Actions of the D-1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L-dopa-primed common marmosets

Common marmosets show parkinsonian motor deficits following 1-methyl-4-phen yl-1,2,3,6-tetrahydropyridine (MPTP) administration and develop dyskinesias during chronic L-dopa exposure. The D-1 agonists A-77636 [(1R, 3S) 3-(1'-a damantyl)-1-aminomethyl-3, 4-dihydro-5, 6-dihydroxy-1H-2-benzopyran HCl] an d A-86929 [(-)-trans 9; 10-hydroxy-2-propyl-4, 5, 5a, 6, 7, 11b-hexahydro-3 -thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride] possess potent ant iparkinsonian activity in the MPTP-treated marmoset and we now assess their influence on L-dopa-induced dyskinesias. MPTP-treated marmosets with stabl e motor deficits were treated with L-dopa plus carbidopa for 28 days to ind uce dyskinesias. Subsequently, they received A-86929 for 10 days, initially at 0.5 mu mol/kg and then at 1.0 mu mol/kg for a further 5 days. Several m onths later, L-dopa 12.5 mg/kg plus carbidopa 12.5 mg/kg was given orally t wice daily for 7 days, followed by A-77636 1 mu mol/kg for 10 days, and the n both A-77636 and L-dopa plus carbidopa were given concurrently for 3 furt her days. In these L-dopa-primed animals, A-86929 effectively reversed akin esia and produced dose-dependent dyskinesias which were significantly less intense than those produced by L-dopa administration. A degree of behaviora l tolerance was encountered, but antiparkinsonian activity was preserved an d elicited behaviour was free of hyperkinesis and stereotypy and more natur alistic than that seen with L-dopa. After a week of twice-daily L-dopa dosi ng, administration of the long-acting D-1 agonist A-77636 initially dramati cally enhanced locomotion and reproduced dyskinesia with prominent dystonia , but after repeated administration of A-77636, dyskinesia and in particula r chorea, gradually disappeared. Tolerance to locomotor stimulation greater than with A-86929 occurred, although activity remained significantly above baseline levels. There was a marked reduction in L-dopa-induced climbing, stereotypy and hyperkinesis and behaviour more closely resembled that of no rmal unlesioned marmosets. Upon reintroduction of L-dopa concurrently with continued A-77636 administration, dystonic, but virtually no choreic dyskin esias appeared and behaviour was once again free of stereotypy and hyperkin esis, contrasting dramatically with the presence of these behaviours along with abundant chorea when L-dopa is given alone. These results show a lesse r liability of A-86929 and A-77636 to reproduce dyskinesia in L-dopa-primed MPTP-lesioned subjects while maintaining effective antiparkinsonian activi ty and producing a more naturalistic motor response. The differential effec ts of A-77636 on chorea and dystonia, with suppression of chorea and stereo typy on coadministration with L-dopa, may reflect an altered balance of act ivity in the direct and indirect striatofugal pathways. These results sugge st a possible role for D-1 agonists in the treatment of Parkinson's disease .