THE DOPAMINE-D-1 AGONIST SKF-81297 AND THE DOPAMINE-D-2 AGONIST LY-171555 ACT SYNERGISTICALLY TO STIMULATE MOTOR BEHAVIOR OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-LESIONED PARKINSONIAN RHESUS-MONKEYS

At present, the pharmacotherapy of Parkinson's disease (PD) consists mainly of L-dihydroxyphenylalanine (L-DOPA) and/or dopamine D-2 receptor agonists. However, in general the clinical efficacy of D-2 agonists is less than that of L-DOPA. Therefore, attention is being focussed on the role of the D-2 receptor as a target for therapeutic intervention in PD. Recently, we reported that SKF 81297 is a selective D-2 agonist that stimulates motor behavior of unilaterally MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus monkeys. Presently, we studied the effect of coadministration of SKF 81297 and the D-2 agonist LY 171555 using the same model of PD. Coadministration of behaviorally active doses of SKF 81297 (0.3 mg/kg) and LY 171555 (0.01 mg/kg) resulted in a prolongation of the motor stimulation induced by either of the drugs alone. Neither administration of SKF 81297, in a dose of 0.03 mg/kg, nor of LY 171555, in a dose of 0.003 mg/kg, were behaviorally active, whereas the combined administration of these compounds induced a significant stimulation of motor behavior. These data suggest that (a) D-2 receptor stimulation will prove to be useful in the treatment of PD and (b) better therapeutic results will be obtained by simultaneous stimulation of D-2 and D-2 receptors as compared with stimulation of both receptors alone.