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

Abstract

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.Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Genetic pre-determinants of concurrent alcohol and opioid dependence: A critical review

“…This study also did not find an association between HTR2A A-1438G polymorphism and alcohol or opioid addiction (25). Enoch et al, (2011) found that low 5-HTTLPR activity and the HTR2B Ser 129 allele were more common in men with concurrent alcohol and drug dependence compared to controls. Together, they had an additive effect.…”

“…Together, they had an additive effect. The study also found no association between HTR3A haplotype and alcohol or drug dependence (24). Serotogenic system appears to be less important for concurrent dependencies.…”

A review of 5-HT transporter linked promoter region (5-HTTLPR) polymorphism and associations with alcohol use problems and sexual risk behaviors

“…In addition, there are two subtypes of L alleles: LA and LG, identified as early as 2005 (Hu et al 2005). Studies show differences between LA and LG subtypes in relation to alcoholism (Enoch et al 2011;Kranzler et al 2011;Philibert et al 2008;Thompson et al 2010;Wang et al 2012). Comparative transcriptional activity between the LG, LA, and the S alleles showed that the LA allele is associated with increased transcriptional activity of 5-HTT, compared to LG, which is closer to the S allele (Hu et al 2005).…”

“…In a study involving 118 subjects of Han Chinese origin, the S allele was associated with increased risk for alcohol dependence and subjects with L alleles were found to be less susceptible (Wang et al 2011). In a study done by Enoch et al (2011), among 360 treatment-seeking African-American male patients, the frequency of the S allele was found to be significantly associated with alcohol dependence. A study by Lin et al (2007) demonstrated that the SS genotype was significantly associated with alcohol consumption and dependence in a group of male Han Chinese population from Taiwan.…”

A mouse model to address unresolved antidepressant issues

“…Beyond SSRIs, other drugs target the SERT, like cocaine and amphetamines. Mechanisms underlying individual differences in sensitivity to these drugs and the transition from impulsive drug use to compulsive drug abuse remain to be identified, and association studies in humans and SERT knockout studies in rodents suggest a contribution of serotonergic genes to reward related processes (6,20). Thompson et al (5) show that cocaine-mediated SERT kinetics are significantly reduced in M172 mice, which challenges further assessment of the new mouse model in, e.g., the cocaine-induced conditioned place preference test.…”