As a complex disorder, CD, like other forms of substance dependence, is the product of both environmental and genetic risk factors. Its genetic determinants likely include interactions among multiple neurochemical systems, including those involving dopamine, GABA, endogenous opioid, endogenous cannabinoid, and serotonin [Saxon et al., 2005]. Variability in these interactions due to genetic effects is a possible source of vulnerability to CD. We found several pairs of variants that approached significance for an association with CD and the two subtypes. An interaction between the genes encoding the beta 1 and beta 3 subunits of the GABA-A receptor was present in both AAs and EAs. Because GABA interneurons synapse on dopamine neurons to inhibit dopamine release, variation in the expression or function of GABA-A receptor subunits could alter the rewarding effects of cocaine [Spanagel and Weiss, 1999]. In AAs, the interaction of variants in DDC and GABRG3 also approached significance for an association with the CD subtype of heavy cocaine use with infrequent intravenous injection, which could affect the dopamine-mediated reward produced by cocaine, both directly (through dopamine metabolism) and indirectly (through GABA interneurons).
