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: 15.15). 11/2011; 16(11):1139-46. DOI: 10.1038/mp.2010.94
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to investigate the efficacy and safety of ondansetron as an augmentative agent to fluvoxamine in the treatment of patients with obsessive-compulsive disorder (OCD). Forty-six men and women, aged 18-60 years, who fulfilled the diagnostic criteria of OCD on the basis of the DSM-IV-TR and had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of at least 21 were recruited into the study. The patients randomly received either ondansetron (8 mg/day) or placebo for 8 weeks. All patients received fluvoxamine (100 mg/day) for the first 4 weeks, followed by 200 mg/day for the rest of the trial. The patients were assessed using the Y-BOCS and the adverse event checklists at baseline, and the second, fourth, sixth, and eighth week. Forty-four patients completed the study. The Y-BOCS total score as well as the Y-BOCS obsession subscale score and compulsion subscale score showed significantly greater reduction in the ondansetron group than in the placebo group. There was no significant difference in adverse events between the two groups. In this 8-week double-blind randomized-controlled trial, ondansetron showed significant beneficial effect as an augmentative agent with fluvoxamine in patients with moderate to severe OCD and it was generally well tolerated.
    International Clinical Psychopharmacology 05/2014; · 3.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The use of psychoactive drugs is a wide spread behaviour in human societies. The systematic use of a drug requires the establishment of different drug use-associated behaviours which need to be learned and controlled. However, controlled drug use may develop into compulsive drug use and addiction, a major psychiatric disorder with severe consequences for the individual and society. Here we review the role of the serotonergic (5-HT) system in the establishment of drug use-associated behaviours on the one hand and the transition and maintenance of addiction on the other hand for the drugs: cocaine, amphetamine, methamphetamine, MDMA (ecstasy), morphine/heroin, cannabis, alcohol, and nicotine. Results show a crucial, but distinct involvement of the 5-HT system in both processes with considerable overlap between psychostimulant and opioidergic drugs and alcohol. A new functional model suggests specific adaptations in the 5-HT system, which coincide with the establishment of controlled drug use-associated behaviours. These serotonergic adaptations render the nervous system susceptible to the transition to compulsive drug use behaviours and often overlap with genetic risk factors for addiction. Altogether we suggest a new trajectory by which serotonergic neuroadaptations induced by first drug exposure pave the way for the establishment of addiction.
    Behavioural brain research 04/2014; · 3.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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). · 1.03 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014