Agonist-induced subsensitivity of adenylate cyclase coupled with a dopamine receptor in slices from rat corpus striatum.

Abstract

Incubation, for 30 min, of striatal slices with 10 .mu.M dopamine, 10 .mu.M apomorphine or 10 .mu.M SKF 38393 [2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzarepine] decreases dopamine-stimulated adenylate cyclase activity by 50-60%. This loss in dopamine-stimulated enzyme activity appears to be mediated by a persistent occupancy of recognition sites of the D-1 receptor, because of 10 .mu.M, SKF 38393, a selective D-1 receptor agonist, facilitates densensitization and LY 241865 [(4.alpha..beta.,7.beta.,8.alpha..gamma.)-4,4.alpha.,5,6,7,8,81,9-octahydro-7-[(methylthi)methyl]-5-propyl-2H-pyrazolo[3,4-g]quinoline], a selective D-2 receptor agonist, fails to elicit desensitization of dopamine-dependent adenylate cyclase, and preincubation with dopamine in the presence of 1 .mu.M haloperidol but not 1 .mu.M sulpiride curtails the desensitization of dopamine-dependent adenylate cyclase. In dopamine-desensitized striatal slices the Kd for N-propylnorapomorphine binding is increased, but the content of membrane-bound calmodulin and the activation of adenylate cyclase by NaF and cholera toxin are decreased significantly. In striatal slices incubated with dopamine for prolonged time periods, the coupling of the GTP-binding protein with adenylate cyclase and dopamine recognition sites may be impaired and the content of membrane-bound calmodulin is described.