Addictive drugs acutely increase levels of extracellular dopamine in the NAc,4 activating adenylyl cyclase and PKA via stimulation of Gs-and Golf-coupled D1 receptors.67 Dopamine also activates D2 receptors coupled to Go, leading to inhibition of several adenylyl cyclase isoforms. Dopamine activation of D2 receptors releases Gβγ subunits, which exert multiple effects that include enhancement of AC2 and AC4 activation, stimulation of G protein-regulated inwardly rectifying K+ (GIRK) channels, and inhibition of L-, N-, and P/Q-type calcium channels. In addition to stimulating dopamine release in the striatum, opiates can activate adenylyl cyclase by binding to opioid receptors that couple to Gi/o.68 The net effect of Gβγ on ion channel function is well established and results in decreased neuronal excitability and neurotransmitter release.67 Gβγ-mediated enhancement of adenylyl cyclase activity by Gi/o-coupled receptors has been documented in vitro and may contribute to signaling in the NAc. Increased firing of accumbal neurons upon co-activation of D1 and D2 receptors appears to involve Gβγ stimulation of adenylyl cylcase.69 Finally, adenylyl cyclases can be modulated by protein kinases, including protein kinase C (PKC), which activates AC2, AC4, and AC7.66
