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

Authors: Enoch, MA  Gorodetsky, E  Hodgkinson, C  Roy, A  Goldman, D 
Citation: Enoch MA, etal., Mol Psychiatry. 2011 Nov;16(11):1139-46. doi: 10.1038/mp.2010.94. Epub 2010 Sep 14.
Pubmed: (View Article at PubMed) PMID:20838391
DOI: Full-text: DOI:10.1038/mp.2010.94

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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CRRD Object Information
CRRD ID: 6480660
Created: 2012-03-29
Species: All species
Last Modified: 2012-03-29
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.