Changing the strength of GPCR signaling in the VTA may affect the response to addictive drugs. In principle, there are three distinct mechanisms for modifying GPCR signaling. One way is through GPCR desensitization, which involves both clathrin-mediated endocytosis [6] and uncoupling of G-proteins [7]. Another mechanism is through changes in effector activity, such as down-regulation of GIRK and calcium channels [5,8]. Lastly, changes in G-protein availability can alter GPCR signaling. G-protein availability can be influenced by guanine nucleotide dissociation inhibitor proteins (GDI) [9] and by RGS proteins. The family of RGS proteins contains a GTPase-activating protein (GAP) domain that promotes the formation of the inactive G protein heterotrimer [10,11]. In addition to the GAP domain, different RGS proteins contain a wide-range of other signaling domains [12]. RGS proteins have received much attention as key proteins in the response to addictive drugs [13]. The functional consequences of changes in RGS proteins are not well understood.
