Jonathan Covault

University of Connecticut, Storrs, Connecticut, United States

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Publications (79)315.35 Total impact

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    ABSTRACT: Genetic variation in a region of chromosome 4p12 that includes the GABAA subunit gene GABRA2 has been reproducibly associated with alcohol dependence (AD). However, the molecular mechanisms underlying the association are unknown. This study examined correlates of in vitro gene expression of the AD-associated GABRA2 rs279858*C-allele in human neural cells using an induced pluripotent stem cell (iPSC) model system. We examined mRNA expression of chromosome 4p12 GABAA subunit genes (GABRG1, GABRA2, GABRA4, and GABRB1) in 36 human neural cell lines differentiated from iPSCs using quantitative polymerase chain reaction and next-generation RNA sequencing. mRNA expression in adult human brain was examined using the BrainCloud and BRAINEAC data sets. We found significantly lower levels of GABRA2 mRNA in neural cell cultures derived from rs279858*C-allele carriers. Levels of GABRA2 RNA were correlated with those of the other 3 chromosome 4p12 GABAA genes, but not other neural genes. Cluster analysis based on the relative RNA levels of the 4 chromosome 4p12 GABAA genes identified 2 distinct clusters of cell lines, a low-expression cluster associated with rs279858*C-allele carriers and a high-expression cluster enriched for the rs279858*T/T genotype. In contrast, there was no association of genotype with chromosome 4p12 GABAA gene expression in postmortem adult cortex in either the BrainCloud or BRAINEAC data sets. AD-associated variation in GABRA2 is associated with differential expression of the entire cluster of GABAA subunit genes on chromosome 4p12 in human iPSC-derived neural cell cultures. The absence of a parallel effect in postmortem human adult brain samples suggests that AD-associated genotype effects on GABAA expression, although not present in mature cortex, could have effects on regulation of the chromosome 4p12 GABAA cluster during neural development. Copyright © 2015 by the Research Society on Alcoholism.
    Alcoholism Clinical and Experimental Research 08/2015; 39(9). DOI:10.1111/acer.12807 · 3.21 Impact Factor
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    ABSTRACT: Smokers may prefer menthol cigarettes to mask the bitter taste of nicotine. Variation in the taste receptor gene, TAS2R38, may contribute to preference for menthol cigarettes. To determine whether two common haplotypes of TAS2R38 (proline-alanine-valine [PAV] and alanine-valine-isoleucine [AVI]), which have been associated, respectively, with bitter taste or a lack of bitter taste produced by propylthiouracil, are associated with preference for menthol cigarettes. Data on smoking and blood for DNA extraction and genotyping were obtained from 323 pregnant non-Hispanic or Hispanic Caucasian smokers. We genotyped three TAS2R38 single nucleotide polymorphisms (rs713598, rs1726866, and rs10246939) and constructed haplotypes. We examined associations between menthol preference and the frequency and distribution of the AVI and PAV haplotypes among study participants. Participants smoked an average of 16 cigarettes per day before pregnancy. The PAV and AVI haplotype frequencies were 48% and 45%, respectively. Non-Hispanic women were less likely than Hispanic women to smoke menthol cigarettes. As hypothesized, the frequency of the PAV haplotype was greater in menthol than non-menthol smokers in both non-Hispanics (54% vs. 30%; χ(2) = 13.04, P < .001) and Hispanics (53% vs. 25%; χ(2) = 5.77, P = .016). This effect persisted after controlling for potential confounders in multivariate logistic regression. Menthol smokers had a greater number of PAV haplotypes/individual than non-menthol smokers [non-Hispanics odds ratio (OR) = 3.02 (1.56-5.85); P = .001; Hispanics OR = 3.60 (1.23-10.56); P = .020]. These preliminary data support the hypothesis that a genetic propensity to experience heightened bitter taste perception increases the preference for menthol cigarettes. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail:
    Nicotine & Tobacco Research 04/2015; DOI:10.1093/ntr/ntv042 · 3.30 Impact Factor
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    ABSTRACT: Research consistently shows a positive association between racial discrimination and problematic alcohol use among African Americans, but little is known about the micro-processes linking this pernicious form of stress to drinking. One possibility is that the cumulative effects of discrimination increase individuals' likelihood of negative-mood-related drinking. In the current study, we examined whether individual differences in lifetime perceived racial discrimination among African American college students moderate relations between daily negative moods and evening alcohol consumption in both social and nonsocial contexts. Data came from an online daily diary study of 441 African Americans (58% female) enrolled at a historically black college/university. Lifetime discrimination was measured at baseline. For 30 days, students reported the number of drinks they consumed the night before both socially and nonsocially, as well as their daytime level of negative mood. In support of the hypotheses, only men who reported higher (vs. lower) lifetime discrimination showed a positive association between daily negative mood and that evening's level of nonsocial drinking. Contrary to expectation, women who reported higher (vs. lower) discrimination showed a negative association between daily negative mood and nonsocial drinking. Neither daily negative mood nor lifetime discrimination predicted level of social drinking. These findings provide further evidence that the cumulative impact of racial discrimination may produce a vulnerability to negative-mood-related drinking-but only for African American men. Importantly, these effects emerged only for nonsocial drinking, which may further explain the robust association between discrimination and problematic alcohol use. (J. Stud. Alcohol Drugs, 76, 229-236, 2015).
    Journal of studies on alcohol and drugs 03/2015; 76(2):229-36. DOI:10.15288/jsad.2015.76.229 · 2.76 Impact Factor
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    ABSTRACT: Previous studies indicate that topiramate reduces alcohol use among problem drinkers, with one study showing that the effect was moderated by a polymorphism (rs2832407) in GRIK1, the gene encoding the GluK1 kainate subunit. We examined whether the interactive effect of medication and genotype (1) altered the association between daily self-efficacy and later-day drinking; and (2) had an indirect effect on drinking via self-efficacy. In a 12-week, placebo-controlled trial of topiramate, we used daily interactive voice response technology to measure self-efficacy (i.e. confidence in avoiding heavy drinking later in the day) and drinking behavior in 122 European-American heavy drinkers. Topiramate's effects on both self-efficacy and drinking level were moderated by rs2832407. C-allele homozygotes treated with topiramate showed higher levels of self-efficacy and lower levels of nighttime drinking across the 12-week trial. Further, the interactive effect of topiramate and genotype on mean nighttime drinking levels was mediated by mean levels of self-efficacy. By modeling topiramate's effects on nighttime drinking across multiple levels of analysis, we found that self-efficacy, a key psychologic construct, mediated the effect of topiramate, which was moderated by rs2832407 genotype. Thus, it may be possible to use an individualized assessment (i.e. genotype) to select treatment to optimize the reduction in heavy drinking and thereby provide a personalized treatment approach.
    Addiction Biology 01/2015; DOI:10.1111/adb.12207 · 5.36 Impact Factor
  • Drug and Alcohol Dependence 01/2015; 146:e269. DOI:10.1016/j.drugalcdep.2014.09.197 · 3.42 Impact Factor
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    ABSTRACT: Background We examined whether the effects of topiramate and a single nucleotide polymorphism (rs2832407) in GRIK1, which encodes a kainate receptor subunit, persisted following a 12-week, placebo-controlled trial in 138 heavy drinkers with a treatment goal of reduced drinking. During treatment, topiramate 200 mg/d significantly reduced heavy drinking days and increased the frequency of abstinent days (Am J Psychiatry, 2014, 171:445). In the European-American (EA) subsample (n = 122), rs2832407 moderated the treatment effect on heavy drinking.Methods Patients were re-interviewed 3 and 6 months after the end of treatment. During treatment, we obtained 92.4% of drinking data, with 89.1 and 85.5% complete data at the 3- and 6-month follow-up visits, respectively. We examined 4 outcomes over time in the overall sample and the EA subsample: percent heavy drinking days (PHDD), percent days abstinent (PDA), serum γ-glutamyl transpeptidase (GGTP) concentration, and a measure of alcohol-related problems.ResultsIn the full sample, the lower PHDD and higher PDA seen with topiramate treatment were no longer significant during follow-up. Nonetheless, the topiramate-treated patients had lower alcohol-related problem scores during treatment and both follow-up periods. Further, in the EA subsample, the greater reduction in PHDD seen with topiramate treatment in rs2832407*C-allele homozygotes persisted throughout follow-up, with no significant effects in A-allele carriers. A reduction in GGTP concentration was consistent with the reduction in heavy drinking, but did not reach statistical significance.Conclusions There are persistent therapeutic effects of topiramate in heavy drinkers, principally in rs2832407*C-allele homozygotes.
    Alcoholism Clinical and Experimental Research 12/2014; 38(12). DOI:10.1111/acer.12578 · 3.21 Impact Factor
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    ABSTRACT: Using retrospective reports obtained during treatment visits in 138 heavy drinkers, we found that topiramate's reduction of heavy drinking was moderated by a polymorphism (rs2832407) in GRIK1, which encodes the GluK1 kainate subunit (Kranzler et al., 2014a). A subsequent analysis of that 12-week topiramate treatment trial showed similar effects of medication and genotype on daily drinking reports obtained via interactive voice response technology (IVR; Kranzler et al., 2014b). Specifically, rs2832407*C-allele homozygotes treated with topiramate reported lower levels of drinking than those receiving placebo. This group also had the largest decreases in the expected positive effects of drinking (i.e., expectancies) and desire to drink. To extend that analysis, which focused on how mean levels of desire and expectancies changed over time with treatment, we used a within-person approach to examine whether daily variation in expectancies and desire to drink interact with topiramate treatment and genotype to predict nighttime drinking levels. In contrast to the previous analysis (Kranzler et al., 2014b), here we focus on whether alcohol expectancies and desire to drink moderate the effects of topiramate on drinking. Results showed a 3-way interaction of daily expectancies with genotype and medication, such that the protective effect of topiramate on nighttime drinking among rs2832407*C-allele homozygotes was decreased on days characterized by relatively high levels of anticipated positive effects of alcohol. There was no moderating effect of desire to drink or negative alcohol expectancies. Thus, there is specific moderation of the effects of topiramate by both genotype and cognitive process. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Experimental and Clinical Psychopharmacology 12/2014; 22(6):494-501. DOI:10.1037/a0038350 · 2.71 Impact Factor
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    ABSTRACT: Despite evidence that African Americans are disproportionately affected by drinking to cope relative to European Americans, African American college students' drinking motives remain understudied. Additionally, most research has only examined between-person differences in drinking to cope as a predictor of alcohol use, ignoring within-person variability. In the current daily diary study of 462 African American undergraduates from a historically Black university, associations between episode-specific drinking to cope motives and alcohol use were tested, an approach more consistent with motivational theories of drinking. At baseline, students completed traditional global drinking motive measures; then for 30 days they reported the number of standard drinks they consumed the previous night, and, if they drank, their coping, enhancement, and social reasons for doing so. Students who reported higher mean levels of episode-specific coping motives, on average, consumed more alcohol on drinking evenings. Furthermore, mean episode-specific coping motives, but not global coping motives, predicted average levels of alcohol use. Additionally, coping motives were particularly important for predicting nonsocial (vs. social) drinking. Finally, during evenings for which students reported higher than usual episode-specific coping motives, men consumed more alcohol in both social and nonsocial contexts; in contrast, women reporting higher than usual drinking-to-cope motives only consumed more nonsocial drinks. In conclusion, drinking among African American college students was related to coping motives, particularly among men and in the context of nonsocial alcohol consumption. Moreover, motivational theories of alcohol use may be refined by measuring episode-specific drinking motives that more accurately capture the drinking-to-cope process. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Psychology of Addictive Behaviors 08/2014; 28(3). DOI:10.1037/a0036303 · 2.09 Impact Factor
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    ABSTRACT: BackgroundA functional polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene has been widely studied as a risk factor and moderator of treatment for a variety of psychopathologic conditions. To evaluate whether 5-HTTLPR moderates the effects of treatment to reduce heavy drinking, we studied 112 high-functioning European-American men who have sex with men (MSM). Subjects participated in a randomized clinical trial of naltrexone (NTX) and cognitive behavioral therapy (CBT) for problem drinking.Methods Subjects were treated for 12 weeks with 100 mg/d of oral NTX or placebo (PBO). All participants received medical management with adjusted brief behavioral compliance enhancement treatment (BBCET) alone or in combination with modified behavioral self-control therapy (MBSCT; an amalgam of motivational interviewing and CBT). Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism (i.e., low-activity S′ or high-activity L′ alleles).ResultsDuring treatment, the number of weekly heavy drinking days (HDD; defined as 5 or more standard drinks per day) was significantly lower in subjects with the L′L′ (N = 26, p = 0.015) or L′S′ (N = 52, p = 0.016) genotype than those with the S′S′ (N = 34) genotype regardless of treatment type. There was a significant interaction of genotype with treatment: For subjects with the S′S′ genotype, the effects of MBSCT or NTX on HDD were significantly greater than the minimal intervention (i.e., BBCET or PBO, p = 0.007 and p = 0.049, respectively). In contrast, for subjects with 1 or 2 L′ alleles, the effects of the more intensive psychosocial treatment (MBSCT) or NTX did not significantly differ from BBCET or PBO.Conclusions These preliminary findings support the utility of the 5-HTTLPR polymorphism for personalizing treatment selection in problem drinkers.
    Alcoholism Clinical and Experimental Research 07/2014; 38(9). DOI:10.1111/acer.12492 · 3.21 Impact Factor
  • Verica Milivojevic · J. Covault · R. Sinha
    Drug and Alcohol Dependence 07/2014; 140:e150. DOI:10.1016/j.drugalcdep.2014.02.425 · 3.42 Impact Factor
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    ABSTRACT: Topiramate, which interacts with multiple neurotransmitter and enzyme systems, is approved by the Food and Drug Administration to treat seizure disorder, prevent migraine, and (in combination with phentermine) reduce weight. Topiramate has also been shown in multiple studies to reduce heavy drinking. The authors found that topiramate 200 mg/day significantly reduced heavy drinking in heavy drinkers with a treatment goal of reduced drinking (Kranzler et al., 2014). Further, in the European American (EA) subsample (n = 122), a single nucleotide polymorphism (rs2832407) in GRIK1, which encodes the GluK1 subunit of the kainate receptor, moderated the effect on heavy drinking days. Here the authors examined the effects of topiramate on body mass index (BMI) and the moderating effect of rs2832407 in the EA subsample from Kranzler et al. (2014). Across the 12 weeks of treatment, BMI was reduced by 1.2 kg/m2 (p < .001) in the topiramate group but was unchanged in the placebo group. There was no evidence of moderation by rs2832407 of topiramate's effects on BMI. Controlling for changes in drinking and other potential confounders did not alter the findings. These results suggest that the effect of topiramate on drinking behavior, in which the GluK1-containing kainate receptor appears to play a key role, can be dissociated from its effect on weight, the specific mechanism of which remains to be determined. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Experimental and Clinical Psychopharmacology 06/2014; 22(5). DOI:10.1037/a0037309 · 2.71 Impact Factor
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    ABSTRACT: Rationale Animal models suggest that neuroactive steroids contribute to alcohol’s acute effects. We previously reported that a common nonsynonymous polymorphism, AKR1C3*2 in the gene encoding the enzyme 3α-HSD2/17β-HSD5, and a synonymous single nucleotide polymorphism (SNP), rs248793, in SRD5A1, which encodes 5α-reductase, were associated with alcohol dependence (AD). Objectives The aim of the study was to investigate whether these polymorphisms moderate subjective effects of alcohol in humans and whether AKR1C3*2 affects neuroactive steroid synthesis. Methods Sixty-five Caucasian men (34 lighter and 31 heavier drinkers; mean age 26.2 years) participated in a double-blind laboratory study where they consumed drinks containing no ethanol or 0.8 g/kg of ethanol. Breath alcohol, heart rate (HR), and self-reported alcohol effects were measured at 40-min intervals, and genotype was examined as a moderator of alcohol’s effects. Levels of the neuroactive steroid 5α-androstane-3α,17β-diol and its precursors, 3α,5α-androsterone and dihydrotestosterone, were measured at study entry using GC/MS. Results Initially, carriers of the AD-protective AKR1C3*2 G allele had higher levels of 5α-androstane-3α,17β-diol relative to the precursor 3α,5α-androsterone than C allele homozygotes. AKR1C3*2 G allele carriers exhibited greater increases in heart rate and stimulant and sedative effects of alcohol than C allele homozygotes. The genotype effects on sedation were observed only in heavier drinkers. The only effect of the SRD5A1 SNP was to moderate HR. There were no interactive effects of the two SNPs. Conclusions The observed effects of variation in a gene encoding a neuroactive steroid biosynthetic enzyme on the rate of 17β-reduction of androsterone relative to androstanediol and on alcohol’s sedative effects may help to explain the association of AKR1C3*2 with AD.
    Psychopharmacology 05/2014; 231(17). DOI:10.1007/s00213-014-3614-2 · 3.88 Impact Factor
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    ABSTRACT: We (Kranzler et al., 2014) reported that topiramate 200 mg/day reduced heavy drinking days and increased abstinent days in 138 heavy drinkers whose treatment goal was to reduce drinking to safe levels. In that 12-week, placebo-controlled study, we measured drinking using the Timeline Follow-back method at each treatment visit. In addition to the intent-to-treat effects of topiramate, we found that a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the GluK1 subunit of the kainate receptor, moderated the treatment effect in European Americans (EAs; n = 122). Topiramate reduced heavy drinking only in rs2832407*C allele homozygotes. Here, we augment those analyses by using patients' daily reports obtained using interactive voice response technology; (a) to validate the interactive effects of GRIK1 and topiramate as predictors of drinking level; and, (b) to examine changes in expected positive effects of drinking (i.e. positive outcome expectancies) and desire to drink. We found that rs2832407*C allele homozygotes treated with topiramate drank less overall during treatment than those receiving placebo, validating our earlier findings for heavy drinking days (Kranzler et al., 2014). There was also a study day × medication group × genotype group interaction that predicted both positive alcohol expectancies and desire to drink, with rs2832407*C-allele homozygotes treated with topiramate showing the largest decreases in these outcomes during the study period. Changes in positive alcohol expectancies or desire to drink did not mediate the effects on drinking. These findings validate and extend our previous pharmacogenetic findings with topiramate.
    The International Journal of Neuropsychopharmacology 04/2014; 17(10):1-8. DOI:10.1017/S1461145714000510 · 4.01 Impact Factor
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    ABSTRACT: Objective: Racial discrimination has been identified as an important predictor of alcohol-related outcomes for African Americans. The goal of the current study was to extend previously found links between lifetime discrimination, alcohol use, and alcohol problems as well as to elucidate the affective mechanisms underlying these associations, as moderated by gender. Method: A multiple-groups structural equation model was computed using survey data collected from 619 students from a historically Black college/university. Results: The final model provided excellent fit to the data, explaining 6% of the variance in alcohol consumption and 37% of the variance in alcohol problems. Discrimination was a significant predictor of alcohol-related problems but not, by and large, level of use. For men, anger-but not discrimination-specific anger-was a significant partial mediator of the link between discrimination and both alcohol use and alcohol problems. Depression partially mediated the link between discrimination and alcohol problems for both men and women. Conclusions: The results suggest that, for African Americans whose drinking leads to drinking-related problems, discrimination and poor affective self-regulation are highly relevant and predictive factors, especially for men.
    Journal of studies on alcohol and drugs 03/2014; 75(2):228-34. DOI:10.15288/jsad.2014.75.228 · 2.76 Impact Factor
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    ABSTRACT: Preclinical studies support the hypothesis that endogenous neuroactive steroids mediate some effects of alcohol. The aim of this study was to examine the effect of dutasteride inhibition of 5α-reduced neuroactive steroid production on subjective responses to alcohol in adult men. Using a within-subject factorial design, 70 men completed four randomly ordered monthly sessions in which pretreatment with 4 mg dutasteride or placebo was paired with a moderate dose of alcohol (0.8 g/kg) or placebo beverage. The pharmacologic effect of dutasteride was measured by an assay of serum androstanediol glucuronide. Self-reports of alcohol effects were obtained at 40-min intervals following alcohol administration using the Biphasic Alcohol Effects Scale (BAES) and the Alcohol Sensation Scale (SS). We used linear mixed models to examine the effects of dutasteride and alcohol on BAES and SS responses and the interaction of dutasteride with the GABRA2 alcohol dependence-associated polymorphism rs279858. We also examined whether exposure to dutasteride influenced drinking in the weeks following each laboratory session. A single 4-mg dose of dutasteride produced a 70 % reduction in androstanediol glucuronide. Dutasteride pretreatment reduced alcohol effects on the BAES sedation and SS anesthesia scales. There was no interaction of dutasteride with rs279858. Heavy drinkers had fewer heavy drinking days during the 2 weeks following the dutasteride sessions and fewer total drinks in the first week after dutasteride. These results provide evidence that neuroactive steroids mediate some of the sedative effects of alcohol in adult men and that dutasteride may reduce drinking, presumably through its effects on neuroactive steroid concentrations.
    Psychopharmacology 02/2014; 231(17). DOI:10.1007/s00213-014-3487-4 · 3.88 Impact Factor
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    ABSTRACT: Objective: Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels. Method: A total of 138 individuals (62.3% men) were randomly assigned to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dose of 200 mg, or matching placebo (N=71). Both groups received brief counseling to reduce drinking and increase abstinent days. It was hypothesized that topiramate-treated patients would be better able to achieve these goals, and it was predicted that based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit. Results: The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. Patients receiving topiramate also had lower concentrations of the liver enzyme γ-glutamyl transpeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European American subsample (N=122), topiramate's effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes. Conclusions: These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramate's effects on heavy drinking.
    American Journal of Psychiatry 02/2014; 171(4). DOI:10.1176/appi.ajp.2013.13081014 · 12.30 Impact Factor
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    ABSTRACT: Health disparities research seeks to eliminate disproportionate negative health outcomes experienced in some racial/ethnic minority groups. This brief review presents findings on factors associated with drinking and alcohol-related problems in racial/ethnic groups. Those discussed are as follows: (i) biological pathways to alcohol problems, (ii) gene × stress interactions, (iii) neighborhood disadvantage, stress, and access to alcohol, and (iv) drinking cultures and contexts. These factors and their interrelationships are complex, requiring a multilevel perspective. The use of interdisciplinary teams and an epigenetic focus are suggested to move the research forward. The application of multilevel research to policy, prevention, and intervention programs may help prioritize combinations of the most promising intervention targets.
    Alcoholism Clinical and Experimental Research 01/2014; 38(3). DOI:10.1111/acer.12304 · 3.21 Impact Factor
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    ABSTRACT: Variation in genes encoding GABAA receptor subunits has been implicated in the risk of alcohol dependence (AD). We sought to replicate and extend previous findings of a moderating effect of single nucleotide polymorphisms (SNPs) in GABRA2 (which encodes the GABAA α-2 subunit) on the subjective effects of alcohol by examining SNPs in this and the adjacent GABRG1 gene on chromosome 4. Fifty-two European-Americans (22 males, 28 light drinkers and 24 heavy drinkers) completed 3 laboratory sessions, during which they drank low-dose, high-dose, or placebo alcohol prior to undergoing periodic assessments of stimulation, sedation and drug enjoyment. We genotyped subjects for three SNPs previously associated with AD: rs279858 in GABRA2, and rs7654165 and rs6447493 in GABRG1. Two SNPs were associated with altered stimulatory effects of alcohol as measured on the Biphasic Alcohol Effects Scale, (rs279858: P = 0.0046; rs6447493: P = 0.0023); both effects were in the opposite direction of previous findings. Carriers of the rs279858 C allele experienced greater stimulation from alcohol. Further inspection of the rs6447493 interaction did not support a pharmacogenetic effect. The effects of rs279858 (but not the other two SNPs) on items from a secondary outcome measure, the Drug Effects Questionnaire (DEQ), were significant. Higher ratings by individuals with the C allele were observed on the DEQ items 'feel the alcohol effect' (P < 0.001), 'like the alcohol effect' (P < 0.001) and feel 'high' (P < 0.001). We did not find that the GABRG1 SNPs rs7654165 and rs6447493 moderated the effects of alcohol. Greater stimulatory and euphoric effects of alcohol in carriers of the rs279858 C allele may, in part, explain the previously reported association of this allele with AD.
    Alcohol and Alcoholism 10/2013; 49(1). DOI:10.1093/alcalc/agt163 · 2.89 Impact Factor
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    ABSTRACT: Topiramate (TOP) blocks glutamate receptors and facilitates GABA (γ-aminobutyric acid), neurotransmission, effects that may facilitate smoking cessation. We compared the effects of behavioral counseling combined with (a) TOP, (b) TOP/nicotine patch (TOP/NIC), or (c) placebo (PLC) for smoking cessation. We conducted a 10-week randomized trial in which subjects and research personnel were blinded to TOP versus PLC but not to the TOP/NIC patch condition. In groups receiving TOP, the medication dosage was titrated gradually up to 200mg/day. The smoking quit date (QD) was scheduled after 2 weeks of medication treatment. NIC (21mg) was started on the QD in subjects randomized to the TOP/NIC condition. The main outcome measure was the end-of-treatment, 4-week continuous abstinence rate (CAR; biochemically confirmed). Fifty-seven subjects were randomized to treatment. The 4-week CAR was 1 of 19 (5%) in the PLC group, 5 of 19 (26%) in the TOP group, and 7 of 19 (37%) in the TOP/NIC group (p = .056). Pairwise comparisons showed a difference between TOP/NIC and PLC (p = .042) and a nonsignificant difference between TOP and PLC (p = .18). The PLC group gained 0.37 lb/week, the TOP group lost 0.41 lb/week, and the TOP/NIC group lost 0.07 lb/week (p = .004). Pairwise comparisons showed a difference between TOP and PLC (p < .001) and between TOP/NIC and PLC groups (p = .035). Paresthesia was more frequent in subjects on TOP than PLC (p = .011). TOP, alone or in combination with the NIC, resulted in a numerically higher quit rate than PLC and decreased weight. A larger, PLC-controlled trial is needed to confirm these findings.
    Nicotine & Tobacco Research 09/2013; 16(3). DOI:10.1093/ntr/ntt141 · 3.30 Impact Factor
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    ABSTRACT: Background: Clinical and genetic studies suggest circadian clock genes may contribute to biological mechanisms underlying alcohol use disorders (AUD). In particular, the Per2 gene regulates alcohol consumption in mutant animals, and in humans with AUD, the 10870 variant in PER2 has been associated with alcohol consumption. However, with respect to function, the molecular clock remains largely uncharacterized in AUD patients. Methods: In skin fibroblast cultures from well-characterized human AUD patients (n = 19) and controls (n = 13), we used a bioluminescent reporter gene (Per2::luc) to measure circadian rhythms in gene expression at high sampling density for 5 days. Cells were genotyped for the PER2 10870 variant. The rhythm parameters period and amplitude were then analyzed using a case-control design and by genetic and clinical characteristics of the AUD subjects. Results: There were no differences between AUD cases and controls in rhythm parameters. However, period was inversely correlated with illness severity (defined as the number of alcohol dependence criteria met). The PER2 variant 10870 was not associated with differences in rhythm parameters. Conclusions: Our data suggest that differences in the cellular circadian clock are not pronounced in fibroblasts from AUD cases and controls. However, we found evidence that the circadian clock may be associated with an altered trajectory of AUD, possibly related to illness severity. Future work will be required to determine the mechanistic basis of this association.
    Alcoholism Clinical and Experimental Research 03/2013; 37(8). DOI:10.1111/acer.12106 · 3.21 Impact Factor

Publication Stats

2k Citations
315.35 Total Impact Points


  • 2008–2015
    • University of Connecticut
      • • Department of Psychiatry
      • • Department of Medicine
      Storrs, Connecticut, United States
  • 2004–2013
    • Yale University
      • Department of Psychiatry
      New Haven, Connecticut, United States
  • 2005
    • First Pavlov State Medical University Of St Petersburg
      Sankt-Peterburg, St.-Petersburg, Russia
  • 2003
    • UConn Health Center
      • Department of Psychiatry
      Farmington, CT, United States