a-77636 and Dyskinesia--Drug-Induced

Dopamine receptor agonists provide symptomatic relief in the early stages of Parkinson's disease, but with disease progression, their efficacy decreases. The reason behind this decrease in effectiveness is unknown, but maximal efficacy may be dependent on endogenous dopaminergic tone to provide stimulation of D1 and D2 receptor subtypes. Therefore, we have investigated the effects of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT) on the actions of D1, D2, and D1/D2 agonists and levodopa (L-dopa) in common marmosets treated with 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Administration of AMPT alone further increased motor disability and decreased locomotor activity. Administration of L-dopa reversed motor disability and increased locomotor activity, and this reversal was not affected by previous AMPT treatment. The D1 agonist A-77636 and the D2 agonist quinpirole reversed motor deficits, but these effects were markedly inhibited by previous AMPT treatment. Administration of quinpirole with A-77636 produced a reversal of motor deficits that was more resistant to AMPT pretreatment than was the effect produced by quinpirole or A-77636 alone. These data suggest that D1 and D2 receptor stimulation are required for dopamine receptor agonists to produce a maximal antiparkinsonian response. The reversal of motor deficits produced by the mixed D1/D2 agonist apomorphine was more resistant to AMPT treatment than that produced by quinpirole or A-77636. However, the motor effects of A-77636 plus quinpirole and of apomorphine were still affected by AMPT treatment. This suggests that loss of tyrosine hydroxylase activity may also alter motor activity through inhibition of endogenous L-dopa or norepinephrine synthesis, because both are also involved in the genesis of motor activity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adamantane; alpha-Methyltyrosine; Animals; Antiparkinson Agents; Apomorphine; Benzopyrans; Callithrix; Dopamine Agents; Dopamine Agonists; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Female; Levodopa; Locomotion; Male; Quinpirole; Receptors, Dopamine D1; Receptors, Dopamine D2; Tyrosine 3-Monooxygenase

Common marmosets show parkinsonian motor deficits following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and develop dyskinesias during chronic L-dopa exposure. The D1 agonists A-77636 [(1R, 3S) 3-(1'-adamantyl)-1-aminomethyl-3, 4-dihydro-5, 6-dihydroxy-1H-2-benzopyran HCl] and 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 antiparkinsonian activity in the MPTP-treated marmoset and we now assess their influence on L-dopa-induced dyskinesias. MPTP-treated marmosets with stable motor deficits were treated with L-dopa plus carbidopa for 28 days to induce dyskinesias. Subsequently, they received A-86929 for 10 days, initially at 0.5 micromol/kg and then at 1.0 micromol/kg for a further 5 days. Several months later, L-dopa 12.5 mg/kg plus carbidopa 12.5 mg/kg was given orally twice daily for 7 days, followed by A-77636 1 micromol/kg for 10 days, and then both A-77636 and L-dopa plus carbidopa were given concurrently for 3 further days. In these L-dopa-primed animals, A-86929 effectively reversed akinesia and produced dose-dependent dyskinesias which were significantly less intense than those produced by L-dopa administration. A degree of behavioral tolerance was encountered, but antiparkinsonian activity was preserved and elicited behaviour was free of hyperkinesis and stereotypy and more naturalistic than that seen with L-dopa. After a week of twice-daily L-dopa dosing, administration of the long-acting D1 agonist A-77636 initially dramatically enhanced locomotion and reproduced dyskinesia with prominent dystonia, but after repeated administration of A-77636, dyskinesia and in particular 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 normal unlesioned marmosets. Upon reintroduction of L-dopa concurrently with continued A-77636 administration, dystonic, but virtually no choreic dyskinesias appeared and behaviour was once again free of stereotypy and hyperkinesis, contrasting dramatically with the presence of these behaviours along with abundant chorea when L-dopa is given alone. These results show a lesser liability of A-86929 and A-77636 to reproduce dyskinesia in L-dopa-primed MPTP-lesioned subje

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adamantane; Animals; Benzopyrans; Callithrix; Disease Models, Animal; Dopamine Agents; Dopamine Agonists; Dyskinesia, Drug-Induced; Female; Levodopa; Locomotion; Male; Quinolones; Receptors, Dopamine D1; Thiophenes