STIMULATION OF ADENYLATE-CYCLASE ACTIVITY BY BENZAZEPINE D-1 DOPAMINEAGONISTS WITH VARYING EFFICACIES IN THE 6-HYDROXYDOPAMINE LESIONED RAT-RELATIONSHIP TO CIRCLING BEHAVIOR

The ability of benzazepine D-1 dopamine agonists with varying efficaci es in stimulating adenylate cyclase and to induce contralateral circli ng was investigated in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the 6-hydroxydopamine lesioned rats , the benzazepines SKF 38393 oxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz azepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 8 3959 (6-Cl, 3-CH3, 3'-CH3 analogue), SKF 83565 (6-Cl, 3-CH3, 3'-Cl ana logue) and SKF 82958 (6-Cl, 3-C3H5 analogue), all produced contralater al circling. The rank order of efficacies (maximal effect, E(max)) bei ng, SKF 83565 = SKF 75670 = SKF 83959 = SKF 80723 > SKF 38393 much gre ater than SKF 82958. In striatal slices from the intact hemisphere, do pamine, SKF 82958, SKF 80723 and SKF 75670 stimulated adenylate cyclas e activity. The rank order of efficacies being SKF 82958 (109%) = dopa mine (100%) = SKF 80723 (98%) > SKF 75670 (72%). Although, SKF 38393 ( 67%), SKF 83565 (64%) and SKF 83959 (59%) tended to stimulate adenylat e cyclase activity, this effect did not reach statistical significance . In the 6-hydroxydopamine lesioned hemisphere, basal levels of adenyl ate cyclase activity were lower (-25%) than in the intact hemisphere. The maximal stimulation of adenylate cyclase activity (expressed as % basal levels) produced by dopamine and the benzazepines in the denerva ted striatum was greater than observed in the intact striatum. The ran k order of efficacies in the dopamine denervated striatum being SKF 82 958 (124%) > SKF 80723 (109%) = dopamine (100%) > SKF 38393 (82%) = SK F 83959 (77%) = SKF 83565 (70%) > SKF 75670 (55%). Moreover, dopamine stimulated adenylate cyclase activity in the denervated striatum with greater potency than in the intact side. The ability of the benzazepin e derivatives to induce circling in the 6-hydroxydopamine lesioned rat is consistent with the general increase in the efficacies of dopamine and benzazepine stimulated adenylate cyclase activity in the dopamine denervated striatum. However, the maximal effects for inducing circli ng and stimulating adenylate cyclase activity do not correspond (e.g. SKF 82958 and SKF 75670). This discrepancy may reflect the involvement of other factors including a behavioural role for extrastriatal D-1 d opamine receptors and/or transduction systems other than adenylate cyc lase.