Increases in guanine nucleotide binding to striatal G proteins is associated with dopamine receptor supersensitivity

The role of the regulatory guanine nucleotide binding proteins (G proteins) in the development of dopamine (DA) receptor supersensitivity was studied in striatal membranes from reserpine treated rats. [α-³²P]GTP labeled two striatal proteins with molecular masses of 45 and 40 kD. These proteins were previously identified as alpha subunits of G(s) and G(i)/G(o), respectively. Seven days of reserpine treatment caused a 43% increase in steady-state basal [α-³²P]GTP binding to striatal G(αs). Basal [α- ³²P]GTP binding to the 40-kD protein band was unchanged by reserpine treatment. Incubation of membranes with DA stimulated [α-³²P]GTP binding to both protein bands. Although 10 μM DA stimulated guanine nucleotide binding to G(αs) and G(αi/o) in control tissue by 317% and 236%, respectively, the increases in [α-³²P]GTP binding in the reserpine- treated animals were 482% (P < .01) and 366% (P < .01), respectively. A single injection of reserpine did not alter basal or DA-stimulated [α- ³²P]GTP binding. Repeated reserpine treatment also enhanced serotonin- induced stimulation of [α-³²P]GTP binding to striatal G(αi/o) but not to G(αs). However, carbachol-stimulated binding was unaffected by the treatment. Reserpine treatment did not change membrane G(αs), G(αi 1/2 ) or G(αo) levels, as assessed by immunoblotting or by toxin-catalyzed ADP ribosylation. These results suggest that increases in both basal and receptor-mediated activations of G proteins are associated with the development of reserpine-induced striatal DA receptor supersensitivity. This mechanism appears to be of particular importance to mediate the supersensitivity of the D₁ DA receptor, which develops during repeated treatment with reserpine.