Abstract
We previously have shown that cue-induced alcohol craving and propensity for higher drinking are modulated by allelic differences in SLC6A4 associated with serotonin transporter (5-HTT) expression level alterations. In an independent study, we characterized another polymorphism, SNP rs1042173, in 3′-untranslated region (3′-UTR) of the same gene, which also altered 5-HTT expression levels; the T allele of rs1042173 was associated with lower mRNA and protein levels. In subsequent analyses, the TT genotype was found to be associated with higher drinking intensity in alcohol-dependent (AD) individuals of Caucasian descent. Building upon these findings, we hypothesized that the low-expressing TT genotype associated with intense drinking would predict higher craving for alcohol in AD individuals. In this pilot study, we sought to test our hypothesis by examining 34 Hispanic AD volunteers (mean age, 34.8 years) for rs1042173 genotype-based [i.e., TT versus TG/GG (Gx)] differences in subjective response to alcohol. We employed a human laboratory paradigm and analyzed the data using a linear mixed-effects model (SAS® PROC MIXED) to assess treatment, cue procedures, and genotype main effects as well as the two-way interaction effects between them. On subjective “urge to drink” and “crave for a drink,” we found a significant main effect of the cue experiment (p ≤ 0.01) and an interaction effect between genotype and cue effects (p < 0.05). TT genotype was associated with higher urge to drink (p = 0.002) and crave for a drink (p = 0.005) when exposed to alcohol cue. Our results not only support the hypothesis that rs1042173 is a genetic marker for cue-induced alcohol craving among AD males but also are suggestive of a neurobiological mechanism associated with the rs1042173-TT genotype that triggers a disproportionate craving in response to alcohol consumption, which in turn may lead to more intense drinking. Future studies with larger sample sizes are needed to characterize the interactive effects of the serotonin transporter-linked polymorphic region (5′-HTTLPR)-L-allele reported in our previous study and of the rs1042173-TT genotype on cue-induced alcohol craving.
Highlights
Serotonin pathways are important modulators of the reward system in the brain both in natural pleasurable activities such as feeding and sexual activity and in addictive behavior
A wealth of literature exists on genetic associations between 5-HTT genetic polymorphisms and phenotypes of alcoholism; among these, the most widely studied polymorphism is the 5HTT 5 -regulatory promoter region variant, the 5-HTT-linked polymorphic region [5 -HTTLPR; long (L) and short (S) alleles]
The visual analog scales of interest included 100-mm lines with adjectival descriptions of “I have an urge for a drink” and “I crave a drink ” that were anchored on the left by “not at all” and on the right by “extremely.”
Summary
Serotonin pathways are important modulators of the reward system in the brain both in natural pleasurable activities such as feeding and sexual activity and in addictive behavior. The precise mechanisms by which serotonin modulates the reward system are still being elucidated. Most of the serotonin receptor subtypes have been linked to areas in the brain associated with addiction and reward. The presynaptic serotonin transporter (5-HTT) has been investigated extensively over the years in the addiction genetics field as an important regulator of drinking behavior (Heinz et al, 2000). A wealth of literature exists on genetic associations between 5-HTT genetic polymorphisms and phenotypes of alcoholism; among these, the most widely studied polymorphism is the 5HTT 5 -regulatory promoter region variant, the 5-HTT-linked polymorphic region [5 -HTTLPR; long (L) and short (S) alleles]. In a group of alcoholdependent (AD), treatment-seeking individuals who were participating in an outpatient clinical trial, the authors showed that TT www.frontiersin.org
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