DIFFERENTIAL ANTI-PARKINSONIAN EFFECTS OF BENZAZEPINE D-1 DOPAMINE AGONISTS WITH VARYING EFFICACIES IN THE MPTP-TREATED COMMON MARMOSET

In common marmosets systemically treated with MPTP (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine), the behavioural effects of benzazepine D- 1 dopamine (DA) agonists with full/supramaximal (SKF 80723 and SKF 829 58), partial (SKF 38393, SKF 75670 and SKF 83565) and no efficacies (S KF 83959) in stimulating adenylate cyclase (AC) activity were investig ated. The benzazepine derivatives, with the exception of SKF 82958 (8 fold D-1 DA receptor selectivity), demonstrated high D-1 DA receptor a ffinity and selectivity (approximately 100 fold or more) in rat striat al homogenates. Administration of MPTP in marmosets induced locomotor hypoactivity, rigidity and motor disability. SKF 38393 roxy-1-phenyl-2 ,3,4,5-tetrahydro-1H-3-benzazepine) and SKF 75670 (3-CH3 analogue) fur ther reduced locomotor activity (by - 70 to - 80%) and increased motor disability (by +22 to +67%) in these animals. SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) had only a slig ht effect on locomotor activity but decreased motor disability at high doses (-46 to -60%). In contrast, SKF 83959 (6-Cl, 3-CH3, 3'-CH3 anal ogue) and SKF 80723 (6-Br analogue) produced pronounced increases in l ocomotion (6-10 fold) and a reversal in motor disability (by -64 to -7 7%). Oral activity, consisting largely of abnormal, 'dyskinetic' tongu e protrusions and vacuous chews, was increased in animals treated with SKF 38393, SKF 83565, SKF 82958 and more especially with SKF 80723 an d SKF 83959. Grooming was increased with SKF 82958 and more especially with SKF 80723 and SKF 83959. In contrast, quinpirole (D-2 DA agonist ), reversed the MPTP-induced motor deficits in the marmoset, with no e ffect on grooming and oral activity. The present findings further demo nstrate the antiparkinsonian actions of some D-1 DA agonists in MPTP-t reated primates. However, in general the behavioural effects of benzaz epines failed to correlate with either their D-1 DA receptor affinity/ selectivity or their efficacy in stimulating adenylate cyclase (AC) ac tivity. These observations further implicate a behavioural role for D- 1 DA receptors uncoupled to AC and/or a role for extrastriatal D-1 DA receptors in mediating the behavioural response to D-1 DA agonists.