Another important finding is the role of PENK SNPs in predicting cannabis dependence. The vulnerability conferred by PENK (and to a lesser extent DRD2) SNPs may reflect disturbances of specific neurobiological systems common to these genes. Both DRD2 and PENK genes are strongly expressed in the striatum and amygdala, brain regions highly relevant to addiction disorders. A vast literature has emphasized the role of DRD2 in addiction [37]; but significant evidence also suggests PENK involvement in mood/reward regulation and anxiety that are often correlated with alterations of the mesocorticolimbic system [38]–[40] and the striatopallidal circuitry in aversive behavior [41]. The amygdala plays a particularly prominent role in negative mood states and enkephalinergic neurons in the central amygdala are known to be critically involved in anxiety and stress responsivity [38], [40]. Interestingly, the association detected in the current study between PENK SNPs and mRNA expression was most pronounced in the central amygdala. The rs2576573 A allele, observed to be more frequent in cannabis subjects, was associated with higher PENK mRNA expression in the central amygdala of the postmortem population in control
