regulated by the microstructural and mechanical properties of the extracellular matrix (ECM). However, it remains unclear how these physical microenvironmental inputs are jointly processed with oncogenic lesions to drive invasion. In this study, we address this open question by combining a microfabricated polyacrylamide channel (μPAC) platform that enables independent control of ECM stiffness and confinement with an isogenically-matched breast tumor progression series in which the oncogenes ErbB2 and 14-3-3ζ are overexpressed independently or in tandem. We find that increasing channel confinement and overexpressing ErbB2 both promote cell migration to a similar degree when other parameters are kept constant. In contrast, 14-3-3ζ overexpression slows migration speed, and does so in a fashion that dwarfs effects of ECM confinement and stiffness. We also find that ECM stiffness dramatically enhances cell motility when combined with ErbB2 overexpression, demonstrating that biophysical cues and cell-intrinsic parameters promote cell invasion in an integrative manner. Morphometric analysis of cells inside the μPAC platform reveals that the rapid cell migration induced by narrow channels and ErbB2 overexpression both are accompanied by increased cell polarization. Disruption of this polarization by pharmacological inhibition of Rac GTPase phenocopies 14-3-3ζ overexpression by reducing cell polarization and slowing migration. By systematically measuring migration speed as a function of matrix stiffness and confinement, we also quantify for the first time the sensitivity of migration speed to microchannel properties and transforming potential. These results demonstrate that oncogenic lesions and ECM biophysical properties can synergistically interact to drive invasive migration, and that both inputs may act through common molecular mechanisms to enhance migration speed. PMID:23832051

  5. Transforming potential and matrix stiffness co-regulate confinement sensitivity of tumor cell migration.

    PubMed

    Pathak, Amit; Kumar, Sanjay

    2013-08-01

    It is now well established that tumor cell invasion through tissue is strongly regulated by the microstructural and mechanical properties of the extracellular matrix (ECM). However, it remains unclear how these physical microenvironmental inputs are jointly processed with oncogenic lesions to drive invasion. In this study, we address this open question by combining a microfabricated polyacrylamide channel (μPAC) platform that enables independent control of ECM stiffness and confinement with an isogenically-matched breast tumor progression series in which the oncogenes ErbB2 and 14-3-3ζ are overexpressed independently or in tandem. We find that increasing channel confinement and overexpressing ErbB2 both promote cell migration to a similar degree when other parameters are kept constant. In contrast, 14-3-3ζ overexpression slows migration speed, and does so in a fashion that dwarfs effects of ECM confinement and stiffness. We also find that ECM stiffness dramatically enhances cell motility when combined with ErbB2 overexpression, demonstrating that biophysical cues and cell-intrinsic parameters promote cell invasion in an integrative manner. Morphometric analysis of cells inside the μPAC platform reveals that the rapid cell migration induced by narrow channels and ErbB2 overexpression are both accompanied by increased cell polarization. Disruption of this polarization occurs by pharmacological inhibition of Rac GTPase phenocopies 14-3-3ζ overexpression by reducing cell polarization and slowing migration. By systematically measuring migration speed as a function of matrix stiffness and confinement, we also quantify for the first time the sensitivity of migration speed to microchannel properties and transforming potential. These results demonstrate that oncogenic lesions and ECM biophysical properties can synergistically interact to drive invasive migration, and that both inputs may act through common molecular mechanisms to enhance migration speed.

  6. Mercury-sensitive water channels as possible sensors of water potentials in pollen

    PubMed Central

    Hill, Adrian E.

    2013-01-01

    The growing pollen tube is central to plant reproduction and is a long-standing model for cellular tip growth in biology. Rapid osmotically driven growth is maintained under variable conditions, which requires osmosensing and regulation. This study explores the mechanism of water entry and the potential role of osmosensory regulation in maintaining pollen growth. The osmotic permeability of the plasmalemma of Lilium pollen tubes was measured from plasmolysis rates to be 1.32±0.31×10–3 cm s–1. Mercuric ions reduce this permeability by 65%. Simulations using an osmotic model of pollen tube growth predict that an osmosensor at the cell membrane controls pectin deposition at the cell tip; inhibiting the sensor is predicted to cause tip bursting due to cell wall thinning. It was found that adding mercury to growing pollen tubes caused such a bursting of the tips. The model indicates that lowering the osmotic permeability per se does not lead to bursting but rather to thickening of the tip. The time course of induced bursting showed no time lag and was independent of mercury concentration, compatible with a surface site of action. The submaximal bursting response to intermediate mercuric ion concentration was independent of the concentration of calcium ions, showing that bursting is not due to a competitive inhibition of calcium binding or entry. Bursting with the same time course was also shown by cells growing on potassium-free media, indicating that potassium channels (implicated in mechanosensing) are not involved in the bursting response. The possible involvement of mercury-sensitive water channels as osmosensors and current knowledge of these in pollen cells are discussed. PMID:24098048

  7. The Use of Germinants to Potentiate the Sensitivity of Bacillus anthracis Spores to Peracetic Acid.

    PubMed

    Celebi, Ozgur; Buyuk, Fatih; Pottage, Tom; Crook, Ant; Hawkey, Suzanna; Cooper, Callum; Bennett, Allan; Sahin, Mitat; Baillie, Leslie

    2016-01-01

    Elimination of Bacillus anthracis spores from the environment is a difficult and costly process due in part to the toxicity of current sporicidal agents. For this reason we investigated the ability of the spore germinants L-alanine (100 mM) and inosine (5 mM) to reduce the concentration of peracetic acid (PAA) required to inactivate B. anthracis spores. While L-alanine significantly enhanced (p = 0.0085) the bactericidal activity of 500 ppm PAA the same was not true for inosine suggesting some form of negative interaction. In contrast the germinant combination proved most effective at 100 ppm PAA (p = 0.0009). To determine if we could achieve similar results in soil we treated soil collected from the burial site of an anthrax infected animal which had been supplemented with spores of the Sterne strain of B. anthracis to increase the level of contamination to 10(4) spores/g. Treatment with germinants followed 1 h later by 5000 ppm PAA eliminated all of the spores. In contrast direct treatment of the animal burial site using this approach delivered using a back pack sprayer had no detectable effect on the level of B. anthracis contamination or on total culturable bacterial numbers over the course of the experiment. It did trigger a significant, but temporary, reduction (p < 0.0001) in the total spore count suggesting that germination had been triggered under real world conditions. In conclusion, we have shown that the application of germinants increase the sensitivity of bacterial spores to PAA. While the results of the single field trial were inconclusive, the study highlighted the potential of this approach and the challenges faced when attempting to perform real world studies on B. anthracis spores contaminated sites.

  8. The Use of Germinants to Potentiate the Sensitivity of Bacillus anthracis Spores to Peracetic Acid

    PubMed Central

    Celebi, Ozgur; Buyuk, Fatih; Pottage, Tom; Crook, Ant; Hawkey, Suzanna; Cooper, Callum; Bennett, Allan; Sahin, Mitat; Baillie, Leslie

    2016-01-01

    Elimination of Bacillus anthracis spores from the environment is a difficult and costly process due in part to the toxicity of current sporicidal agents. For this reason we investigated the ability of the spore germinants L-alanine (100 mM) and inosine (5 mM) to reduce the concentration of peracetic acid (PAA) required to inactivate B. anthracis spores. While L-alanine significantly enhanced (p = 0.0085) the bactericidal activity of 500 ppm PAA the same was not true for inosine suggesting some form of negative interaction. In contrast the germinant combination proved most effective at 100 ppm PAA (p = 0.0009). To determine if we could achieve similar results in soil we treated soil collected from the burial site of an anthrax infected animal which had been supplemented with spores of the Sterne strain of B. anthracis to increase the level of contamination to 104 spores/g. Treatment with germinants followed 1 h later by 5000 ppm PAA eliminated all of the spores. In contrast direct treatment of the animal burial site using this approach delivered using a back pack sprayer had no detectable effect on the level of B. anthracis contamination or on total culturable bacterial numbers over the course of the experiment. It did trigger a significant, but temporary, reduction (p < 0.0001) in the total spore count suggesting that germination had been triggered under real world conditions. In conclusion, we have shown that the application of germinants increase the sensitivity of bacterial spores to PAA. While the results of the single field trial were inconclusive, the study highlighted the potential of this approach and the challenges faced when attempting to perform real world studies on B. anthracis spores contaminated sites. PMID:26858699

  9. Adaptive locomotor behavior in larval zebrafish.

    PubMed

    Portugues, Ruben; Engert, Florian

    2011-01-01

    In this study we report that larval zebrafish display adaptive locomotor output that can be driven by unexpected visual feedback. We develop a new assay that addresses visuomotor integration in restrained larval zebrafish. The assay involves a closed-loop environment in which the visual feedback a larva receives depends on its own motor output in a way that resembles freely swimming conditions. The experimenter can control the gain of this closed feedback loop, so that following a given motor output the larva experiences more or less visual feedback depending on whether the gain is high or low. We show that increases and decreases in this gain setting result in adaptive changes in behavior that lead to a generalized decrease or increase of motor output, respectively. Our behavioral analysis shows that both the duration and tail beat frequency of individual swim bouts can be modified, as well as the frequency with which bouts are elicited. These changes can be implemented rapidly, following an exposure to a new gain of just 175 ms. In addition, modifications in some behavioral parameters accumulate over tens of seconds and effects last for at least 30 s from trial to trial. These results suggest that larvae establish an internal representation of the visual feedback expected from a given motor output and that the behavioral modifications are driven by an error signal that arises from the discrepancy between this expectation and the actual visual feedback. The assay we develop presents a unique possibility for studying visuomotor integration using imaging techniques available in the larval zebrafish.

  10. Adaptive Locomotor Behavior in Larval Zebrafish

    PubMed Central

    Portugues, Ruben; Engert, Florian

    2011-01-01

    In this study we report that larval zebrafish display adaptive locomotor output that can be driven by unexpected visual feedback. We develop a new assay that addresses visuomotor integration in restrained larval zebrafish. The assay involves a closed-loop environment in which the visual feedback a larva receives depends on its own motor output in a way that resembles freely swimming conditions. The experimenter can control the gain of this closed feedback loop, so that following a given motor output the larva experiences more or less visual feedback depending on whether the gain is high or low. We show that increases and decreases in this gain setting result in adaptive changes in behavior that lead to a generalized decrease or increase of motor output, respectively. Our behavioral analysis shows that both the duration and tail beat frequency of individual swim bouts can be modified, as well as the frequency with which bouts are elicited. These changes can be implemented rapidly, following an exposure to a new gain of just 175 ms. In addition, modifications in some behavioral parameters accumulate over tens of seconds and effects last for at least 30 s from trial to trial. These results suggest that larvae establish an internal representation of the visual feedback expected from a given motor output and that the behavioral modifications are driven by an error signal that arises from the discrepancy between this expectation and the actual visual feedback. The assay we develop presents a unique possibility for studying visuomotor integration using imaging techniques available in the larval zebrafish. PMID:21909325

  11. Muscle pain in athletes with locomotor disability.

    PubMed

    Bernardi, Marco; Castellano, Vincenzo; Ferrara, Michael S; Sbriccoli, Paola; Sera, Francesco; Marchetti, Marco

    2003-02-01

    Athletes with locomotor disabilities (LDA) participate in many competitive sport activities, yet little is known about sport-related muscle pain (SRMP). This study assessed the prevalence, determinants, and main characteristics of SRMP in LDA. A cross-disability epidemiological survey was used to investigate the occurrence of SRMP during the previous year by using a questionnaire administrated by medical doctors. SRMP was defined as any muscle pain experienced during the past 12 months that either occurred during sport activity (training or competition) and/or was reported as a consequence of physical exercise, causing discomfort for at least 1 d and not related to systemic disease. A total of 227 LDA were recruited randomly from the population (567 LDA) who participated in selected National sports events (including swimming, athletics, wheelchair basketball matches, and others) organized by the Italian Federation of Sports for Disabled. Collected data were statistically analyzed with univariate and multivariate logistic regression models to identify possible determinants of SRMP, through the estimate of the prevalence odds ratios. The SRMP period prevalence rate was equal to 50.7% (95% confidence interval (44.0-57.4%)), ranging from 47.0% (swimmers) to 58.8% (basketball athletes). In 71.1% of cases, SRMP lasted less than 1 wk and only 8.7% experienced pain for more than 1 month. SRMP had a higher prevalence in amputees (75.0%) and spinal cord injured LDA (58.1%) than the other groups. There was increased prevalence rate of SRMP with increased training volume. The multivariate logistic regression model showed disorder type, body mass index, and training volume as determinants of SRMP. Prospective studies could be devised to assess the role of anthropometric characteristics and training volume as risk factors of SRMP.

  12. A fluorescence high throughput screening method for the detection of reactive electrophiles as potential skin sensitizers

    USDA-ARS?s Scientific Manuscript database

    Skin sensitization is an important toxicological end-point in the risk assessment of chemical allergens. Because of the complexity of the biological mechanisms associated with skin sensitization integrated approaches combining different chemical, biological and in silico methods are recommended to r...

  13. Leuco-crystal-violet micelle gel dosimeters: I. Influence of recipe components and potential sensitizers.

    PubMed

    Nasr, A T; Alexander, K; Schreiner, L J; McAuley, K B

    2015-06-21

    Radiochromic leuco crystal violet (LCV) micelle gel dosimeters are promising three-dimensional radiation dosimeters because of their spatial stability and suitability for optical readout. The effects of surfactant type and surfactant concentration on dose sensitivity of LCV micelle gels are tested, demonstrating that dose sensitivity and initial colour of the gel increases with increasing Triton x-100 (Tx100) concentration. Using Cetyl Trimethyl Ammonium Bromide (CTAB) in place of Tx100 produces gels that are nearly colourless prior to irradiation, but reduces the dose sensitivity. The separate effects of Tri-chloro acetic acid concentration and pH are investigated, revealing that controlling the pH near 3.6 is crucial for achieving high dose sensitivity. The sensitizing effect of chlorinated species on dose sensitivity is tested using 2,2,2-trichloroethanol (TCE), chloroform, and 1,1,1-trichloro-2-methyl-2-propanol hemihydrate. TCE gives the largest improvement in dose sensitivity and is recommended for use in micelle gel dosimeters because it is less volatile and safer to use than chloroform. Preliminary experiments on a new gel containing CTAB as the surfactant and TCE show that this new gel gives a dose sensitivity that is 24% higher than that of previous LCV micelle gels and is nearly colourless prior to irradiation.

  14. Leuco-crystal-violet micelle gel dosimeters: I. Influence of recipe components and potential sensitizers

    NASA Astrophysics Data System (ADS)

    Nasr, A. T.; Alexander, K.; Schreiner, L. J.; McAuley, K. B.

    2015-06-01

    Radiochromic leuco crystal violet (LCV) micelle gel dosimeters are promising three-dimensional radiation dosimeters because of their spatial stability and suitability for optical readout. The effects of surfactant type and surfactant concentration on dose sensitivity of LCV micelle gels are tested, demonstrating that dose sensitivity and initial colour of the gel increases with increasing Triton x-100 (Tx100) concentration. Using Cetyl Trimethyl Ammonium Bromide (CTAB) in place of Tx100 produces gels that are nearly colourless prior to irradiation, but reduces the dose sensitivity. The separate effects of Tri-chloro acetic acid concentration and pH are investigated, revealing that controlling the pH near 3.6 is crucial for achieving high dose sensitivity. The sensitizing effect of chlorinated species on dose sensitivity is tested using 2,2,2-trichloroethanol (TCE), chloroform, and 1,1,1-trichloro-2-methyl-2-propanol hemihydrate. TCE gives the largest improvement in dose sensitivity and is recommended for use in micelle gel dosimeters because it is less volatile and safer to use than chloroform. Preliminary experiments on a new gel containing CTAB as the surfactant and TCE show that this new gel gives a dose sensitivity that is 24% higher than that of previous LCV micelle gels and is nearly colourless prior to irradiation.

  15. Modeling the action-potential-sensitive nonlinear-optical response of myelinated nerve fibers and short-term memory

    NASA Astrophysics Data System (ADS)

    Shneider, M. N.; Voronin, A. A.; Zheltikov, A. M.

    2011-11-01

    The Goldman-Albus treatment of the action-potential dynamics is combined with a phenomenological description of molecular hyperpolarizabilities into a closed-form model of the action-potential-sensitive second-harmonic response of myelinated nerve fibers with nodes of Ranvier. This response is shown to be sensitive to nerve demyelination, thus enabling an optical diagnosis of various demyelinating diseases, including multiple sclerosis. The model is applied to examine the nonlinear-optical response of a three-neuron reverberating circuit—the basic element of short-term memory.

  16. Limitations imposed by wearing armour on Medieval soldiers' locomotor performance.

    PubMed

    Askew, Graham N; Formenti, Federico; Minetti, Alberto E

    2012-02-22

    In Medieval Europe, soldiers wore steel plate armour for protection during warfare. Armour design reflected a trade-off between protection and mobility it offered the wearer. By the fifteenth century, a typical suit of field armour weighed between 30 and 50 kg and was distributed over the entire body. How much wearing armour affected Medieval soldiers' locomotor energetics and biomechanics is unknown. We investigated the mechanics and the energetic cost of locomotion in armour, and determined the effects on physical performance. We found that the net cost of locomotion (C(met)) during armoured walking and running is much more energetically expensive than unloaded locomotion. C(met) for locomotion in armour was 2.1-2.3 times higher for walking, and 1.9 times higher for running when compared with C(met) for unloaded locomotion at the same speed. An important component of the increased energy use results from the extra force that must be generated to support the additional mass. However, the energetic cost of locomotion in armour was also much higher than equivalent trunk loading. This additional cost is mostly explained by the increased energy required to swing the limbs and impaired breathing. Our findings can predict age-associated decline in Medieval soldiers' physical performance, and have potential implications in understanding the outcomes of past European military battles.

  17. Limitations imposed by wearing armour on Medieval soldiers' locomotor performance

    PubMed Central

    Askew, Graham N.; Formenti, Federico; Minetti, Alberto E.

    2012-01-01

    In Medieval Europe, soldiers wore steel plate armour for protection during warfare. Armour design reflected a trade-off between protection and mobility it offered the wearer. By the fifteenth century, a typical suit of field armour weighed between 30 and 50 kg and was distributed over the entire body. How much wearing armour affected Medieval soldiers' locomotor energetics and biomechanics is unknown. We investigated the mechanics and the energetic cost of locomotion in armour, and determined the effects on physical performance. We found that the net cost of locomotion (Cmet) during armoured walking and running is much more energetically expensive than unloaded locomotion. Cmet for locomotion in armour was 2.1–2.3 times higher for walking, and 1.9 times higher for running when compared with Cmet for unloaded locomotion at the same speed. An important component of the increased energy use results from the extra force that must be generated to support the additional mass. However, the energetic cost of locomotion in armour was also much higher than equivalent trunk loading. This additional cost is mostly explained by the increased energy required to swing the limbs and impaired breathing. Our findings can predict age-associated decline in Medieval soldiers' physical performance, and have potential implications in understanding the outcomes of past European military battles. PMID:21775328

  18. Modafinil Induces Rapid-Onset Behavioral Sensitization and Cross-Sensitization with Cocaine in Mice: Implications for the Addictive Potential of Modafinil.

    PubMed

    Wuo-Silva, Raphael; Fukushiro, Daniela F; Hollais, André W; Santos-Baldaia, Renan; Mári-Kawamoto, Elisa; Berro, Laís F; Yokoyama, Thaís S; Lopes-Silva, Leonardo B; Bizerra, Carolina S; Procópio-Souza, Roberta; Hashiguchi, Debora; Figueiredo, Lilian A; Costa, Jose L; Frussa-Filho, Roberto; Longo, Beatriz M

    2016-01-01

    There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross-sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing per se and can enhance the reinforcing effects of stimulants like cocaine within hours after administration.

  19. Modafinil Induces Rapid-Onset Behavioral Sensitization and Cross-Sensitization with Cocaine in Mice: Implications for the Addictive Potential of Modafinil

    PubMed Central

    Wuo-Silva, Raphael; Fukushiro, Daniela F.; Hollais, André W.; Santos-Baldaia, Renan; Mári-Kawamoto, Elisa; Berro, Laís F.; Yokoyama, Thaís S.; Lopes-Silva, Leonardo B.; Bizerra, Carolina S.; Procópio-Souza, Roberta; Hashiguchi, Debora; Figueiredo, Lilian A.; Costa, Jose L.; Frussa-Filho, Roberto; Longo, Beatriz M.

    2016-01-01

    There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross-sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing per se and can enhance the reinforcing effects of stimulants like cocaine within hours after administration. PMID:27872594

  20. Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish.

    PubMed

    Issa, Fadi A; Mazzochi, Christopher; Mock, Allan F; Papazian, Diane M

    2011-05-04

    Whether changes in neuronal excitability can cause neurodegenerative disease in the absence of other factors such as protein aggregation is unknown. Mutations in the Kv3.3 voltage-gated K(+) channel cause spinocerebellar ataxia type 13 (SCA13), a human autosomal-dominant disease characterized by locomotor impairment and the death of cerebellar neurons. Kv3.3 channels facilitate repetitive, high-frequency firing of action potentials, suggesting that pathogenesis in SCA13 is triggered by changes in electrical activity in neurons. To investigate whether SCA13 mutations alter excitability in vivo, we expressed the human dominant-negative R420H mutant subunit in zebrafish. The disease-causing mutation specifically suppressed the excitability of Kv3.3-expressing, fast-spiking motor neurons during evoked firing and fictive swimming and, in parallel, decreased the precision and amplitude of the startle response. The dominant-negative effect of the mutant subunit on K(+) current amplitude was directly responsible for the reduced excitability and locomotor phenotype. Our data provide strong evidence that changes in excitability initiate pathogenesis in SCA13 and establish zebrafish as an excellent model system for investigating how changes in neuronal activity impair locomotor control and cause cell death.

  1. Morphology and locomotor adaptations of the bovid femur in relation to habitat.

    PubMed

    Kappelman, J

    1988-10-01

    Extant bovids inhabit a wide diversity of environments that range from forest to savanna and display locomotor patterns that are habitat specific. I report here on an investigation of the linkage between these locomotor patterns and habitat based on a study of the morphology of the bovid femur. Femoral head shape, shaft dimensions, and knee structure are examined and support a statistically significant separation of the different morphological complexes present in bovids from forest, broken cover, and savanna habitats. Morphological differences are primarily related to locomotor patterns as reflected in the degree of cursoriality displayed by bovids in different habitats. Cursorial bovids from savanna environments have laterally expanded femoral heads that act to limit the degree of abduction and axial rotation at the hip, and elliptically shaped distal femora that increase the moment arm of the extensor muscles that cross the knee. Forest bovids have spherically shaped femoral heads. This morphology permits a much higher degree of abduction and axial rotation at the hip and appears to provide greater maneuverability in a vegetationally complex habitat. Bovids living in broken cover environments that fall between the extremes of closed canopy forest and savanna display an intermediate set of femoral characters. This approach to the relationship between habitat and locomotion offers a potentially powerful means with which to examine the interplay between structural form and function in bovid evolution.

  2. Impact of Tail Loss on the Behaviour and Locomotor Performance of Two Sympatric Lampropholis Skink Species

    PubMed Central

    Cromie, Gillian L.; Chapple, David G.

    2012-01-01

    Caudal autotomy is an anti-predator behaviour that is used by many lizard species. Although there is an immediate survival benefit, the subsequent absence of the tail may inhibit locomotor performance, alter activity and habitat use, and increase the individuals' susceptibility to future predation attempts. We used laboratory experiments to examine the impact of tail autotomy on locomotor performance, activity and basking site selection in two lizard species, the delicate skink (Lampropholis delicata) and garden skink (L. guichenoti), that occur sympatrically throughout southeastern Australia and are exposed to an identical suite of potential predators. Post-autotomy tail movement did not differ between the two Lampropholis species, although a positive relationship between the shed tail length and distance moved, but not the duration of movement, was observed. Tail autotomy resulted in a substantial decrease in sprint speed in both species (28–39%), although this impact was limited to the optimal performance temperature (30°C). Although L. delicata was more active than L. guichenoti, tail autotomy resulted in decreased activity in both species. Sheltered basking sites were preferred over open sites by both Lampropholis species, although this preference was stronger in L. delicata. Caudal autotomy did not alter the basking site preferences of either species. Thus, both Lampropholis species had similar behavioural responses to autotomy. Our study also indicates that the impact of tail loss on locomotor performance may be temperature-dependent and highlights that future studies should be conducted over a broad thermal range. PMID:22523555

  3. Perturbation schedule does not alter retention of a locomotor adaptation across days

    PubMed Central

    Hussain, Sara J.

    2014-01-01

    Motor adaptation in response to gradual vs. abrupt perturbation schedules may involve different neural mechanisms, potentially leading to different levels of motor memory. However, no study has investigated whether perturbation schedules alter memory of a locomotor adaptation across days. We measured adaptation and retention (memory) of altered interlimb symmetry during walking in two groups of participants over 2 days. On day 1, participants adapted to either a single, large perturbation (abrupt schedule) or a series of small perturbations that increased in size over time (gradual schedule). Retention was examined on day 2. On day 1, initial swing time and foot placement symmetry error sizes differed between groups but overall adaptation magnitudes were similar. On day 2, participants in both groups showed similar retention, readaptation, and aftereffect sizes, although there were some trends for improved memory in the abrupt group. These results conflict with previous data but are consistent with newer studies reporting no behavioral differences following adaptation using abrupt vs. gradual schedules. Although memory levels were very similar between groups, we cannot rule out the possibility that the neural mechanisms underlying this memory storage differ. Overall, it appears that adaptation of locomotor patterns via abrupt and gradual perturbation schedules produces similar expression of locomotor memories across days. PMID:24647433

  4. Characterization of sacral interneurons that mediate activation of locomotor pattern generators by sacrocaudal afferent input.

    PubMed

    Etlin, Alex; Finkel, Eran; Mor, Yoav; O'Donovan, Michael J; Anglister, Lili; Lev-Tov, Aharon

    2013-01-09

    Identification of the neural pathways involved in retraining the spinal central pattern generators (CPGs) by afferent input in the absence of descending supraspinal control is feasible in isolated rodent spinal cords where the locomotor CPGs are potently activated by sacrocaudal afferent (SCA) input. Here we study the involvement of sacral neurons projecting rostrally through the ventral funiculi (VF) in activation of the CPGs by sensory stimulation. Fluorescent labeling and immunostaining showed that VF neurons are innervated by primary afferents immunoreactive for vesicular glutamate transporters 1 and 2 and by intraspinal neurons. Calcium imaging revealed that 55% of the VF neurons were activated by SCA stimulation. The activity of VF neurons and the sacral and lumbar CPGs was abolished when non-NMDA receptors in the sacral segments were blocked by the antagonist CNQX. When sacral NMDA receptors were blocked by APV, the sacral CPGs were suppressed, VF neurons with nonrhythmic activity were recruited and a moderate-drive locomotor rhythm developed during SCA stimulation. In contrast, when the sacral CPGs were activated by SCA stimulation, rhythmic and nonrhythmic VF neurons were recruited and the locomotor rhythm was most powerful. The activity of 73 and 27% of the rhythmic VF neurons was in-phase with the ipsilateral and contralateral motor output, respectively. Collectively, our studies indicate that sacral VF neurons serve as a major link between SCA and the hindlimb CPGs and that the ability of SCA to induce stepping can be enhanced by the sacral CPGs. The nature of the ascending drive to lumbar CPGs, the identity of subpopulations of VF neurons, and their potential role in activating the locomotor rhythm are discussed.

  5. An Intensive Locomotor Training Paradigm Improves Neuropathic Pain following Spinal Cord Compression Injury in Rats.

    PubMed

    Dugan, Elizabeth A; Sagen, Jacqueline

    2015-05-01

    Spinal cord injury (SCI) is often associated with both locomotor deficits and sensory dysfunction, including debilitating neuropathic pain. Unfortunately, current conventional pharmacological, physiological, or psychological treatments provide only marginal relief for more than two-thirds of patients, highlighting the need for improved treatment options. Locomotor training is often prescribed as an adjunct therapy for peripheral neuropathic pain but is rarely used to treat central neuropathic pain. The goal of this study was to evaluate the potential anti-nociceptive benefits of intensive locomotor training (ILT) on neuropathic pain consequent to traumatic SCI. Using a rodent SCI model for central neuropathic pain, ILT was initiated either 5 d after injury prior to development of neuropathic pain symptoms (the "prevention" group) or delayed until pain symptoms fully developed (∼3 weeks post-injury, the "reversal" group). The training protocol consisted of 5 d/week of a ramping protocol that started with 11 m/min for 5 min and increased in speed (+1 m/min/week) and time (1-4 minutes/week) to a maximum of two 20-min sessions/d at 15 m/min by the fourth week of training. ILT prevented and reversed the development of heat hyperalgesia and cold allodynia, as well as reversed developed tactile allodynia, suggesting analgesic benefits not seen with moderate levels of locomotor training. Further, the analgesic benefits of ILT persisted for several weeks once training had been stopped. The unique ability of an ILT protocol to produce robust and sustained anti-nociceptive effects, as assessed by three distinct outcome measures for below-level SCI neuropathic pain, suggests that this adjunct therapeutic approach has great promise in a comprehensive treatment strategy for SCI pain.

  6. Interactions between morphine and the morphine-glucuronides measured by conditioned place preference and locomotor activity.

    PubMed

    Vindenes, Vigdis; Ripel, Ase; Handal, Marte; Boix, Fernando; Mørland, Jørg

    2009-07-01

    After intake of heroin or morphine, active metabolites are formed in the body. The two most important morphine metabolites are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G and M3G are present for longer time periods and in higher concentrations than the parent drug, but their potential contribution to reward and to development of dependence and addiction is not clear. We tested the effects of morphine and M6G separately (doses of 10, 20, 30 and 50 micromol/kg), administered together, and also in combination with with 200 microm l/kg M3G in male C57BL/6J-Bom mice. M3G in doses of 50, 100, 200, 300 and 400 micromol/kg were also tested alone. We evaluated the rewarding effects in a conditioning place preference (CPP) model and the psychomotor stimulating effects by recording locomotor activity. Mice were subjected to three consecutive conditioning days with drugs or saline before testing. Changes in locomotor activity from conditioning day one to day three were also compared to the expression of CPP on the test day. This study revealed that coadministration of morphine and M6G induced CPP of similar magnitude to the sum of equimolar doses of these compounds alone, and different ratios of the two drugs did not affect the results. M3G did not cause CPP and reduced the CPP induced by both morphine and M6G when coadministered with these drugs. Morphine induced locomotor activity was reduced by coadministration of M3G, but this was not seen when M3G was co-injected with M6G. The changes in locomotor activity during the conditioning periods did not correlated with the expression of CPP. This study revealed that the morphine-glucuronides in different and complex ways can influence the pharmacological effects of psychomotor activation and reward observed after intake of morphine.

  7. Highly Sensitive Measurement of Bio-Electric Potentials by Boron-Doped Diamond (BDD) Electrodes for Plant Monitoring.

    PubMed

    Ochiai, Tsuyoshi; Tago, Shoko; Hayashi, Mio; Fujishima, Akira

    2015-10-23

    We describe a sensitive plant monitoring system by the detection of the bioelectric potentials in plants with boron-doped diamond (BDD) electrodes. For sensor electrodes, we used commercially available BDD, Ag, and Pt plate electrodes. We tested this approach on a hybrid species in the genus Opuntia (potted) and three different trees (ground-planted) at different places in Japan. For the Opuntia, we artificially induced bioelectric potential changes by the surface potential using the fingers. We detected substantial changes in bioelectric potentials through all electrodes during finger touches on the surface of potted Opuntia hybrid plants, although the BDD electrodes were several times more sensitive to bioelectric potential change compared to the other electrodes. Similarly for ground-planted trees, we found that both BDD and Pt electrodes detected bioelectric potential change induced by changing environmental factors (temperature and humidity) for months without replacing/removing/changing electrodes, BDD electrodes were 5-10 times more sensitive in this detection than Pt electrodes. Given these results, we conclude that BDD electrodes on live plant tissue were able to consistently detect bioelectrical potential changes in plants.

  8. Highly Sensitive Measurement of Bio-Electric Potentials by Boron-Doped Diamond (BDD) Electrodes for Plant Monitoring

    PubMed Central

    Ochiai, Tsuyoshi; Tago, Shoko; Hayashi, Mio; Fujishima, Akira

    2015-01-01

    We describe a sensitive plant monitoring system by the detection of the bioelectric potentials in plants with boron-doped diamond (BDD) electrodes. For sensor electrodes, we used commercially available BDD, Ag, and Pt plate electrodes. We tested this approach on a hybrid species in the genus Opuntia (potted) and three different trees (ground-planted) at different places in Japan. For the Opuntia, we artificially induced bioelectric potential changes by the surface potential using the fingers. We detected substantial changes in bioelectric potentials through all electrodes during finger touches on the surface of potted Opuntia hybrid plants, although the BDD electrodes were several times more sensitive to bioelectric potential change compared to the other electrodes. Similarly for ground-planted trees, we found that both BDD and Pt electrodes detected bioelectric potential change induced by changing environmental factors (temperature and humidity) for months without replacing/removing/changing electrodes, BDD electrodes were 5–10 times more sensitive in this detection than Pt electrodes. Given these results, we conclude that BDD electrodes on live plant tissue were able to consistently detect bioelectrical potential changes in plants. PMID:26512663

  9. Inversion of gas--surface scattering data for potential determination using functional sensitivity analysis. I. A case study for the He--Xe/C(0001) potential

    SciTech Connect

    Ho, T.; Rabitz, H. )

    1991-02-01

    A general iterative inversion procedure based on functional sensitivity analysis is presented for determining the gas--surface interaction potential from low energy elastic scattering data. Formally, Tikhonov regularization, singular function analysis, and a recently developed exact transformation technique are implemented to render the inversion stable and efficient. Specifically, the simulation of helium scattering from a rigid periodic xenon monolayer on the graphite (0001) face is considered. It is found that the functional sensitivity densities of the diffraction intensities with respect to the He--Xe/C(0001) potential contain profound information, thus are invaluable in guiding the inversion of scattering data to yield the potential. Although, unequivocal determination of the full three-dimensional potential from the inevitably incomplete experimental data may be difficult, we demonstrate that simulated input data consisting of a finite number of polar scan specular intensities can be used to accurately recover the underlying He--Xe/C(0001) potential. The recovered potential has been obtained without imposing any explicit functional form on the potential per se. The resulting procedure is quite promising for treating real laboratory data.

  10. Myeloid differentiation-2 is a potential biomarker for the amplification process of allergic airway sensitization in mice.

    PubMed

    Koyama, Daisuke; Maruoka, Shuichiro; Gon, Yasuhiro; Shintani, Yoshitaka; Sekiyama, Tadataka; Hiranuma, Hisato; Shikano, Sotaro; Kuroda, Kazumichi; Takeshita, Ikuko; Tsuboi, Eriko; Soda, Kaori; Hashimoto, Shu

    2015-09-01

    Allergic sensitization is a key step in the pathogenesis of asthma. However, little is known about the molecules that are critical regulators for establishing allergic sensitization of the airway. Thus, we conducted global gene expression profiling to identify candidate genes and signaling pathways involved in house dust mite (HDM)-induced allergic sensitization in the murine airway. We sensitized and challenged mice with HDM or saline as a control through the airway on days 1 and 8. We evaluated eosinophilia in bronchoalveolar lavage fluid (BALF), airway inflammation, and mucus production on days 7 and 14. We extracted total RNA from lung tissues of HDM- and saline-sensitized mice on days 7 and 14. Microarray analyses were performed to identify up-regulated genes in the lungs of HDM-sensitized mice compared to the control mice. Data analyses were performed using GeneSpring software and gene networks were generated using Ingenuity Pathways Analysis (IPA). We identified 50 HDM-mediated, stepwise up-regulated genes in response to allergic sensitization and amplification of allergic airway inflammation. The highest expressed gene was myeloid differentiation-2 (MD-2), a lipopolysaccharide (LPS)-binding component of Toll-like receptor (TLR) 4 signaling complex. MD-2 protein was expressed in lung vascular endothelial cells and was increased in the serum of HDM-sensitized mice, but not in the control mice. Our data suggest MD-2 is a critical regulator of the establishment of allergic airway sensitization to HDM in mice. Serum MD-2 may represent a potential biomarker for the amplification of allergic sensitization and allergic inflammation. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  11. ERK potentiates p38 in central sensitization induced by traumatic occlusion.

    PubMed

    Jing, Lei; Liu, Xiao-Dong; Yang, Hong-Xu; Zhang, Mian; Wang, Ying; Duan, Li; Zhang, Jing; Lu, Lei; Yang, Ting; Wang, Dong-Mei; Chen, Liang-Wei; Wang, Mei-Qing

    2017-01-06

    This study was to investigate the role of p38 activation via ERK1/2 phosphorylation in neurons and microglia of the spinal trigeminal subnucleus caudalis (Vc) in the promotion of orofacial hyperalgesia induced by unilateral anterior crossbite (UAC) traumatic occlusion in adult rats. U0126, a p-ERK1/2 inhibitor, was injected intracisternally before UAC implant. The effects of the U0126 injection were compared to those following the injection of SB203580, a p-p38 inhibitor. Mechanical hyperalgesia was evaluated via pressure pain threshold measurements. Brain stem tissues were processed for a Western blot analysis to evaluate the activation of ERK1/2 and p38. Double immunofluorescence was also performed to observe the expression of p-ERK1/2 and p-p38 in neurons (labeled by NeuN) and microglia (labeled by OX42). The data showed that UAC caused orofacial hyperalgia ipsilaterally on d1 to d7, peaking on d3 (P<0.05). An upregulation of p-ERK1/2 was observed in the ipsilateral Vc on d1 to d3, peaking on d1. An upregulation of p-p38 was also observed on d1 to d7, peaking on d3 (P<0.05). p-ERK1/2 primarily co-localized with NeuN and, to a lesser extent, with OX42, while p-p38 co-localized with both NeuN and OX42. Pretreatment with U0126 prevented the upregulation of both p-ERK1/2 and p-p38. Similarly to an intracisternal injection of SB203580, U0126 pretreatment attenuated the UAC-induced orofacial hyperalgesia. These data indicate that UAC caused orofacial hyperalgesia by inducing central sensitization via the activation of ERK1/2 and p38 in both neurons and microglia in the Vc, potentially impacting the effects of p-ERK1/2 during p38 activation.

  12. Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity.

    PubMed

    Sándor, Nikolett; Schilling-Tóth, Boglárka; Kis, Enikő; Benedek, Anett; Lumniczky, Katalin; Sáfrány, Géza; Hegyesi, Hargita

    2015-11-01

    We have investigated the importance of GDF-15 (secreted cytokine belonging to the TGF-β superfamily) in low and high dose radiation-induced cellular responses. A telomerase immortalized human fibroblast cell line (F11hT) was used in the experiments. A lentiviral system encoding small hairpin RNAs (shRNA) was used to establish GDF-15 silenced cells. Secreted GDF-15 levels were measured in culture medium by ELISA. Cell cycle analysis was performed by flow cytometry. The experiments demonstrated that in irradiated human fibroblasts GDF-15 expression increased with dose starting from 100mGy. Elevated GDF-15 expression was not detected in bystander cells. The potential role of GDF-15 in radiation response was investigated by silencing GDF-15 in immortalized human fibroblasts with five different shRNA encoded in lentiviral vectors. Cell lines with considerably reduced GDF-15 levels presented increased radiation sensitivity, while a cell line with elevated GDF-15 was more radiation resistant than wild type cells. We have investigated how the reduced GDF-15 levels alter the response of several known radiation inducible genes. In F11hT-shGDF-15 cells the basal expression level of CDKN1A was unaltered relative to F11hT cells, while GADD45A and TGF-β1 mRNA levels were slightly higher, and TP53INP1 was considerably reduced. The radiation-induced expression of TP53INP1 was lower in the silenced than in wild type fibroblast cells. Cell cycle analysis indicated that radiation-induced early G2/M arrest was abrogated in GDF-15 silenced cells. Moreover, radiation-induced bystander effect was less pronounced in GDF-15 silenced fibroblasts. In conclusion, the results suggest that GDF-15 works as a radiation inducible radiation resistance increasing factor in normal human fibroblast cells, acts by regulating the radiation-induced transcription of several genes and might serve as a radiation-induced early biomarker in exposed cells.

  13. Two Components of Nocturnal Locomotor Suppression by Light

    PubMed Central

    Morin, Lawrence P.; Lituma, Pablo J.; Studholme, Keith M.

    2010-01-01

    In nocturnal rodents, millisecond light (“flash”) stimuli can induce both a large circadian rhythm phase shift and an associated state change from highly active to quiescence followed by behavioral sleep. Suppression of locomotion (“negative masking”) is an easily measured correlate of the state change. The present mouse studies used both flashes and longer light stimuli (“pulses”) to distinguish initiation from maintenance effects of light on locomotor suppression and to determine whether the locomotor suppression exhibits temporal integration as is thought to be characteristic of phase shift responses to pulse, but not flash, stimuli. In Expt. 1, locomotor suppression increased with irradiance (0.01–100 μW/cm2), in accordance with previous reports. It also increased with stimulus duration (3–3000 sec), but interpretation of this result is complicated by the ability of light to both initiate and maintain locomotor suppression. In Expt. 2, an irradiance response curve was determined using a stimulus series of 10 flashes, 2 msec each, with total flash energy varying from 0.0025 – 110.0 J/m2. This included a test for temporal integration in which the effects of two equal energy series of flashes were compared, but which differed in the number of flashes per series (10 vs 100). The 10 flash series more effectively elicited locomotor suppression than the 100 flash series, a result consistent with prior observations involving flash-induced phase shifts. In Expt. 3, exposure of mice to an 11 hr light stimulus yielded irradiance-dependent locomotor suppression that can be maintained for the entire stimulus duration by a 100 μW/cm2 stimulus. Light has the ability to initiate a time-limited (30–40 min) interval of locomotor suppression (initiation effect) that can be extended by additional light (maintenance effect). Temporal integration resembling that seen in phase shifting responses to light does not exist for either phase shift or locomotor

  14. Differentiating event-related potential components sensitive to emotion in middle childhood: evidence from temporal-spatial PCA.

    PubMed

    Kujawa, Autumn; Weinberg, Anna; Hajcak, Greg; Klein, Daniel N

    2013-07-01

    Event-related potentials (ERPs) may be particularly useful for examining emotional processing across development. Though a number of ERP components are sensitive to emotional content in adults, previous studies have yet to systematically examine the components sensitive to emotion in children. The current study used temporal-spatial principal components analysis (PCA) to identify ERP components in response to complex emotional images in 9-year-old children. Three components were modulated by emotional content and were similar to those previously observed in adults, including: the early posterior negativity, the P300, and a sustained relative positivity similar to the late positive potential (LPP). Compared to those previously observed in adults, the components sensitive to emotion in children were maximal over more occipital regions and the LPP component appeared to be less protracted in time, perhaps indicative of less elaborative processing of emotional stimuli. Copyright © 2012 Wiley Periodicals, Inc.

  15. Assessment of the Sensitizing Potential of Processed Peanut Proteins in Brown Norway Rats: Roasting Does Not Enhance Allergenicity

    PubMed Central

    Kroghsbo, Stine; Rigby, Neil M.; Johnson, Philip E.; Adel-Patient, Karine; Bøgh, Katrine L.; Salt, Louise J.; Mills, E. N. Clare; Madsen, Charlotte B.

    2014-01-01

    Background IgE-binding of process-modified foods or proteins is the most common method for examination of how food processing affects allergenicity of food allergens. How processing affects sensitization capacity is generally studied by administration of purified food proteins or food extracts and not allergens present in their natural food matrix. Objectives The aim was to investigate if thermal processing increases sensitization potential of whole peanuts via the oral route. In parallel, the effect of heating on sensitization potential of the major peanut allergen Ara h 1 was assessed via the intraperitoneal route. Methods Sensitization potential of processed peanut products and Ara h 1 was examined in Brown Norway (BN) rats by oral administration of blanched or oil-roasted peanuts or peanut butter or by intraperitoneal immunization of purified native (N-), heated (H-) or heat glycated (G-)Ara h 1. Levels of specific IgG and IgE were determined by ELISA and IgE functionality was examined by rat basophilic leukemia (RBL) cell assay. Results In rats dosed orally, roasted peanuts induced significant higher levels of specific IgE to NAra h 1 and 2 than blanched peanuts or peanut butter but with the lowest level of RBL degranulation. However, extract from roasted peanuts was found to be a superior elicitor of RBL degranulation. Process-modified Ara h 1 had similar sensitizing capacity as NAra h 1 but specific IgE reacted more readily with process-modified Ara h 1 than with native. Conclusions Peanut products induce functional specific IgE when dosed orally to BN rats. Roasted peanuts do not have a higher sensitizing capacity than blanched peanuts. In spite of this, extract from roasted peanuts is a superior elicitor of RBL cell degranulation irrespectively of the peanut product used for sensitization. The results also suggest that new epitopes are formed or disclosed by heating Ara h 1 without glucose. PMID:24805813

  16. Assessment of the sensitizing potential of processed peanut proteins in Brown Norway rats: roasting does not enhance allergenicity.

    PubMed

    Kroghsbo, Stine; Rigby, Neil M; Johnson, Philip E; Adel-Patient, Karine; Bøgh, Katrine L; Salt, Louise J; Mills, E N Clare; Madsen, Charlotte B

    2014-01-01

    IgE-binding of process-modified foods or proteins is the most common method for examination of how food processing affects allergenicity of food allergens. How processing affects sensitization capacity is generally studied by administration of purified food proteins or food extracts and not allergens present in their natural food matrix. The aim was to investigate if thermal processing increases sensitization potential of whole peanuts via the oral route. In parallel, the effect of heating on sensitization potential of the major peanut allergen Ara h 1 was assessed via the intraperitoneal route. Sensitization potential of processed peanut products and Ara h 1 was examined in Brown Norway (BN) rats by oral administration of blanched or oil-roasted peanuts or peanut butter or by intraperitoneal immunization of purified native (N-), heated (H-) or heat glycated (G-)Ara h 1. Levels of specific IgG and IgE were determined by ELISA and IgE functionality was examined by rat basophilic leukemia (RBL) cell assay. In rats dosed orally, roasted peanuts induced significant higher levels of specific IgE to NAra h 1 and 2 than blanched peanuts or peanut butter but with the lowest level of RBL degranulation. However, extract from roasted peanuts was found to be a superior elicitor of RBL degranulation. Process-modified Ara h 1 had similar sensitizing capacity as NAra h 1 but specific IgE reacted more readily with process-modified Ara h 1 than with native. Peanut products induce functional specific IgE when dosed orally to BN rats. Roasted peanuts do not have a higher sensitizing capacity than blanched peanuts. In spite of this, extract from roasted peanuts is a superior elicitor of RBL cell degranulation irrespectively of the peanut product used for sensitization. The results also suggest that new epitopes are formed or disclosed by heating Ara h 1 without glucose.

  17. Right Hemisphere Sensitivity to Word- and Sentence-Level Context: Evidence From Event-Related Brain Potentials

    ERIC Educational Resources Information Center

    Coulson, Seana; Federmeier, Kara D.; Van Petten, Cyma; Kutas, Marta

    2005-01-01

    Researchers using lateralized stimuli have suggested that the left hemisphere is sensitive to sentence-level context, whereas the right hemisphere (RH) primarily processes word-level meaning. The authors investigated this message-blind RH model by measuring associative priming with event-related brain potentials (ERPs). For word pairs in…

  18. Right Hemisphere Sensitivity to Word- and Sentence-Level Context: Evidence From Event-Related Brain Potentials

    ERIC Educational Resources Information Center

    Coulson, Seana; Federmeier, Kara D.; Van Petten, Cyma; Kutas, Marta

    2005-01-01

    Researchers using lateralized stimuli have suggested that the left hemisphere is sensitive to sentence-level context, whereas the right hemisphere (RH) primarily processes word-level meaning. The authors investigated this message-blind RH model by measuring associative priming with event-related brain potentials (ERPs). For word pairs in…

  19. Stereotactic radiosurgery improves locomotor recovery after spinal cord injury in rats.

    PubMed

    Zeman, Richard J; Wen, Xialing; Ouyang, Nengtai; Rocchio, Ronald; Shih, Lynn; Alfieri, Alan; Moorthy, Chitti; Etlinger, Joseph D

    2008-11-01

    Currently, because of the precision of stereotactic radiosurgery, radiation can now be delivered by techniques that shape the radiation beam to the tissue target for a variety of clinical applications. This avoids unnecessary and potentially damaging irradiation of surrounding tissues inherent in conventional irradiation, so that irradiation of the minimum volume of tissue necessary for optimal therapeutic benefit can be achieved. Although conventional x-irradiation has been shown to improve recovery from spinal cord injury in animals, the efficacy of targeted irradiation of the injured spinal cord has not been demonstrated previously. The purpose of these studies was to determine whether stereotactic x-irradiation of the injured spinal cord can enhance locomotor function and spare spinal cord tissue after contusion injury in a standard experimental model of spinal cord injury. Contusion injury was produced in rats at the level of T10 with a weight-drop device, and doses of x-irradiation were delivered 2 hours after injury via a Novalis, 6-MeV linear accelerator shaped beam radiosurgery system (BrainLAB USA, Westchester, IL) in 4 sequential fractions, with beam angles 60 to 70 degrees apart, at a rate of 6.4 Gy/minute. The target volume was a 4 x 15-mm cylinder along the axis of the spinal cord, with the isocenter positioned at the contusion epicenter. Locomotor function was determined for 6 weeks after injury with the 21-point Basso, Beattie, and Bresnahan (BBB) locomotor scale and tissue sparing in histological sections of the spinal cord. Locomotor function recovered progressively during the 6-week postinjury observation period. BBB scores were significantly greater in the 10-Gy x-irradiated group compared with controls (9.4 versus 7.3; P < 0.05), indicating hind limb weight support or dorsal stepping in contrast to hind limb joint mobility without weight bearing. Doses in the range of 2 to 10 Gy increased BBB scores progressively, whereas greater doses of 15 to

  20. Deconstructing locomotor networks with experimental injury to define their membership.

    PubMed

    Nistri, Andrea; Taccola, Giuliano; Mladinic, Miranda; Margaryan, Gayane; Kuzhandaivel, Anujaianthi

    2010-06-01

    Although spinal injury is a major cause of chronic disability, the mechanisms responsible for the lesion pathophysiology and their dynamic evolution remain poorly understood. Hence, current treatments aimed at blocking damage extension are unsatisfactory. To unravel the acute spinal injury processes, we have developed a model of the neonatal rat spinal cord in vitro subjected to kainate-evoked excitotoxicity or metabolic perturbation (hypoxia, aglycemia, and free oxygen radicals) or their combination. The study outcome is fictive locomotion one day after the lesion and its relation to histological damage. Excitotoxicity always suppresses locomotor network activity and produces large gray matter damage, while network bursting persists supported by average survival of nearly half premotoneurons and motoneurons. Conversely, metabolic perturbation simply depresses locomotor network activity as damage mainly concerns white rather than gray matter. Coapplication of kainate and metabolic perturbation completely eliminates locomotor network activity. These results indicate distinct cellular targets for excitotoxic versus dysmetabolic damage with differential consequences on locomotor pattern formation. Furthermore, these data enable to estimate the minimal network membership compatible with expression of locomotor activity.

  1. Modular diversification of the locomotor system in damselfishes (Pomacentridae).

    PubMed

    Aguilar-Medrano, Rosalía; Frédérich, Bruno; Barber, Paul H

    2016-05-01

    As fish move and interact with their aquatic environment by swimming, small morphological variations of the locomotor system can have profound implications on fitness. Damselfishes (Pomacentridae) have inhabited coral reef ecosystems for more than 50 million years. As such, habitat preferences and behavior could significantly constrain the morphology and evolvability of the locomotor system. To test this hypothesis, we used phylogenetic comparative methods on morphometric, ecological and behavioral data. While body elongation represented the primary source of variation in the locomotor system of damselfishes, results also showed a diverse suite of morphological combinations between extreme morphologies. Results show clear associations between behavior, habitat preferences, and morphology, suggesting ecological constraints on shape diversification of the locomotor system. In addition, results indicate that the three modules of the locomotor system are weakly correlated, resulting in versatile and independent characters. These results suggest that Pomacentridae is shape may result from the interaction between (1) integrated parts of morphological variation that maintain overall swimming ability and (2) relatively independent parts of the morphology that facilitate adaptation and diversification. © 2016 Wiley Periodicals, Inc.

  2. Validation of a microwave radar system for the monitoring of locomotor activity in mice

    PubMed Central

    Pasquali, Vittorio; Scannapieco, Eugenio; Renzi, Paolo

    2006-01-01

    Background The general or spontaneous motor activity of animals is a useful parameter in chronobiology. Modified motion detectors can be used to monitor locomotor activity rhythms. We modified a commercial microwave-based detection device and validated the device by recording circadian and ultradian rhythms. Methods Movements were detected by microwave radar based on the Doppler effect. The equipment was designed to detect and record simultaneously 12 animals in separate cages. Radars were positioned at the bottom of aluminium bulkheads. Animal cages were positioned above the bulkheads. The radars were connected to a computer through a digital I/O board. Results The apparatus was evaluated by several tests. The first test showed the ability of the apparatus to detect the exact frequency of the standard moving object. The second test demonstrated the stability over time of the sensitivity of the radars. The third was performed by simultaneous observations of video-recording of a mouse and radar signals. We found that the radars are particularly sensitive to activities that involve a displacement of the whole body, as compared to movement of only a part of the body. In the fourth test, we recorded the locomotor activity of Balb/c mice. The results were in agreement with published studies. Conclusion Radar detectors can provide automatic monitoring of an animal's locomotor activity in its home cage without perturbing the pattern of its normal behaviour or initiating the spurt of exploration occasioned by transfer to a novel environment. Recording inside breeding cages enables long-term studies with uninterrupted monitoring. The use of electromagnetic waves allows contactless detection and freedom from interference of external stimuli. PMID:16674816

  3. Heteromeric heat-sensitive transient receptor potential channels exhibit distinct temperature and chemical response.

    PubMed

    Cheng, Wei; Yang, Fan; Liu, Shuang; Colton, Craig K; Wang, Chunbo; Cui, Yuanyuan; Cao, Xu; Zhu, Michael X; Sun, Changsen; Wang, KeWei; Zheng, Jie

    2012-03-02

    TRPV1 and TRPV3 are two heat-sensitive ion channels activated at distinct temperature ranges perceived by human as hot and warm, respectively. Compounds eliciting human sensations of heat or warmth can also potently activate these channels. In rodents, TRPV3 is expressed predominantly in skin keratinocytes, whereas in humans TRPV1 and TRPV3 are co-expressed in sensory neurons of dorsal root ganglia and trigeminal ganglion and are known to form heteromeric channels with distinct single channel conductances as well as sensitivities to TRPV1 activator capsaicin and inhibitor capsazepine. However, how heteromeric TRPV1/TRPV3 channels respond to heat and other stimuli remains unknown. In this study, we examined the behavior of heteromeric TRPV1/TRPV3 channels activated by heat, capsaicin, and voltage. Our results demonstrate that the heteromeric channels exhibit distinct temperature sensitivity, activation threshold, and heat-induced sensitization. Changes in gating properties apparently originate from interactions between TRPV1 and TRPV3 subunits. Our results suggest that heteromeric TRPV1/TRPV3 channels are unique heat sensors that may contribute to the fine-tuning of sensitivity to sensory inputs.

  4. Heteromeric Heat-sensitive Transient Receptor Potential Channels Exhibit Distinct Temperature and Chemical Response*

    PubMed Central

    Cheng, Wei; Yang, Fan; Liu, Shuang; Colton, Craig K.; Wang, Chunbo; Cui, Yuanyuan; Cao, Xu; Zhu, Michael X.; Sun, Changsen; Wang, KeWei; Zheng, Jie

    2012-01-01

    TRPV1 and TRPV3 are two heat-sensitive ion channels activated at distinct temperature ranges perceived by human as hot and warm, respectively. Compounds eliciting human sensations of heat or warmth can also potently activate these channels. In rodents, TRPV3 is expressed predominantly in skin keratinocytes, whereas in humans TRPV1 and TRPV3 are co-expressed in sensory neurons of dorsal root ganglia and trigeminal ganglion and are known to form heteromeric channels with distinct single channel conductances as well as sensitivities to TRPV1 activator capsaicin and inhibitor capsazepine. However, how heteromeric TRPV1/TRPV3 channels respond to heat and other stimuli remains unknown. In this study, we examined the behavior of heteromeric TRPV1/TRPV3 channels activated by heat, capsaicin, and voltage. Our results demonstrate that the heteromeric channels exhibit distinct temperature sensitivity, activation threshold, and heat-induced sensitization. Changes in gating properties apparently originate from interactions between TRPV1 and TRPV3 subunits. Our results suggest that heteromeric TRPV1/TRPV3 channels are unique heat sensors that may contribute to the fine-tuning of sensitivity to sensory inputs. PMID:22184123

  5. Potential Roles of Amiloride-Sensitive Sodium Channels in Cancer Development

    PubMed Central

    Xu, Siguang; Liu, Cui; Ma, Yana; Ji, Hong-Long; Li, Xiumin

    2016-01-01

    The ENaC/degenerin ion channel superfamily includes the amiloride-sensitive epithelial sodium channel (ENaC) and acid sensitive ionic channel (ASIC). ENaC is a multimeric ion channel formed by heteromultimeric membrane glycoproteins, which participate in a multitude of biological processes by mediating the transport of sodium (Na+) across epithelial tissues such as the kidney, lungs, bladder, and gut. Aberrant ENaC functions contribute to several human disease states including pseudohypoaldosteronism, Liddle syndrome, cystic fibrosis, and salt-sensitive hypertension. Increasing evidence suggests that ion channels not only regulate ion homeostasis and electric signaling in excitable cells but also play important roles in cancer cell behaviors such as proliferation, apoptosis, invasion, and migration. Indeed, ENaCs/ASICs had been reported to be associated with cancer characteristics. Given their cell surface localization and pharmacology, pharmacological strategies to target ENaC/ASIC family members may be promising cancer therapeutics. PMID:27403419

  6. Mirtazapine prevents induction and expression of cocaine-induced behavioral sensitization in rats.

    PubMed

    Salazar-Juárez, Alberto; Barbosa-Méndez, Susana; Jurado, Noe; Hernández-Miramontes, Ricardo; Leff, Philippe; Antón, Benito

    2016-07-04

    Cocaine abuse is a major health problem worldwide. Treatment based on both 5-HT2A/C and 5-HT3 receptor antagonists attenuate not only the effects of cocaine abuse but also the incentive/motivational effect related to cocaine-paired cues. Mirtazapine, an antagonist of postsynaptic α2-adrenergic, 5-HT2A/C and 5HT3 receptors and inverse agonist of the 5-HT2C receptor, has been shown to effectively modify, at the preclinical and clinical levels, various behavioral alterations induced by drugs abuse. Therefore, it is important to assess whether chronic dosing of mirtazapine alters locomotor effects of cocaine as well as induction and expression of cocaine sensitization. Our results reveal that a daily mirtazapine regimen administered for 30days effectively induces a significant attenuation of cocaine-dependent locomotor activity and as well as the induction and expression of behavioral sensitization. These results suggest that mirtazapine may be used as a potentially effective therapy to attenuate induction and expression of cocaine-induced locomotor sensitization. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. KM3NeT/ARCA sensitivity and discovery potential for neutrino point-like sources

    NASA Astrophysics Data System (ADS)

    Trovato, A.

    2016-04-01

    KM3NeT is a large research infrastructure with a network of deep-sea neutrino telescopes in the abyss of the Mediterranean Sea. Of these, the KM3NeT/ARCA detector, installed in the KM3NeT-It node of the network, is optimised for studying high-energy neutrinos of cosmic origin. Sensitivities to galactic sources such as the supernova remnant RXJ1713.7-3946 and the pulsar wind nebula Vela X are presented as well as sensitivities to a generic point source with an E-2 spectrum which represents an approximation for the spectrum of extragalactic candidate neutrino sources.

  8. The sensitization potential of sunscreen after ablative fractional skin resurfacing using modified human repeated insult patch test.

    PubMed

    Boonchai, Waranya; Sathaworawong, Angkana; Wongpraparut, Chanisada; Wanitphakdeedecha, Rungsima

    2015-10-01

    Ablative fractional skin resurfacing has become popular and proven to be useful in treating scars, photoaging and wrinkles. Although post-inflammatory hyperpigmentation (PIH) is the most common complication especially in dark-skinned patients like Asian. Several modalities have been used to overcome the PIH. To determine the sensitization potential of sunscreen applied immediately after ablative fractional skin resurfacing. Sixty volunteers were recruited. Of these 30 subjects were from previous ablative fractional skin resurfacing study who applied broad-spectrum sunscreen containing anti-inflammatory agent starting on the first day after resurfacing and another 30 non-resurfacing subjects had applied the same sunscreen on the intact skin. All subjects were patch/photopatch tested for sensitization study by using modified human repeated insult patch test (HRIPT). There were significantly higher sensitization rate of UV-filter, octocrylene and the sunscreen in resurfacing group than in non-resurfacing group. Early application of sunscreen after ablative fractional skin resurfacing has increased the incidence of sensitization potential of sunscreen. The sunscreen is recommended to start using from D3 after fractional ablative skin resurfacing to ensure the complete recovery of skin barrier and minimize the risk of sensitization.

  9. Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity

    SciTech Connect

    Mickley, G.A.; Stevens, K.E.; Galbraith, J.A.; White, G.A.; Gibbs, G.L.

    1984-04-01

    The present study attempted to determine the relative role of the peripheral and central nervous system in the production of morphine-induced or radiation-induced locomotor hyperactivity of the mouse. Toward this end, we used a quaternary derivative of an opiate antagonist (naltrexone methobromide), which presumably does not cross the blood-brain barrier. Quaternary naltrexone was used to challenge the stereotypic locomotor response observed in these mice after either an i.p. injection of morphine or exposure to 1500 rads /sup 60/Co. The quaternary derivative of naltrexone reversed the locomotor hyperactivity normally observed in the C57BL/6J mouse after an injection of morphine. It also significantly attenuated radiation-induced locomotion. The data reported here support the hypothesis of endorphin involvement in radiation-induced and radiogenic behaviors. However, these conclusions are contingent upon further research which more fully evaluates naltrexone methobromide's capacity to cross the blood-brain barrier.

  10. Perception--action coupling model for human locomotor pointing.

    PubMed

    de Rugy, A; Taga, G; Montagne, G; Buekers, M J; Laurent, M

    2002-08-01

    How do humans achieve the precise positioning of the feet during walking, for example, to reach the first step of a stairway? We addressed this question at the visuomotor integration level. Based on the optical specification of the required adaptation, a dynamical system model of the visuomotor control of human locomotor pointing was devised for the positioning of a foot on a visible target on the floor during walking. Visuomotor integration consists of directly linking optical information to a motor command that specifically modulates step length in accordance with the ongoing dynamics of locomotor pattern generation. The adaptation of locomotion emerges from a perception-action coupling type of control based on temporal information rather than on feedforward planning of movements. The proposed model reproduces experimental results obtained for human locomotor pointing.

  11. Developing Sensorimotor Countermeasures to Mitigate Post-Flight Locomotor Dysfunction

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Mulavara, A. P.; Cohen, H.; Miller, C. A.; Richards, J. T.; Houser, J.; McDonald, P. V.; Seidler, R. D.; Merkle, L. A.; Stelmach, G. E.

    2001-01-01

    Following spaceflight, crewmembers experience postural and locomotor instability. The magnitude and duration of post-flight sensorimotor disturbances increase with longer duration exposure to microgravity. These post-flight postural and locomotor alterations can pose a risk to crew safety and to mission objectives if nominal or emergency vehicle egress is required immediately following long-duration spaceflight. Gait instabilities could prevent or extend the time required to make an emergency egress from the Orbiter, Crew Return Vehicle or a future Martian lander leading to compromised mission objectives. We propose a countermeasure that aids in maintaining functional locomotor performance. This includes retaining the ability to perform vehicular egress and meet early mission objectives soon after landing on a planetary surface.

  12. Chronic Treatment With Aripiprazole Prevents Development of Dopamine Supersensitivity and Potentially Supersensitivity Psychosis

    PubMed Central

    Tadokoro, Shigenori; Okamura, Naoe; Sekine, Yoshimoto; Kanahara, Nobuhisa; Hashimoto, Kenji; Iyo, Masaomi

    2012-01-01

    Background: Long-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D2 dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity. Methods: We administered ARI (1.5 mg/kg/d), haloperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D2 receptor density (N = 4-10/condition/experiment). Results: Chronic treatment with HAL led to significant increases in locomotor response and D2 receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D2 density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D2 density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D2 density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH. Conclusions: Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia. PMID:21402722

  13. Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: low doses induce hypolocomotion.

    PubMed

    Singh, Rana A K; Kosten, Therese A; Kinsey, Berma M; Shen, Xiaoyun; Lopez, Angel Y; Kosten, Thomas R; Orson, Frank M

    2012-12-01

    The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.01 and 0.03mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3-10mg/kg). In Experiment 3, separate sets of mice were pre-treated with various meth doses once or twice (one injection/week) prior to a locomotor challenge with a low meth dose. Finally, in Experiment 4, we tested whether locomotor activation would be affected by pretreatment with a low or moderate dose of meth one month prior to the low meth dose challenge. Results show that low doses of meth induce hypolocomotion whereas moderate to high doses induce hyperlocomotion. Prior exposure to either one moderate or high dose of meth or to two, low doses of meth attenuated the hypolocomotor effect of a low meth dose one week later. This effect was also attenuated in mice tested one month after administration of a moderate meth dose. These results show that low and high doses of meth can have opposing effects on locomotor activity. Further, prior exposure to the drug leads to tolerance, rather than sensitization, of the hypolocomotor response to low meth doses. Published by Elsevier Inc.

  14. Intralaboratory validation of four in vitro assays for the prediction of the skin sensitizing potential of chemicals.

    PubMed

    Bauch, Caroline; Kolle, Susanne N; Fabian, Eric; Pachel, Christina; Ramirez, Tzutzuy; Wiench, Benjamin; Wruck, Christoph J; van Ravenzwaay, Bennard; Landsiedel, Robert

    2011-09-01

    Allergic contact dermatitis is induced by repeated skin contact with an allergen. Assessment of the skin sensitizing potential of chemicals, agrochemicals, and especially cosmetic ingredients is currently performed with the use of animals. Animal welfare and EU legislation demand animal-free alternatives reflected in a testing and marketing ban for cosmetic ingredients beginning in 2013. The underlying mechanisms of induction and elicitation of skin sensitization are complex and a chemical needs to comply several properties being skin sensitizing. To account for the multitude of events in the induction of skin sensitization an in vitro test system will consist of a battery of various tests. Currently, we performed intralaboratory validations of four assays addressing three different events during induction of skin sensitization. (1) The Direct Peptide Reactivity Assay (DPRA) according to Gerberick and co-workers (Gerberick et al., 2004) using synthetic peptides and HPLC analysis. (2) Two dendritic cell activation assays based on the dendritic cell like cell lines U-937 and THP-1 and flow cytometric detection of the maturation markers CD54 and/or CD86 (Ashikaga et al., 2006; Python et al., 2007; Sakaguchi et al., 2006). (3) Antioxidant response element (ARE)-dependent gene activity in a HaCaT reporter gene cell line (Emter et al., 2010). We present the results of our intralaboratory validation of these assays with 23 substances of known sensitizing potential. The sensitivity, specificity, and accuracy of the individual tests were obtained by comparison to human epidemiological data as well as to data from animal tests such as the local lymph node assay. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Contact sensitizing potential of pyrogallol and 5-amino-o-cresol in female BALB/c Mice

    PubMed Central

    Guo, T.L.; Germolec, D.R.; Zhang, Ling X.; Auttachoat, W.; Smith, M.J.; White, K.L.

    2013-01-01

    Hair dye components such as pyrogallol and cresol have been shown previously to promote allergic reactions such as rashes, dermal inflammation, irritation and dermatitis. The objective of this study was to determine the contact sensitization potential of pyrogallol (PYR) and 5-amino-o-cresol (AOC) when applied dermally to female BALB/c mice. Measurement of the contact hypersensitivity response was initially accomplished using the local lymph node assay. For PYR, significant increases in the proliferation of lymph node cells were observed at concentrations of 0.5% (w/v) and higher. For AOC, borderline increases, albeit significant, in auricular lymph node cell proliferation were observed at 5% and 10%. Results from the irritancy assay suggested that PYR, but not AOC, was an irritant. To further delineate whether PYR was primarily an irritant or a contact sensitizer, the mouse ear swelling test (MEST) was conducted. A significant increase in mouse ear thickness was observed at 72 hr following challenge with 0.5% PYR in mice that had been sensitized with 5% PYR. In contrast, no effects were observed in the MEST in mice sensitized and challenged with the highest achievable concentration of AOC (10%). Additional studies examining lymph node subpopulations and CD86 (B7.2) expression by B cells further support the indication that PYR was a sensitizer in BALB/c mice. The results demonstrate that PYR is both a sensitizer and an irritant in female BALB/c mice. However, the contact sensitization potential of AOC is minimal in this strain of mouse. PMID:24172597

  16. Nitric oxide-mediated modulation of the murine locomotor network.

    PubMed

    Foster, Joshua D; Dunford, Catherine; Sillar, Keith T; Miles, Gareth B

    2014-02-01

    Spinal motor control networks are regulated by neuromodulatory systems to allow adaptability of movements. The present study aimed to elucidate the role of nitric oxide (NO) in the modulation of mammalian spinal locomotor networks. This was investigated with isolated spinal cord preparations from neonatal mice in which rhythmic locomotor-related activity was induced pharmacologically. Bath application of the NO donor diethylamine NONOate (DEA/NO) decreased the frequency and modulated the amplitude of locomotor-related activity recorded from ventral roots. Removal of endogenous NO with coapplication of a NO scavenger (PTIO) and a nitric oxide synthase (NOS) blocker [nitro-l-arginine methyl ester (l-NAME)] increased the frequency and decreased the amplitude of locomotor-related activity. This demonstrates that endogenously derived NO can modulate both the timing and intensity of locomotor-related activity. The effects of DEA/NO were mimicked by the cGMP analog 8-bromo-cGMP. In addition, the soluble guanylyl cyclase (sGC) inhibitor ODQ blocked the effects of DEA/NO on burst amplitude and frequency, although the frequency effect was only blocked at low concentrations of DEA/NO. This suggests that NO-mediated modulation involves cGMP-dependent pathways. Sources of NO were studied within the lumbar spinal cord during postnatal development (postnatal days 1-12) with NADPH-diaphorase staining. NOS-positive cells in the ventral horn exhibited a rostrocaudal gradient, with more cells in rostral segments. The number of NOS-positive cells was also found to increase during postnatal development. In summary, we have shown that NO, derived from sources within the mammalian spinal cord, modulates the output of spinal motor networks and is therefore likely to contribute to the fine-tuning of locomotor behavior.

  17. Locomotor adaptability in persons with unilateral transtibial amputation.

    PubMed

    Darter, Benjamin J; Bastian, Amy J; Wolf, Erik J; Husson, Elizabeth M; Labrecque, Bethany A; Hendershot, Brad D

    2017-01-01

    Locomotor adaptation enables walkers to modify strategies when faced with challenging walking conditions. While a variety of neurological injuries can impair locomotor adaptability, the effect of a lower extremity amputation on adaptability is poorly understood. Determine if locomotor adaptability is impaired in persons with unilateral transtibial amputation (TTA). The locomotor adaptability of 10 persons with a TTA and 8 persons without an amputation was tested while walking on a split-belt treadmill with the parallel belts running at the same (tied) or different (split) speeds. In the split condition, participants walked for 15 minutes with the respective belts moving at 0.5 m/s and 1.5 m/s. Temporal spatial symmetry measures were used to evaluate reactive accommodations to the perturbation, and the adaptive/de-adaptive response. Persons with TTA and the reference group of persons without amputation both demonstrated highly symmetric walking at baseline. During the split adaptation and tied post-adaptation walking both groups responded with the expected reactive accommodations. Likewise, adaptive and de-adaptive responses were observed. The magnitude and rate of change in the adaptive and de-adaptive responses were similar for persons with TTA and those without an amputation. Furthermore, adaptability was no different based on belt assignment for the prosthetic limb during split adaptation walking. Reactive changes and locomotor adaptation in response to a challenging and novel walking condition were similar in persons with TTA to those without an amputation. Results suggest persons with TTA have the capacity to modify locomotor strategies to meet the demands of most walking conditions despite challenges imposed by an amputation and use of a prosthetic limb.

  18. Locomotor adaptability in persons with unilateral transtibial amputation

    PubMed Central

    Bastian, Amy J.; Wolf, Erik J.; Husson, Elizabeth M.; Labrecque, Bethany A.; Hendershot, Brad D.

    2017-01-01

    Background Locomotor adaptation enables walkers to modify strategies when faced with challenging walking conditions. While a variety of neurological injuries can impair locomotor adaptability, the effect of a lower extremity amputation on adaptability is poorly understood. Objective Determine if locomotor adaptability is impaired in persons with unilateral transtibial amputation (TTA). Methods The locomotor adaptability of 10 persons with a TTA and 8 persons without an amputation was tested while walking on a split-belt treadmill with the parallel belts running at the same (tied) or different (split) speeds. In the split condition, participants walked for 15 minutes with the respective belts moving at 0.5 m/s and 1.5 m/s. Temporal spatial symmetry measures were used to evaluate reactive accommodations to the perturbation, and the adaptive/de-adaptive response. Results Persons with TTA and the reference group of persons without amputation both demonstrated highly symmetric walking at baseline. During the split adaptation and tied post-adaptation walking both groups responded with the expected reactive accommodations. Likewise, adaptive and de-adaptive responses were observed. The magnitude and rate of change in the adaptive and de-adaptive responses were similar for persons with TTA and those without an amputation. Furthermore, adaptability was no different based on belt assignment for the prosthetic limb during split adaptation walking. Conclusions Reactive changes and locomotor adaptation in response to a challenging and novel walking condition were similar in persons with TTA to those without an amputation. Results suggest persons with TTA have the capacity to modify locomotor strategies to meet the demands of most walking conditions despite challenges imposed by an amputation and use of a prosthetic limb. PMID:28704467

  19. Peptide reactivity assay using spectrophotometric method for high-throughput screening of skin sensitization potential of chemical haptens.

    PubMed

    Jeong, Yun Hyeok; An, Susun; Shin, Kyeho; Lee, Tae Ryong

    2013-02-01

    Haptens must react with cellular proteins to be recognized by antigen presenting cells. Therefore, monitoring reactivity of chemicals with peptide/protein has been considered an in vitro skin sensitization testing method. The reactivity of peptides with chemicals (peptide reactivity) has usually been monitored by chromatographic methods like HPLC or LC/MS, which are robust tools for monitoring common chemical reactions but are rather expensive and time consuming. Here, we examined the possibility of using spectrophotometric methods to monitor peptide reactivity. Two synthetic peptides, Ac-RWAACAA and Ac-RWAAKAA, were reacted with 48 chemicals (34 sensitizers and 14 non-sensitizers). Peptide reactivity was measured by monitoring unreacted peptides with UV-Vis spectrophotometer using 5,5'-dithiobis-2-nitrobenzoic acid as a detection reagent for the free thiol group of cysteine-containing peptide or fluorometer using fluorescamine™ as a detection reagent for the free amine group of lysine-containing peptide. Chemicals were categorized as sensitizers when they induced more than 10% depletion of cysteine-containing peptide or 20% depletion of lysine-containing peptide. The sensitivity, specificity, and accuracy of this method were 82.4%, 85.7%, and 83.3%, respectively. These results demonstrate that spectrophotometric methods can be easy, fast, and high-throughput screening tools for the prediction of the skin sensitization potential of chemical haptens.

  20. Determination of the interatomic potential from elastic differential cross sections at fixed energy: Functional sensitivity analysis approach

    SciTech Connect

    Ho, T.; Rabitz, H.

    1989-02-01

    Elastic differential cross sections in atomic crossed beam experiments contain detailed information about the underlying interatomic potentials. The functional sensitivity density of the cross sections with respect to the potential deltasigma(theta)/deltaV(R) reveals such information and has been implemented in an iterative inversion procedure, analogous to that of the Newton--Raphson technique. The stability of the inversion is achieved with the use of the regularization method of Tikhonov and Miller. It is shown that given a set of well resolved and noise-free differential cross section data within a limited angular range and given a reasonable starting reference potential, the recovered potential accurately resembles the desired one in the important region, i.e., the region to which the scattering data are sensitive. The region of importance depends upon the collision energy relative to the well depth of the potential under