While it is clear that RGS levels can be up- or down-regulated in specific regions of the brain in response to drugs of abuse, the functional consequence of this change in expression has remained more elusive. Few studies have examined the behavioral consequences of changes in RGS protein levels. In one study, overexpression of RGS9-2 in the NAc reduced the locomotor responses to cocaine while RGS9-deficient mice showed augmented locomotor and rewarding responses to cocaine [32]. Conversely, we found that chronic exposure to GHB decreases RGS2 protein (Figure 2, [2]), which significantly enhances the coupling efficiency between GABAB receptors and GIRK channels in the DA neurons of the VTA. This shift in the EC50 to lower concentrations (increase in coupling efficiency) is sufficient such that low concentrations of GHB, which normally do not activate GIRK currents in DA neurons, can now hyperpolarize DA neurons and decrease DA firing rates. Remarkably, this decrease in DA neuron excitability is associated with a behavioral loss of drinking preference for GHB.
