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

Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
Molecular Psychiatry (Impact Factor: 14.5). 11/2011; 16(11):1139-46. DOI: 10.1038/mp.2010.94
Source: PubMed


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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Available from: Colin A Hodgkinson, Apr 08, 2014
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    • "Thus, modulation of 5-HTTLPR by rs25531 results in three common alleles: LA (high-expressing), LG and S (both low expressing) which appear to act co-dominantly. Only few studies evaluated the 5-HTT tri-allelic polymorphism among alcoholic subjects (Philibert et al., 2008; Thompson et al., 2010; Enoch et al., 2011; Wang et al., 2012), and more recently (Kranzler et al., 2011) it has been shown that the 5-HTT tri-allelic genotype acts as a moderator of AD pharmacological treatment in different subtypes of alcoholism. Thus, studies in different populations are necessary to evaluate the relevance of the 5-HTT tri-allelic polymorphism with alcoholic subtypes taking into account both gender and age of onset of AD. "
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    ABSTRACT: The role of the serotonin transporter gene (SLC6A4) in alcohol dependence (AD) is still unclear. In this paper, we have evaluated the association of the SLC6A4 gene polymorphisms 5-HTTLPR and rs25531 in AD and assessed the polymorphic patterns both in alcoholics and in healthy people of an Italian population. Genotyping of the 5-HTTLPR (L/S) and rs25531 (A/G) polymorphisms of the SLC6A4 gene was performed on 403 alcoholics outpatients and 427 blood donors. Comparing AD and control populations and taking into account statistical correction for multiple testing, we found no statistically significant differences for 5-HTTLPR (L/S) and rs25531 polymorphisms in terms of either genotypes or alleles frequencies. By univariate ANOVA, a statistically significant difference was found in the onset of AD: the mean age of onset resulted to be of 25.4 years in males in respect to 28.1 in females. In particular in males, the early AD onset was different, in a statistically significant manner, depending on the presence of at least one S or Lg allele (24.6 years) in respect to La homozygotes (27.5 years) (P = 0.03). These findings suggest that genetic factors contribute, together with gender and age, to the onset differences in alcohol-dependent phenotypes. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.
    Alcohol and alcoholism (Oxford, Oxfordshire). Supplement 03/2015; 50(3). DOI:10.1093/alcalc/agv014
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    • "The findings of the team led by[57] produce similar findings. In their study, 360 treatment-seeking African American male patients with single and co morbid 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). "
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    ABSTRACT: Recent advances in the study of alcoholism have thrown light on the involvement of various neurotransmitters in the phenomenon of alcohol addiction. Various neurotransmitters have been implicated in alcohol addiction due to their imbalance in the brain, which could be either due to their excess activity or inhibition. This review paper aims to consolidate and to summarize some of the recent papers which have been published in this regard. The review paper will give an overview of the neurobiology of alcohol addiction, followed by detailed reviews of some of the recent papers published in the context of the genetics of alcohol addiction. Furthermore, the author hopes that the present text will be found useful to novices and experts alike in the field of neurotransmitters in alcoholism.
    Indian Journal of Human Genetics 05/2014; 20(1). DOI:10.4103/0971-6866.132750
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    • "Many theories of addiction or dependence assume it to be a pathological state that is progressively caused by various factors, primarily the pharmacological properties of drugs and alcohol (Booth et al., 2010; Robbins, Ersche, & Everitt, 2008), and secondarily genetics (Enoch, Gorodetsky, Hodgkinson, Roy, & Goldman, 2011; Wei et al., 2011), psychological processes, both normal (Leventhal & Schmitz, 2006) and pathological (Mills, Teesson, Darke, & Ross, 2007; Schilling, Aseltine, & Gore, 2007) and dysfunctional socioeconomic conditions (Foster, 2000; Seddon, 2000). Addiction research strives to understand how this pathological state of dependence comes about, and how it might be prevented and treated. "
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    ABSTRACT: Aims: A new theory of substance dependence is presented that models dependence as the absence of cognitive constraints on substance use. Methods: (1) Critical review of the predominant paradigm that assumes that substance dependence is a pathological state fundamentally caused by the neuropsychopharmacological effects of drugs (NPP paradigm) identified four counter-factual assumptions. Contrary to the NPP paradigm: (I) dependence can occur on a-typical substances and other things; (II) dependence is a complex, gradated phenomenon, not a state; (III) heavy protracted substance use can occur without dependence; and (IV) NPP interventions against dependence have not worked other than as drug substitutes. (2) Reconceptualisation of dependence as substance use with few cognitive, behavioural or social constraints. (3) Development of an exhaustive list of constraints on substance use with a panel of experts, achieving theoretical saturation. (4) Modelling of dependence, specifically to explain why socioeconomic deprivation is correlated with substance dependence. Results: Fifteen common constraints are described, which prevent most substance users becoming dependent. People in more socioeconomically deprived conditions tend to have fewer constraints. Similarities between Constraint Theory and previous sociological and social cognitive theories are discussed. Conclusions: Constraint theory describes the known nature of substance dependence better than theories from the NPP paradigm. Conceptualising dependence as an absence of constraints shows promise as a theory of addiction and fits with existing knowledge about what works to prevent and treat substance dependence.
    Addiction Research and Theory 01/2014; 22(1). DOI:10.3109/16066359.2013.779678 · 1.03 Impact Factor
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