Increased dopamine receptor signaling and dopamine receptor-G protein coupling in denervated striatum

Chronic interruption of the nigrostriatal dopaminergic pathway leads to sensitized dopaminergic responses in striatum. We attempted to explore the mechanism(s) underlying this dopaminergic supersensitivity by assessing dopamine receptor signaling and receptor-G protein coupling in unilateral 6-hydroxydopamine-lesioned rats. Dopamine-stimulated adenylyl cyclase activity as well as dopamine-activated guanosine 5'-O-(3-[S-35] thiotriphosphate) ([S-35]GTPgammaS) binding and [H-3] palmitate incorporation by Galpha proteins were enhanced in tissues obtained from denervated striata without apparent changes in Galpha protein levels. Moreover, high-affinity binding sites of the D-1 dopamine receptor increased in lesioned compared with control striata without altering the expression level of the receptor. These denervation-mediated changes appear to correlate with the increase in D-1 dopamine receptor binding sites that co-immuno-precipitated with Galphas(olf)/q(11) proteins. In contrast, the total number of D-2 receptor binding sites was increased, yielding an increase in absolute number of high-affinity sites without significant changes in the proportion of high-affinity sites. Stimulation of the D-2 dopamine receptor enhanced coupling to Galphai protein; this was increased in the striata lesioned. The results provide an important molecular mechanism by which dopamine receptor-regulated signaling is enhanced following denervation of dopaminergic input to striatum. Although D-1 dopamine receptor supersensitivity appears to be mediated by enhanced coupling of the receptor to its G proteins, sensitization in the D-2 dopamine receptor system is mediated by increased D-2 receptor density and enhanced D-2 receptor-Gi protein coupling.