Objective-Severe alcohol consumption can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT 3 receptor antagonist, ondansetron.Method-We randomized 283 alcoholics by genotype in the 5′-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single nucleotide polymorphism (T/G), rs1042173, in the 3′-untranslated region, in a controlled double-blind trial. Subjects received ondansetron (4 μg/kg twice daily) or placebo for 11 weeks, plus standardized cognitive behavioral therapy.Results-LL subjects who received ondansetron vs. placebo had fewer mean drinks per drinking day (DDD) and a higher percentage of days abstinent (PDA) (−1.62; p=0.007 and 11.27%; p=0.023). Within ondansetron recipients, DDD was lower and PDA higher in LL vs. LS/SS subjects (−1.53; p=0.005 and 9.73%; p=0.03). Ondansetron LL subjects also had fewer DDD and greater PDA than all other genotype and treatment groups combined (−1.45; p=0.002 and 9.65%; p=0.013). For both DDD and PDA, 5′-HTTLPR and rs1042173 variants interacted significantly (p=0.023 and 0.009). Ondansetron LL/TT had fewer DDD and a greater PDA than all other genotype and treatment groups combined (−2.63; p<0.0001 and 16.99%; p=0.002). Conclusions-We propose a new pharmacogenetic approach using ondansetron to reduce the severity of alcohol consumption and improve abstinence in alcoholics.

Objective Previously, we reported that the 5′-HTTLPR-LL and rs1042173-TT (SLC6A4-LL/TT) genotypes in the serotonin transporter gene predicted a significant reduction in the severity of alcohol consumption among alcoholics receiving the 5-HT3 antagonist ondansetron. In this study, we explored additional markers of ondansetron treatment response in alcoholics by examining polymorphisms in the HTR3A and HTR3B genes, which regulate directly the function and binding of 5-HT3 receptors to ondansetron. Method We genotyped 1 rare and 18 common single-nucleotide polymorphisms in HTR3A and HTR3B in the same sample that we had genotyped for SLC6A4-LL/TT in the previous randomized, double-blind, 11-week clinical trial. Participants were 283 European Americans who received oral ondansetron (4 μg/kg twice daily) or placebo along with weekly cognitive behavioral therapy. Associations of individual and combined genotypes with treatment response on drinking outcomes were analyzed. Results Individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942-AC in HTR3B showed a significant overall mean difference between ondansetron and placebo in drinks per drinking day (−2.50; effect size (ES)=0.867), percentage of heavy drinking days (−20.58%; ES=0.780), and percentage of days abstinent (18.18%; ES=0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in our previous study) to 34%. Conclusions We present initial evidence suggesting that a combined 5-marker genotype panel can be used to predict the outcome of treatment of alcohol dependence with ondansetron. Additional, larger pharmacogenetic studies would help to validate our results.

IMPORTANCE No medication has been established as an efficacious treatment for cocaine dependence. We hypothesized that dual modulation of the mesocorticolimbic dopamine system by topiramate-a glutamate receptor antagonist and γ-aminobutyric acid receptor agonist-would result in efficacious treatment for cocaine dependence compared with placebo. OBJECTIVE To determine the efficacy of topiramate vs placebo as a treatment for cocaine dependence.

Background The propensity for severe drinking is hypothesized to be regulated by differential expression of serotonin transporter gene (SLC6A4) in the human brain. The SLC6A4 promoter region 5-HTTLPR has been examined previously as a candidate polymorphic variant associated with severe drinking. In this study, we investigated whether other SLC6A4 single nucleotide polymorphisms (SNPs) are associated with drinking intensity among treatment-seeking alcoholics and whether these polymorphic variants result in differential SLC6A4 expression levels. Methods We analyzed associations of drinking intensity in 275 (78.5% male) treatment-seeking alcoholics of Caucasian and Hispanic origin, with 6 SLC6A4 polymorphisms. Next, to examine the functionality of the SNP that showed a significant association with drinking intensity, we transfected the two alleles of rs1042173 into HeLa cell cultures and measured serotonin transporter mRNA and protein expression levels by using qRT-PCR and western blotting techniques. Results One of the 6 polymorphisms we examined, rs1042173 in the 3’ untranslated region (3’-UTR) of SLC6A4, showed a significant association with drinking intensity. The G allele carriers for rs1042173 were associated with significantly lower drinking intensity (P=0.0034) compared to T allele homozygotes. In HeLa cell cultures, the cells transfected with G allele showed a significantly higher mRNA and protein levels than the T allele-transfected cells. Conclusion These findings suggest that the allelic variations of rs1042173 affect drinking intensity in alcoholics possibly by altering serotonin transporter expression levels. This provides additional support to the hypothesis that SLC6A4 polymorphisms play an important role in regulating propensity for severe drinking.

Serotonin transporter (5-HTT) activity is greater in carriers of the long (L) vs. short (S) alleles of the 5-HTT-linked polymorphic region (5′-HTTLPR) among healthy control subjects but not alcoholdependent adults. In 198 alcoholics, we determined the relationship between current or lifetime drinking and platelet 5-HTT function and density among allelic variants of the 5′-HTTLPR. SS subjects were younger than L-carriers (LL and LS) (p < 0.0085) and had fewer years of lifetime drinking. For L-carriers, the mean of B max for paroxetine binding, but not V max for serotonin (5-HT) uptake, was lower than that for SS subjects (p < 0.05). More L-carriers than their SS counterparts had V max for 5-HT uptake below 200 nmol/10 7 platelets-min (p < 0.05) and B max for paroxetine binding below 600 nmol/mg protein (p < 0.06). Current drinking (drinks per day during the past 14 days) correlated positively with K m and V max of platelet 5-HT uptake (p < 0.05) and negatively with B max , but not K d , of paroxetine binding (p < 0.05) for L-carriers alone. Years of lifetime drinking correlated negatively with K m and V max of platelet 5-HT uptake (p < 0.05) and B max , but not K d , of paroxetine binding (p < 0.05) for L-carriers alone. Among L-carriers alone, there were higher levels of platelet 5-HT uptake and lower levels of platelet paroxetine binding with increased drinking, and more lifetime drinking was associated with modestly lower levels of 5-HT uptake and paroxetine binding. Thus, 5-HTT expression varies with current and lifetime drinking in L-carriers alone.