Converging evidence obtained from animal and human brain studies has shown that early cannabis exposure selectively alters dopamine receptor D2 (DRD2) and proenkephalin (PENK) expression in the mesocorticolimbic system, disturbances that persist into adulthood and modulate drug-seeking behavior later in life [16], [17]. The sensitivity of striatal PENK and 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. Moreover, the fact that these genes in the striatum are specifically 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]–[20], endophenotypes known to be involved in addiction vulnerability. As such, we focused a priori on whether individual genetic differences of the DRD2 and PENK genes associate with cannabis dependence and explored the possible mediation or moderation of intermediate
