Search

ObjectiveAlcohol 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 (POMC) rs2071345 polymorphism and alcohol dependence on anxiety symptoms of male problem drinkers, and further test the exact form of interaction on two competing models: the diathesis-stress model vs. the differential susceptibility model.MethodsA total of 440 male problem drinkers (Mage = 44.5 years, SD = 9.45) were recruited from nine main psychiatric hospitals of northern China during acute alcohol withdrawal. Blood samples were collected for genotyping, self-reported anxiety symptoms, and levels of alcohol dependence were assessed.ResultsResults indicated that the POMC rs2071345 polymorphism significantly moderated anxiety symptoms associated with alcohol dependence. A region of significance (RoS) test showed that male problem drinkers with T allele were more likely to experience more anxiety symptoms than those with CC homozygote when the standardized score of concurrent alcohol dependence was above 0.31. Confirmatory model evaluation indicated that the interaction effect involving POMC gene polymorphism conformed to the diathesis-stress model rather than differential-susceptibility model of person × environment interaction.ConclusionsThis study suggested that the SNP in POMC rs2071345 was associated with alcohol dependence in anxiety symptoms of male problem drinkers and further provided evidence in support of the diathesis-stress hypothesis of alcohol dependence in terms of anxiety symptoms.

Objective: Alcohol use disorder (AUD) is the most common substance use disorder, which may relate to increased impulsivity. A more detailed understanding of the potential moderating factor on association between AUD and impulsivity is likely to have far-reaching effects. This study aims to examine whether the interaction between a genetic variant ZNF804A rs1344706 and alcohol use is related to impulsivity in Chinese Han adult males diagnosed with AUD.Methods: A total of 455 Chinese Han adult males diagnosed with AUD were included in this study. Impulsivity was assessed using Barratt Impulsiveness Scale. Alcohol dependence was measured by Michigan Alcoholism Screening Test. Genomic DNA was extracted from peripheral blood of participants and genotyped.Results: Hierarchical multiple regression yielded a significant interaction between ZNF804A rs1344706 and alcohol use (β = 0.20, p = 0.0237). Then, A region of significance (RoS) test was performed to interpret the interaction effect. Re-parameterized regression models revealed that the interaction between ZNF804A rs1344706 and alcohol problem severity fit to the weak diathesis-stress model (R2 = 0.15, p < 0.0010), indicating that the T allele carriers are more susceptible to alcohol problem severity, jointly contributing to impulsivity.Conclusions: This study, which analyzed a specific gene-environment interaction, demonstrated that carriers of the T allele of ZNF804A rs1344706 may be more susceptible to alcohol problem severity, correlated with higher levels of impulsivity during withdrawal.

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.

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