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Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence

Molecular Psychiatry volume 16, pages 1139–1146 (2011)Cite this article

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Abstract

The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory serotonin (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 single-nucleotide polymorphisms (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, odds ratio (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.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH and in part by grant RO1 DA 10336-02 to AR from the National Institute of Drug Abuse, NIH.

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Authors and Affiliations

  1. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA

    M-A Enoch, C Hodgkinson & D Goldman

  2. Mood and Anxiety Program, National Institute of Mental Health, NIH, Bethesda, MD, USA

    E Gorodetsky

  3. Department of Veterans Affairs, Psychiatry Service, New Jersey VA Health Care System, East Orange, NJ, USA

    A Roy

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  1. M-A Enoch
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Correspondence to M-A Enoch.

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Enoch, MA., Gorodetsky, E., Hodgkinson, C. et al. Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence. Mol Psychiatry 16, 1139–1146 (2011). https://doi.org/10.1038/mp.2010.94

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