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Alcohol dependence can increase the level of anxiety. A growing body of research has identified a link between anxiety symptoms of problem drinkers and their genetic or environment factors, respectively. However, to date few studies have directly examined gene-environment (G × E) interaction on their anxiety symptoms during the acute alcohol withdrawal. The present study aims to examine the interaction between the proopiomelanocortin (A total of 440 male problem drinkers (Results indicated that theThis study suggested that the SNP in

We define behavioral sensitization as an augmented response to subsequent dosing after chronic intermittent administration of a drug. However, the biphasic effects of ethanol (EtOH), first stimulatory followed by depressive, make animal models of behavioral sensitization rare.This study aimed to determine a dose of EtOH that did not depress wheel-running (WR) in CD1 mice and then to develop a model of EtOH-induced behavioral sensitization.For the first part of this study, male CD1 mice (n = 24, 6/group) were administered either phosphate buffer saline (PBS), 0.5 g/kg, 1 g/kg, or 2 g/kg EtOH at a volume of 3 ml/kg, intraperitoneally (IP). Mice were divided into equal groups and received the weight-based dose once daily on Days 1, 2, 3, 4, and 5. All mice received a challenge dose of 0.5 g/kg on Day 10. In both parts of the study, mice were habituated to the running wheel for 5 min prior to dosing and wheel running was measured for 10 min after each dose.The acute dose-response of EtOH effects on wheel running determined a significant difference between doses in wheel running (p 0.05), with a post-hoc analysis establishing that 0.5 g/kg EtOH resulted in significantly more WR compared to 2 g/kg EtOH (p 0.05). The chronic study demonstrated a significant main effect of Day (1 vs. 5 vs. Challenge, p 0.001) and an interaction between Day and Treatment, with post-hoc analysis determining the effect to be between PBS and EtOH WR on Day 5 (p 0.05). In addition, Bonferroni post-hoc analysis determined no differences between Days in the PBS condition, but a significant difference in the EtOH condition between Day 1 and Day 5 (p 0.001) and that difference from Day 1 persisted when comparing to the Challenge Day (p 0.01).After chronic, intermittent, low dose administration of EtOH, male mice showed an increase in activity as measured by wheel running. Therefore, we laid the groundwork for a potentially useful rodent model for EtOH-induced behavioral sensitization.

Gamma-aminobutyric acid A (GABA(A)) receptors moderate several of the behavioral effects of alcohol. In fact, recent studies have shown an association between the gene for the alpha2-subunit of the GABA(A) receptor (GABRA2) and alcoholism. In the present study, we examined the functional relevance of the GABRA2 gene in alcohol dependence by assessing brain GABRA2 mRNA and GABA(A)alpha2-subunit protein levels in post-mortem prefrontal cortical tissue collected from control and alcohol-dependent individuals. In addition, using an endophenotype approach, we tested whether the GABRA2 gene moderates sensitivity to the acute effects of alcohol in two independent samples from distinct human alcohol challenge studies. Results indicated that GABRA2 mRNA levels significantly differed by GABRA2 genotype. GABRA2 single nucleotide polymorphisms (rs573400, rs279871 and rs279858) were significantly associated with sensitivity to the acute effects of alcohol. Specifically, there was a significant main effect of GABRA2 x breath alcohol concentration on several measures of subjective responses to alcohol, including the hedonic value of alcohol. Importantly, reanalysis of a previous intravenous alcohol administration study confirmed the results of the oral alcohol challenge study. In summary, these results extend previous findings and provide new insights into the putative biobehavioral mechanisms that may moderate the association between the GABRA2 gene, sensitivity to the acute effects of alcohol and ultimately alcohol dependence.

A growing number of imaging studies suggest that alcohol cues, mainly visual, elicit activation in mesocorticolimbic structures. Such findings are consistent with the growing recognition that these structures play an important role in the attribution of incentive salience and the pathophysiology of addiction. The present study investigated whether the presentation of alcohol taste cues can activate brain regions putatively involved in the acquisition and expression of incentive salience. Using functional magnetic resonance imaging, we recorded BOLD activity while delivering alcoholic tastes to 37 heavy drinking but otherwise healthy volunteers. The results yielded a pattern of BOLD activity in mesocorticolimbic structures (ie prefrontal cortex, striatum, ventral tegmental area/substantia nigra) relative to an appetitive control. Further analyses suggested strong connectivity between these structures during cue-elicited urge and demonstrated significant positive correlations with a measure of alcohol use problems (ie the Alcohol Use Disorders Identification Test). Thus, repeated exposure to the taste alcohol in the scanner elicits activation in mesocorticolimbic structures, and this activation is related to measures of urge and severity of alcohol problems.

This study investigated the influence of age on the behavioral responses elicited by psychostimulants in male CD-1 mice. Behavioral activity including locomotion and stereotypy was measured following acute or repeated administration of cocaine, methylphenidate, amphetamine or saline to postweanling (24 days old), periadolescent (33 days old) and adult (60 days old) mice. Postweanling mice exhibited less total and ambulatory activity than periadolescent mice following a single acute injection of cocaine (20 or 30 and 30 mg/kg, respectively). Further, postweanling mice showed less total activity than both periadolescent and adult mice at a dose of 10 mg/kg methylphenidate. Less stereotypy was also seen in postweanling mice when compared to adolescent mice after 30 mg/kg amphetamine. Seven daily injections of cocaine resulted in a heightened behavioral response on day 7 as compared to day 1, indicative of behavioral sensitization in adult and periadolescent, but not postweanling mice. Repeated methylphenidate resulted in increased total activity in adult, but not periadolescent or postweanling mice. None of the animals were sensitized to the behavioral activating effects of amphetamine. The magnitude of behavioral response and the development of sensitization were dependent upon the age of the animal and the agent tested.

Few studies have examined the influence of the age and the strain of mouse on the pharmacokinetics of psychostimulants, or the role of pharmacokinetics in age-related differences in drug responses. The present study compared concentrations of cocaine, and its metabolite, benzoylecgonine (BZE), in the blood and brain of early (P35) and later (P42) periadolescent and adult (P63) CD-1 and C57BL/6 male mice 15 min after acute intraperitoneal injection of cocaine (20 mg/kg). Brain levels of cocaine and BZE after seven daily cocaine injections in CD-1 and C57BL/6 mice beginning on P35 and on P63 were also measured. P35 periadolescents of both strains had lower blood cocaine levels than did the adults, but only C57BL/6 periadolescents had lower brain cocaine levels than the adults. C57BL/6 mice of both ages had higher blood cocaine levels than did the corresponding CD-1 mice. Concomitant with lower cocaine levels, periadolescent CD-1 mice had higher blood BZE levels than the adults, suggesting that periadolescents may metabolize cocaine faster. Brain cocaine levels in P42 C57BL/6 mice were similar to those of adults. Cocaine-induced activity did not differ between periadolescent and adult CD-1 mice after a single injection of cocaine, whereas periadolescent C57BL/6 mice had lower activity levels than did the adults after a single cocaine injection. Periadolescent CD-1 mice exhibited higher levels of locomotor activity following cocaine injection than did periadolescent C57BL/6 mice. Following chronic cocaine administration, cocaine and BZE levels in the brains of periadolescent and adult mice did not differ from each other in either strain. However, brain cocaine levels at both ages were lower in CD-1 mice than in C57BL/6 mice. In conclusion, the age and the strain of mouse significantly affect the levels of cocaine obtained in brain and blood following acute administration. Our data are consistent with the notion that CD-1 and C57BL/6 mice metabolize cocaine faster during the early periadolescent period than as adults. Furthermore, potentially important strain differences between CD-1 and C57BL/6 mice were noted in cocaine levels following acute and chronic cocaine administration, and in locomotor activity following acute cocaine administration.

There is growing recognition that cannabinoid receptor type 1 (CB1) plays a major role in alcohol and other drug addictions.1–6 Much of this work has focused on the interaction between the cannabinoid system and neuronal substrates that underlie drug-seeking behavior (Kalivas and Volkow7 provide a review of the neurobiologic mechanisms). The CB1 receptor is the most prevalent G protein–coupled receptor in the brain, and the CB1 receptor is densely localized to the same structures that underlie drug-seeking behavior (eg, the ventral tegmental area [VTA], nucleus accumbens [NAcc], prefrontal cortex [PFC], basolateral amygdala, and hippocampus). On a mechanistic level, the cannabinoid system regulates the release of dopamine, γ-aminobutyric acid (GABA), and glutamate. The CB1 receptors located on GABA interneurons suppress GABA release, which disinhibits dopaminergic projections to the accumbens and increases dopaminergic activation (Maldonado et al5 and De Vries and Schoffelmeer6 provide reviews). The CB1 receptors also regulate glutamatergic projections from the basolateral amygdala and hippocampus by inhibiting the release ofGABA and GABAergic projections from the accumbens to the VTA, indirectly activating the VTA.5,6 With respect to alcohol, the CB1 receptor mediates the effects of alcohol on the neuronal circuitry that underlies reward and the attribution of incentive salience. Recent studies have demonstrated that CB1 antagonists (eg, rimonabant) block the ability of alcohol to initiate the release of dopamine in the accumbens,3 decrease alcohol intake in alcohol- preferring8–12 and normal13 rats, and prevent the ability of cues associated with alcohol and other drugs to reinstate consumption. 6,14–16 In addition, CB1 agonists increase alcohol intake in rats.17 Moreover, CB1 knockout mice consume less alcohol, 3,18–20 show deficits in cue-initiated reinstatement and place preference,20,21 and do not demonstrate alcohol withdrawal symptoms22 or alcohol-induced increases in dopamine release in the accumbens. 3,19 Furthermore, alcohol-preferring animals have greater levels of CB1 messenger RNA in the structures that underlie drug-seeking behavior.23 Thus, the evidence is clear about the importance of the CB1 receptor and the gene that codes for this receptor (CNR1 [OMIM 114610]).3 Despite findings from the animal literature, similar studies in the human literature are almost nonexistent. Although a CB1 antagonist has been tested with nicotine dependence, to our knowledge, there have been no published trials with alcohol dependence. Regarding the gene that codes for the CB1 receptor, several studies24–26 found an association between CNR1 genetic variants and alcohol dependence, and 2 others27,28 did not. Contradictory results are not surprising given the many variables that affect the development of alcohol dependence, the potential error in the assignment of the diagnosis, and the dichotomous nature of a variable that reflects a spectrum disorder. Thus, the use of alcohol dependence as the sole phenotypic end point is a limitation. One of these studies25 noted that several single-nucleotide polymorphisms (SNPs) were associated with messenger RNA changes, and these same SNPs also overlap with SNPs associated with a reward-related neuroimaging phenotype.29 The present investigation encompassed multiple approaches, including receptor binding in postmortem brain tissue, functional magnetic resonance imaging, human laboratory models, and analyses of treatment outcome data. Specifically, this investigation was designed to test the effect of a specific CNR1 SNP (rs2023239) associated with substance dependence and CNR1 messenger RNA changes25 and linked to loci associated with a neuroimaging phenotype. 29 Three hypotheses were tested: (1) rs2023239 may be associated with differential CB1 binding in the PFC based on previous evidence suggesting a link with messenger RNA levels25; (2) rs2023239 may be associated with differences in brain activation during the presentation of alcohol cues using a neuroimaging paradigm and may be associated with the rewarding effects of alcohol based on previous evidence suggesting an association with neuroimaging phenotypes and the extensive literature on the importance of the CB1 receptor in alcohol reward; and (3) rs2023239 may be associated with the effects of a medication on the incentive salience of alcohol and drinking behavior in a treatment outcome trial based on the notion that the medication is effective because it dampens mesocorticolimbic activity.

s / Drug and Alcohol Dependence 146 (2015) e34–e117 e51 no effect on the conditioned locomotor response. Cyclohexamide (2.5–10mg/kg) attenuated acquisition of the conditioned response. Conclusions: The ability of these compounds to inhibit or exacerbate the conditionedbehavior suggests that plasticity-dependent signalingpathwaysmediate associations of context following acute cocaine exposure and are necessary for the acquisition and expression of the cocaine-conditioned locomotor response. Financial support: n/a. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.508 Preclinical evaluation of JPC-141 as a novel treatment for methamphetamine abuse Justin R. Nickell 1, Emily D. Denehy2, John P. Culver1, Peter A. Crooks3, M.T. Bardo2, Linda P. Dwoskin1 1 Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States 2 Psychology, University of Kentucky, Lexington, KY, United States 3 University of Arkansas, Fayetteville, AR, United

Chronic cocaine administration produces alterations in mu and kappa opioid receptor density as well as striatal and accumbens opioid-regulated adenylyl cyclase activity, suggesting a psychostimulant responsive interaction between opioidergic and dopaminergic systems. Stimulation of G-protein-coupled opioid receptors inhibits adenylyl cyclase production of cyclic AMP. The present study employed in situ [35S]GTPγS binding to measure opioid receptor-stimulated activation of G-proteins in response to acute and chronic cocaine exposure. Male Fischer rats received acute (1 or 3 days) or chronic (14 days) binge pattern cocaine administration. Three and 14 days of cocaine injections resulted in greater increases in the ability of the mu receptor agonist DAMGO to stimulate [35S]GTPγS binding in both the core and the shell of the nucleus accumbens, all regions of the caudate putamen and the cingulate cortex compared with saline-matched controls. The greatest increases in DAMGO-stimulated [35S]GTPγS binding were observed in the dorsal areas of the caudate putamen in animals that received 14 days of cocaine. No significant changes in delta (DPDPE), or kappa (dynorphin A1–17) receptor-stimulated [35S]GTPγS binding were found in any brain region in response to cocaine administration. These results demonstrate that binge pattern cocaine administration induce changes in mu but not delta or kappa opioid receptor-mediated G-protein activity. This study provides support for the hypothesis that the addictive properties of both psychostimulants and opiates may share common neurochemical signaling substrates. Synapse 47:26–32, 2003. © 2002 Wiley-Liss, Inc.