Locomotor Stimulation Research Articles

Locomotor stimulant and discriminative stimulus effects of ‘bath salt’ cathinones

A number of psychostimulant-like cathinone compounds are being sold as 'legal' alternatives to methamphetamine or cocaine. The purpose of these experiments was to determine whether cathinone compounds stimulate motor activity and have discriminative stimulus effects similar to those of cocaine and/or methamphetamine. 3,4-Methylenedioxypyrovalerone (MDPV), methylone, mephedrone, naphyrone, flephedrone, and butylone were tested for locomotor stimulant effects in mice and subsequently for substitution in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally) or methamphetamine (1 mg/kg, intraperitoneally) from saline. All compounds fully substituted for the discriminative stimulus effects of cocaine and methamphetamine. Several commonly marketed cathinones produce discriminative stimulus effects comparable with those of cocaine and methamphetamine, which suggests that these compounds are likely to have similar abuse liabilities. MDPV and naphyrone produced locomotor stimulant effects that lasted much longer than those of cocaine or methamphetamine and therefore may be of particular concern, particularly because MDPV is one of the most commonly found substances associated with emergency room visits because of adverse effects of taking 'bath salts'.

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

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.

Unique genetic factors influence sensitivity to the rewarding and aversive effects of methamphetamine versus cocaine

Genetic factors significantly influence addiction-related phenotypes. This is supported by the successful bidirectional selective breeding of two replicate sets of mouse lines for amount of methamphetamine consumed. Some of the same genetic factors that influence methamphetamine consumption have been previously found also to influence sensitivity to the conditioned rewarding and aversive effects of methamphetamine. The goal of the current studies was to determine if some of the same genetic factors influence sensitivity to the conditioned rewarding and aversive effects of cocaine. Cocaine conditioned reward was examined in methamphetamine high drinking and low drinking line mice using a conditioned place preference procedure and cocaine conditioned aversion was measured using a conditioned taste aversion procedure. In addition, a general sensitivity measure, locomotor stimulant response to cocaine, was assessed in these lines; previous data indicated no difference between the selected lines in sensitivity to methamphetamine-induced stimulation. In contrast to robust differences for methamphetamine, the methamphetamine high and low drinking lines did not differ in sensitivity to either the rewarding or aversive effects of cocaine. They also exhibited comparable sensitivity to cocaine-induced locomotor stimulation. These data suggest that the genetic factors that influence sensitivity to the conditioned rewarding and aversive effects of methamphetamine in these lines of mice do not influence sensitivity to these effects of cocaine. Thus, different genetic factors may influence risk for methamphetamine versus cocaine use.

Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems

Dopamine (DA) is accumulated and compartmentalized by the dopamine transporter (DAT; SLC3A6) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2). These transporters work at the plasma and vesicular membranes of dopaminergic neurons, respectively, and thus regulate levels of DA in neuronal compartments that include the extravesicular cytoplasmic compartment. DA in this compartment has been hypothesized to contribute to oxidative damage that can reduce the function of dopaminergic neurons in aging brains and may contribute to reductions in dopaminergic neurochemical markers, locomotor behavior and responses to dopaminergic drugs that are found in aged animals. The studies reported here examined aged mice with heterozygous deletions of VMAT2 or of DAT, which each reduce transporter expression to about 50% of levels found in wild-type (WT) mice. Aged mice displayed reduced locomotor responses under a variety of circumstances, including in response to locomotor stimulants, as well as changes in monoamine levels and metabolites in a regionally dependent manner. Several effects of aging were more pronounced in heterozygous VMAT2 knockout (KO) mice, including aging induced reductions in locomotion and reduced locomotor responses to cocaine. By contrast, some effects of aging were reduced or not observed in heterozygous DAT KO mice. These findings support the idea that altered DAT and VMAT2 expression affect age-related changes in dopaminergic function. These effects are most likely mediated by alterations in DA compartmentalization, and might be hypothesized to be exacerbated by other factors that affect the metabolism of cytosolic DA.This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.

Histamine is required for H3 receptor‐mediated alcohol reward inhibition, but not for alcohol consumption or stimulation

Conflicting data have been published on whether histamine is inhibitory to the rewarding effects of abused drugs. The purpose of this study was to clarify the role of neuronal histamine and, in particular, H₃ receptors in alcohol dependence-related behaviours, which represent the addictive effects of alcohol. Alcohol-induced conditioned place preference (alcohol-CPP) was used to measure alcohol reward. Alcohol-induced locomotor stimulation, alcohol consumption and kinetics were also assessed. mRNA levels were quantified using radioactive in situ hybridization. Low doses of H₃ receptor antagonists, JNJ-10181457 and JNJ-39220675, inhibited alcohol reward in wild-type (WT) mice. However, these H₃ receptor antagonists did not inhibit alcohol reward in histidine decarboxylase knock-out (HDC KO) mice and a lack of histamine did not alter alcohol consumption. Thus H₃ receptor antagonists inhibited alcohol reward in a histamine-dependent manner. Furthermore, WT and HDC KO mice were similarly stimulated by alcohol. The expression levels of dopamine D₁ and D₂ receptors, STEP61 and DARPP-32 mRNA in striatal subregions were unaltered in HDC KO mice. No differences were seen in alcohol kinetics in HDC KO compared to WT control animals. In addition, JNJ-39220675 had no effect on alcohol kinetics in WT mice. These data suggest that histamine is required for the H₃ receptor-mediated inhibition of alcohol-CPP and support the hypothesis that the brain histaminergic system has an inhibitory role in alcohol reward. Increasing neuronal histamine release via H₃ receptor blockade could therefore be a novel way of treating alcohol dependence.

S10 * EMERGING DRUGS FOR TREATING ALCOHOL USE DISORDERS: PRECLINICAL EVIDENCE

S10 * EMERGING DRUGS FOR TREATING ALCOHOL USE DISORDERS: PRECLINICAL EVIDENCE

Selectively Bred Crossed High-Alcohol-Preferring Mice Drink to Intoxication and Develop Functional Tolerance, But Not Locomotor Sensitization During Free-Choice Ethanol Access

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 addition to buttressing the hypothesized importance of tolerance in drinking, our findings suggest that cHAP mice may be a unique, translational resource for studying tolerance as a contributor to and consequence of chronic, excessive EtOH consumption.

Expression of behavioral sensitization to ethanol is increased by energy drink administration

Alcohol abuse and dependence are important medical, social and economical problems, affecting millions of people. A relatively recent habit among young people is mixing alcohol with energy drinks (ED), in spite of the risks involved may be higher than those associated with alcohol consumption alone. The mixture of alcohol and energy drinks, both with stimulant properties, may alter the perception of intoxication and could lead individuals to believe they are less drunk and can drink more or for longer periods of time. In animals, the repeated administration of ethanol can lead to a progressive increase of the locomotor stimulant effect, known as behavioral sensitization, a drug-dependent behavioral plasticity associated with vulnerability to addiction. As well as for addiction, there are clear individual differences in the level of sensitization to ethanol among species and even among individuals from the same strain. The present study assessed how ED affects the expression of ethanol sensitization. Female mice chronically treated with ethanol (2.4g/kg) were classified as low-sensitized or high-sensitized. Two days later, different groups of mice were submitted to saline+water, ethanol+water or ethanol+ED systemic challenges. As expected, only the high-sensitized group expressed clear sensitization after ethanol administration. However, the administration of ethanol+ED triggered the sensitization expression in the low-sensitized group. These data indicate that the combined use of ED and ethanol can potentiate the stimulant and, consequently, the reward effects of ethanol in previously treated mice. If a similar process occurs in human beings, the use of ED can increase the risk of developing alcohol abuse or dependence.

The Glucagon-Like Peptide 1 Analogue, Exendin-4, Attenuates the Rewarding Properties of Psychostimulant Drugs in Mice

Glucagon-like peptide 1 (GLP-1) is an incretine hormone that controls consummatory behavior and glucose homeostasis. It is released in response to nutrient ingestion from the intestine and production in the brain has also been identified. Given that GLP-1 receptors are expressed in reward areas, such as the nucleus accumbens and ventral tegmental area, and that common mechanisms regulate food and drug-induced reward we hypothesize that GLP-1 receptors are involved in reward regulation. Herein the effect of the GLP-1 receptor agonist Exendin-4 (Ex4), on amphetamine- and cocaine-induced activation of the mesolimbic dopamine system was investigated in mice. In a series of experiments we show that treatment with Ex4, at a dose with no effect per se, reduce amphetamine- as well as cocaine-induced locomotor stimulation, accumbal dopamine release as well as conditioned place preference in mice. Collectively these data propose a role for GLP-1 receptors in regulating drug reward. Moreover, the GLP-1 signaling system may be involved in the development of drug dependence since the rewarding effects of addictive drugs involves interferences with the mesolimbic dopamine system. Given that GLP-1 analogues, such as exenatide and liraglutide, are clinically available for treatment of type II diabetes, we propose that these should be elucidated as treatments of drug dependence.

Opposite effects of typical and atypical anti-psychotic drugs on sensitized dopamine receptors: Sub-chronic low dose Olanzapine exposure reverses sensitization but a similar regimen of low dose haloperidol potentiates sensitization effects

Both typical and atypical antipsychotic drugs are D2 receptor antagonists but yet appear to have markedly different effects upon the induction of dopamine sensitization. This study aims to compare the effects of subchronic regimens of low-dose olanzapine and haloperidol administered to rats previously sensitized to apomorphine. Initially, rats received apomorphine (2.0mg/kg) or vehicle treatments for five consecutive days followed by a conditioning test and an apomorphine challenge test. Next, there was an antipsychotic exposure phase in which three vehicle groups and three apomorphine groups received 10 daily injections of either vehicle, haloperidol (0.03mg/kg) or olanzapine (0.01mg/kg). In the final phase, all groups were given a second conditioning test and apomorphine challenge test. Apomorphine induced sensitization and conditioning effects. Following haloperidol exposure, apomorphine conditioned and sensitization effects were potentiated but, in contrast, olanzapine exposure eliminated apomorphine sensitization effects. In addition, the sensitization induced by apomorphine transformed the low-dose haloperidol treatment into a potent locomotor stimulant treatment. In the vehicle groups, haloperidol and olanzapine exposure effects were equivalent and not different from vehicle treatment. The profound differences observed between typical and atypical antipsychotic exposure in animals with an upregulated dopamine system are consistent with clinical evidence for lower risk of psychomotor disturbances with chronic treatment with atypical antipsychotic. Importantly, the finding that a very low dose of olanzapine reversed sensitization effects suggests that low-dose olanzapine may have clinical utility in a variety of disorders linked to sensitization of the dopamine system.

Determining the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection

Sensitization to the locomotor stimulant effects of alcohol (ethanol) is thought to be a heritable risk factor for the development of alcoholism that reflects progressive increases in the positive motivational effects of this substance. However, very little is known about the degree to which genes influence this complex behavioral phenomenon. The primary goal of this work was to determine the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection. Genetically heterogeneous C57BL/6J (B6) × DBA/2J (D2) F2 mice were generated from B6D2F1 progenitors, phenotyped for the expression of locomotor sensitization, and bred for high (HLS) and low (LLS) expression of this behavior. Selective breeding was conducted in two independently generated replicate sets to increase the confidence of our heritability estimates and for future correlated trait analyses. Large and significant differences in locomotor sensitization between HLS and LLS lines were evident by the fourth generation. Twenty-two percent of the observed line difference(s) were attributable to genes (h² = .22). Interestingly, locomotor activity in the absence of ethanol was genetically correlated with ethanol sensitization; high activity was associated with high sensitization. That changes in ethanol sensitivity following repeated exposures are genetically regulated highlights the relevance of studies aimed at determining how genes regulate susceptibility to ethanol-induced behavioral and neural adaptations. As alcohol use and abuse disorders develop following many repeated alcohol exposures, these data emphasize the need for future studies determining the genetic basis by which changes in response to alcohol occur.

Effect of post-trial L-NAME administration on cocaine sensitization

This study determined if Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) administered after the cocaine-conditioning trial attenuated the development of sensitization to cocaine's locomotor-stimulating effect and secondly, determined if L-NAME blocked conditioned-locomotor activity (LMA) elicited by a saline-challenge injection. Results revealed that cocaine-injected animals (10 mg/kg, i.p.) showed enhanced locomotor activity across the three conditioning trials (all p's < .05). Cocaine-injected animals administered L-NAME (30 mg/kg, i.p.) after each conditioning trial showed a slight increase in cocaine-stimulated LMA from the first to the second conditioning trial (all p's < .05) and no further increases in LMA thereafter. A saline-challenge injection administered 72 hr after the last conditioning trial revealed that cocaine-injected animals displayed as much locomotor stimulation to a saline injection as they did during their initial exposure to cocaine on the first conditioning trial - indicating the development of cocaine-conditioned LMA.The present findings show that L-NAME administered after the cocaine-conditioning trial attenuates the development of sensitization to cocaine's locomotor-stimulating effect. The failure of L-NAME to block cocaine-conditioned LMA suggests that the pharmacological and conditioning mechanisms of sensitization can be dissociated. It is unlikely that L-NAME's effect is due to a sedative action produced by residual L-NAME since animals administered L-NAME (30 mg/kg, i.p.) for 10 consecutive days exhibited a similar responsiveness to a cocaine challenge administered 3 and 10 days following the termination of L-NAME administration. These data support a role for nitric oxide's involvement in the neuroadaptive responses that result from continued stimulant administration and demonstrate the importance of conditioned drug effects.

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

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.

Rufy1 or Hnrnph1 is a likely quantitative trait gene for methamphetamine sensitivity

Sensitivity to the locomotor stimulant properties of drugs of abuse is a heritable trait and its genetic basis may be shared with alleles that modulate activation of the mesolimbic reward pathway. We previously used mouse lines derived from C57BL/6J and DBA/2J alleles that were selected for high and low methamphetamine (MA) sensitivity and identified a genome‐wide significant quantitative trait locus (QTL) on chromosome 11. In order to further pursue this QTL, we utilized the power of an F2 cross and the iterative nature of interval‐specific congenic lines in an effort to identify the causal gene(s) underlying this QTL. The results of F2 mice and the larger congenic lines revealed two large‐effect QTLs for MA‐induced locomotor activity; however, the phenotypic results of the smaller subcongenic lines revealed additional smaller effect QTLs with different modes of inheritance. One subcongenic locus converged remarkably well with the QTL peak in the F2 cross and altered methamphetamine sensitivity in a time‐dependent manner. We generated eight sub‐subcongenic lines derived from this subcongenic line (17 congenic lines total). Owing to a fortuitous recombination event, we identified and replicated a 0.23 Mb region spanning 50.17–50.40 Mb that was critical for MA sensitivity. This region contains only three genes (Rufy1, Hnrnph1, and Cby3) and only two of these genes are expressed in the brain (Rufy1 and Hnrnph1). This study exemplifies how a careful and detailed use of congenic lines can yield narrow QTL intervals and a tractable number of genes for quantitative trait gene identification.

Participation of the nociceptin/orphanin FQ receptor in ethanol-mediated locomotor activation and ethanol intake in preweanling rats

Activation of nociceptin/orphanin FQ (NOP) receptors seems to attenuate ethanol-induced reinforcement in adult rodents. Since early ethanol exposure results in later increased responsiveness to ethanol, it is important to analyze NOP receptor modulation of ethanol-related behaviors during early ontogeny. By measuring NOP involvement in ethanol intake and ethanol-induced locomotor activation, we analyzed the specific participation of NOP receptors on these ethanol-related behaviors in two-week-old rats. In each experiment animals were pre-treated with the endogenous ligand for this receptor (nociceptin/orphanin FQ at 0.0, 0.5, 1.0 or 2.0μg) or a selective NOP antagonist (J-113397 at 0.0, 0.5, 2.0 or 5.0mg/kg). Results indicated that activation of the nociceptin receptor system had no effect on ethanol or water intake, while blockade of the NOP receptor has an unspecific effect on consummatory behavior: J-113397 increased ethanol (at a dose of 0.5mg/kg) and water intake (at 0.5 and 5.0mg/kg). Ethanol-mediated locomotor stimulation was attenuated by activation of the NOP system (nociceptin at 1.0 and 2.0μg). Nociceptin had no effect on basal locomotor activity. Blockade of NOP receptors did not modify ethanol-induced locomotor activation. Contrary to what has been reported for adult rodents, nociceptin failed to suppress intake of ethanol in infants. Attenuation of ethanol-induced stimulation by activation of NOP receptor system suggests an early role of this receptor in this ethanol-related behavior.

Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference

Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist “JMV2959”. We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs.

Adolescent Cocaine Exposure Causes Enduring Macroscale Changes in Mouse Brain Structure

Cocaine dependence is associated with abnormalities in brain structure in humans. However, it is unclear whether these differences in brain structure predispose an individual to drug use or are a result of cocaine's action on the brain. This study investigates the impact of chronic cocaine exposure on brain structure and drug-related behavior in mice. Specifically, mice received daily cocaine or saline injections for 20 d during two developmental time periods: adolescence (27-46 d old) and young adulthood (60-79 d old). Following 30 d of abstinence, either fixed brain T2 weighted magnetic resonance images were acquired on a 7 T scanner at 32 μm isotropic voxel dimensions or mice were assessed for sensitization to the locomotor stimulant effects of cocaine. Three automated techniques (deformation-based morphometry, striatum shape analysis, and cortical thickness assessment) were used to identify population differences in brain structure in cocaine-exposed versus saline-exposed mice. We found that cocaine induced changes in brain structure, and these were most pronounced in mice exposed to cocaine during adolescence. Many of these changes occurred in brain regions previously implicated in addiction including the nucleus accumbens, striatum, insular cortex, orbitofrontal cortex, and medial forebrain bundle. Furthermore, exposure to the same cocaine regimen caused sensitization to the locomotor stimulant effects of cocaine, and these effects were again more pronounced in mice exposed to cocaine during adolescence. These results suggest that altered brain structure following 1 month of abstinence may contribute to these persistent drug-related behaviors, and identify cocaine exposure as the cause of these morphological changes.

Levetiracetam Has Opposite Effects on Alcohol- and Cocaine-Related Behaviors in C57BL/6J Mice

The antiepileptic drug levetiracetam (LEV) is a potential treatment for alcohol use disorders, yet few preclinical studies exist on its effects in animal models relevant to drug or alcohol abuse. We investigated the effects of LEV on locomotor stimulation following acute and repeated administration of alcohol or cocaine and on alcohol- and cocaine-mediated changes in responding for brain stimulation reward (BSR) in C57BL/6J mice. LEV alone (10.0-100.0 mg/kg intraperitoneally) had no significant effect on locomotor activity or intracranial self-stimulation. Pretreatment with LEV reduced acute locomotor stimulation by 2.0 g/kg alcohol, attenuated the development of locomotor sensitization to alcohol with repeated exposure, and produced a shift in the dose-response curve for alcohol on BSR threshold without affecting maximum operant response rate (MAX). Conversely, LEV pretreatment enhanced both acute locomotor stimulation by 15 mg/kg cocaine and development of locomotor sensitization following repeated exposure and produced a leftward shift in the dose-response curve for cocaine on BSR threshold without affecting MAX. Electrophysiological recordings in vitro showed that LEV reduced excitatory currents in both ventral tegmental area (VTA) dopamine neurons and nucleus accumbens (NAc) medium spiny neurons, consistent with a presynaptic effect. The opposite effects of LEV pretreatment on alcohol- and cocaine-related behaviors may predict its clinical utility in the treatment of patients with alcohol, but not psychostimulant abuse disorders.

Acute ethanol treatment upregulates th1, th2, and hdc in larval zebrafish in stable networks

Earlier studies in zebrafish have revealed that acutely given ethanol has a stimulatory effect on locomotion in fish larvae but the mechanism of this effect has not been revealed. We studied the effects of ethanol concentrations between 0.75 and 3.00% on 7-day-old larval zebrafish (Danio rerio) of the Turku strain. At 0.75-3% concentrations ethanol increased swimming speed during the first minute. At 3% the swimming speed decreased rapidly after the first minute, whereas at 0.75 and 1.5% a prolonged increase in swimming speed was seen. At the highest ethanol concentration dopamine levels decreased significantly after a 10-min treatment. We found that ethanol upregulates key genes involved in the biosynthesis of histamine (hdc) and dopamine (th1 and th2) following a short 10-min ethanol treatment, measured by qPCR. Using in situ hybridization and immunohistochemistry, we further discovered that the morphology of the histaminergic and dopaminergic neurons and networks in the larval zebrafish brain was unaffected by both the 10-min and a longer 30-min treatment. The results suggest that acute ethanol rapidly decreases dopamine levels, and activates both forms or th to replenish the dopamine stores within 30 min. The dynamic changes in histaminergic and dopaminergic system enzymes occurred in the same cells which normally express the transcripts. As both dopamine and histamine are known to be involved in the behavioral effects of ethanol and locomotor stimulation, these results suggest that rapid adaptations of these networks are associated with altered locomotor activity.

Assessment of Behaviors Modeling Aspects of Schizophrenia in Csmd1 Mutant Mice

Schizophrenia is a debilitating psychotic disorder that affects up to 1.5% of the population worldwide. Two recent studies in humans identified genome-wide significant associations between schizophrenia and single-nucleotide polymorphisms (SNPs) in an intron of CSMD1. The effect of deleting CSMD1 on mouse behavior is unknown. The present study utilized mice with a mutant Csmd1 allele in which the first exon had been ablated (KO mice). All Csmd1 transcripts that included the first exon were absent in the brains of KO mice, but there was persistent expression of at least one other transcript that does not include the first exon. Wild type (WT), heterozygous (HET), and KO mice were assessed using several well-established behavioral paradigms that model aspects of schizophrenia. Csmd1 KO mice did not differ from wild-type littermates for sensorimotor gating (measured as prepulse inhibition), social interaction, anhedonia (measured by sucrose preference), or sensitivity to the locomotor stimulant effects of the dopaminergic agent d-amphetamine. These data demonstrate that loss of Csmd1 transcripts that include the first exon does not alter multiple well-established behaviors that model aspects of schizophrenia. The SNP most strongly associated with schizophrenia in humans is between exons 3 and 4; therefore, ablation of exon 1 appeared to be a logical animal model. Nevertheless, future studies should consider alternative mouse models including gain-of-function mutations, and loss-of-function mutations that target alternative transcripts of Csmd1.