Functional Genetic Variants that Increase Synaptic Serotonin and 5-HT3 Receptor Sensitivity Predict Alcohol and Drug Dependence

The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory 5-HT transmission that modulates dopamine release in the reward circuitry. The 5-HT transporter regulates synaptic 5-HT availability. Functional polymorphisms in genes encoding the transporter and receptor may therefore influence addiction vulnerability. In this study, 360 treatment-seeking African American male patients with single and comorbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4) and 16 haplotype-tagging SNPs across HTR3B (including the functional rs1176744 Tyr129Ser) and HTR3A, genes encoding 5-HT3 receptors. The HTR3B rs1176744 gain of function Ser129 allele predicted alcohol dependence (p = 0.002) and low 5-HTTLPR activity predicted cocaine/heroin dependence (p = 0.01). Both the HTR3B Ser129 allele (p = 0.014, OR = 1.7 [1.1–2.6]) and low 5-HTTLPR activity (p = 0.011, OR = 2.5 [1.3–4.6]) were more common in men with alcohol + drug dependence compared with controls. Moreover, the HTR3B Ser129 allele and low 5-HTTLPR activity had an additive (but not an interactive) effect on alcohol + drug dependence (OR = 6.0 [2.1–16.6]) that accounted for 13% of the variance. One possible explanation of our findings is that increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness may result in enhanced dopamine transmission in the reward pathway, a predictor of increased risk for addiction. Our results may have pharmacogenetic implications for 5-HT3 therapeutic antagonists such as ondansetron.