Abstract
BackgroundMany young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown.Methodology/Principal FindingsHealthy young adults (18–27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%–19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect.Conclusions/SignificanceOverall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk.
Highlights
Marijuana (Cannabis sativa) is the illicit drug most commonly used in most Western societies [1,2,3]; it was consumed by at least 11.5% of individuals 12 years or older in the United States in 2010, even more so among teenagers (14%) and young adults (30%) [3]
Conclusions/Significance: Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk
The sensitivity of striatal PENK and Dopamine receptor D2 (DRD2) expression to delta-tetrahydrocannabinol (THC) raises the question as to whether genetic polymorphisms of these genes could in turn be associated with cannabis dependence. The fact that these genes in the striatum are colocalized in striatopallidal neurons, a critical component of the neuronal circuitry underlying inhibitory control, may have important implications to addiction vulnerability. While it is unknown whether genetic disturbances of DRD2 or PENK could contribute to cannabis dependence, behavioral studies have demonstrated that single nucleotide polymorphisms (SNPs) in DRD2 predict specific behavioral traits pertaining to reward sensitivity, inhibitory control and affect [18,19,20], endophenotypes known to be involved in addiction vulnerability
Summary
Marijuana (Cannabis sativa) is the illicit drug most commonly used in most Western societies [1,2,3]; it was consumed by at least 11.5% of individuals 12 years or older in the United States in 2010, even more so among teenagers (14%) and young adults (30%) [3]. Only a subset of teens and young adults using cannabis (25.4% and 19.0%, respectively) progress to abuse or dependence [4] Such individuals become dependent on cannabis at a young age though cannabis typically has a delayed progression to dependence as compared to other drugs of abuse [5]. The fact that these genes in the striatum are colocalized in striatopallidal neurons, a critical component of the neuronal circuitry underlying inhibitory control, may have important implications to addiction vulnerability While it is unknown whether genetic disturbances of DRD2 or PENK could contribute to cannabis dependence, behavioral studies have demonstrated that SNPs in DRD2 predict specific behavioral traits pertaining to reward sensitivity, inhibitory control and affect [18,19,20], endophenotypes known to be involved in addiction vulnerability. Given the current lack of information as to the functional relevance of the PENK SNPs, we assessed potential genotype relationships to mRNA expression levels in the postmortem human brain from another population sample
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