PMC:3780360 / 36649-40978 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3780360","sourcedb":"PMC","sourceid":"3780360","source_url":"http://www.ncbi.nlm.nih.gov/pmc/3780360","text":"Genetic determinants of the ECBS and psychostimulant addiction\nIt is worth mentioning that not every subject who experiences the pleasurable effects of psychostimulants will become a chronic user. Indeed it is more likely that additional factors such as: (1) genetic variabilities (e.g., polymorphisms in the catechol O-methyltransferase gene (Val158met) and in the serotonin transporter gene (5-HTTLPR) (230, 231); (2) monoamine receptors deficiency – either genetically or as a result of their drug excesses – also contribute to the psychostimulants addiction process (232–235) (see Table 1). In the ECBS, different genetic variants of the CB1 receptors – CNR1 – and FAAH genes have been associated with increased susceptibility to drug addiction. Indeed, genetic analyses demonstrate that the CNR1 gene exhibits elevated numbers of (AAT)n triplet repetition in a sample of 192 non-Hispanic Caucasian subjects. Interestingly, this CNR1 polymorphism increases the risk of intravenous drug use in this population, with strongest correlation observed in cocaine, amphetamine, and marijuana dependence (236). Similarly, a study from Ballon and colleagues shows that detection of this CNR1 polymorphism in a sample of 142 African-Caribbean individuals predisposed them to cocaine addiction (237). Unfortunately, while single sequence repetitions can alter transcriptional rates and thereby induced gene overexpression or silencing (238), the functional nature of the microsatellite polymorphism triplet repetition (AAT)n in modulating CNR1 gene expression remains blurred (239). It has been hypothesized that the presence of long alleles with high numbers of AAT triplets alter CNR1 transcriptional gene expression, ultimately leading to low levels of CNR1 protein synthesis (240). A recent meta-analysis of 11 studies aimed at investigating the contribution of three CNR1 polymorphisms (rs1049353, rs806379, and the AAT triplet repetitions) to drug dependence vulnerability confirmed the presence of (AAT)n repeats, but only in the Caucasian population [reviewed in Ref. (239)]. Unfortunately, the effect of the three CNR1 polymorphisms appeared to be insignificant and showed high heterogeneity. Important caveats have to be considered when looking at these studies. First, the ethnicity of the different subjects may prove important, as some studies included several ethnic groups in their samples, and in some cases, these groups were not even mentioned (241, 242). Some reports also examined CNR1 gene polymorphisms in connection with a different phenotype or stage of drug addiction such as craving, drug consumption, dependence, or drug withdrawal (243). Furthermore, a detailed description of the repercussions of CNR1 polymorphisms on CB1 function from a neurobiological standpoint is lacking from the reviewed studies.\nTable 1 ECBS and factors contributing to vulnerability to psychostimulants in humans. Polymorphisms in the gene coding for the endocannabinoid-inactivating enzyme FAAH may constitute another risk factor for problematic drug use, as described by initial reports identifying C385A, a mis-sense single nucleotide polymorphism (SNP) causing reduced FAAH enzymatic activity (245, 246). Indeed, a study from Sipe et al. reveals significant association between C385A SNP and street drug abuse in a sample of 1737 Caucasian subjects with addictive disorders. Neuroimaging studies combined with genetic analysis reveal that low FAAH activity enhances AEA protein expression levels which, in turn, modulate brain regions implicated in drug addiction and reward circuitry such as the OFC, AC gyrus, and NAc (242). Additional neuroimaging studies show that C385A carriers exhibit increased ventral striatal reactivity – a correlate for heightened impulsivity and reward sensitivity. C385A carriers display low threat-related amygdala reactivity – a pattern observed in individuals with high familial risk of alcoholism. Moreover, C385A polymorphism-reduced FAAH functional activity increases risk-taking behavior associated with addiction through abnormal impulsivity and threat perception [reviewed in Ref. (224, 243)]. Contribution of SNPs that modulate FAAH functions to stimulant addiction remain to be explored as the aforementioned data were not obtained in individuals specifically addicted to stimulants.","divisions":[{"label":"Title","span":{"begin":0,"end":62}},{"label":"Table 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