Numerous studies have shown that sustained exposure to addictive drugs can regulate mRNA expression of several members of the RGS family. We have recently discovered that drug-dependent down-regulation of RGS2 protein significantly enhances coupling efficiency of GABAB receptors with GIRK channels. These changes were associated with a polarity switch in the output of the VTA, in which the behavioral response to GHB is converted from reinforcing to aversive in animals chronically treated with GHB. The unique expression of GIRK2/3 channels and RGS2 proteins in the VTA-DA neurons, combined with selective molecular interactions between GIRK3 and RGS2 in a signaling complex, enable the electrophysiological and behavioral polarity switch in DA neurons from the VTA. These studies highlight RGS proteins as powerful regulators of GPCR-GIRK coupling efficiency and suggest a mechanism for a special form of tolerance (Box 1).
