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GRIK1 genotype moderates topiramate's effects on daily drinking level, expectations of alcohol's positive effects and desire to drink.

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.

SUBMITTER: Kranzler HR

PROVIDER: S-EPMC4161658 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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GRIK1 genotype moderates topiramate's effects on daily drinking level, expectations of alcohol's positive effects and desire to drink.

Kranzler Henry R HR Armeli Stephen S Feinn Richard R Tennen Howard H Gelernter Joel J Covault Jonathan J

The international journal of neuropsychopharmacology 20140430 10

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 re ...[more]

PMID: 24786948

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Project description:BackgroundRodent models of high alcohol drinking offer opportunities to better understand factors for alcohol use disorders (AUD) and test potential treatments. Selective breeding was carried out to create 2 unique High Drinking in the Dark (HDID-1, HDID-2) mouse lines that represent models of genetic risk for binge-like drinking. A number of studies have indicated that neuroimmune genes are important for regulation of alcohol drinking. We tested whether compounds shown to reduce drinking in other models also reduce alcohol intake in these unique genetic lines.MethodsWe report tests of gabapentin, tesaglitazar, fenofibrate, caffeic acid phenethyl ester (CAPE), ibrutinib, and rolipram. Although these compounds have different mechanisms of action, they have all been shown to reduce inflammatory responses. We evaluated effects of these compounds on alcohol intake. In order to facilitate comparison with previously published findings for some compounds, we employed similar schedules that were previously used for that compound.ResultsGabapentin increased ethanol (EtOH) binge-like alcohol drinking in female HDID-1 and HS/NPT mice. Tesaglitazar and fenofibrate did not alter 2-bottle choice (2BC) drinking in male HDID-1 or HS/NPT mice. However, tesaglitazar had no effect on DID EtOH intake but reduced blood alcohol levels (BAL), and fenofibrate increased DID intake with no effects on BAL. CAPE had no effect on EtOH intake. Ibrutinib reduced intake in female HDID-1 in initial testing, but did not reduce intake in a second week of testing. Rolipram reduced DID intake and BALs in male and female HDID-1, HDID-2, and HS/NPT mice.ConclusionsA number of compounds shown to reduce EtOH drinking in other models, and genotypes are not effective in HDID mice or their genetically heterogeneous founders, HS/NPT. The most promising compound was the PDE4 inhibitor, rolipram. These results highlight the importance of assessing generalizability when rigorously testing compounds for therapeutic development.

Dataset Information

GRIK1 genotype moderates topiramate's effects on daily drinking level, expectations of alcohol's positive effects and desire to drink.

Publications

GRIK1 genotype moderates topiramate's effects on daily drinking level, expectations of alcohol's positive effects and desire to drink.

Similar Datasets

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