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

Abstract

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 subjects while maintaining effective antiparkinsonian activity and producing a more naturalistic motor response. The differential effects of A-77636 on chorea and dystonia, with suppression of chorea and stereotypy on co-administration with L-dopa, may reflect an altered balance of activity in the direct and indirect striatofugal pathways. These results suggest a possible role for D1 agonists in the treatment of Parkinson's disease.

Mapping the Effects of Three Dopamine Agonists with Different Dyskinetogenic Potential and Receptor Selectivity Using Pharmacological Functional Magnetic Resonance Imaging

“…Our present findings confirm that D1/D5 agonists can induce AIMs in parkinsonian rodents (Monville et al, 2005). Studies performed in MPTP-lesioned monkeys are to some extent contradictory on this matter, yet most emphasize that D1/D5 agonists induce significant dyskinesia (Blanchet et al, 1996;Pearce et al, 1999;Goulet and Madras, 2000) and the D1/D5 agonist ABT-431 is as potent as levodopa in inducing dyskinesia in patients (Rascol et al, 2001). Remarkably, we found that SKF-81297 induced significantly more MD than apomorphine and quinpirole, what is consistent with reports showing that D1/D5 agonists increase oral movements in rats and monkeys with intact dopaminergic pathways (Bedard and Boucher, 1989;Waddington et al, 1995) and produce abnormal dyskinetic oral movements in MPTP-lesioned marmosets (Gnanalingham et al, 1995).…”

“…But the neural mechanisms of dopamine agonist-induced dyskinesia are thought to essentially concern the indirect pathway (Crossman, 1990;Obeso et al, 2000) and our findings suggest a primary involvement of the D1 receptor regulated direct pathway. A primary involvement of D1 receptors and the direct basal ganglia pathway is suggested by other recent studies too (Aubert et al, 2005;Fiorentini et al, 2006), and by the fact that D2 family agonists are less likely to induce dyskinesia in patients and animal models of PD than unselective and D1/D5 selective agonists (present findings; Gnanalingham et al, 1995;Blanchet et al, 1996;Pearce et al, 1999;Goulet and Madras, 2000;Nutt, 2000;Rascol et al, 2001;Lundblad et al, 2002;Monville et al, 2005). A recent study established that levodopa-induced dyskinesia in the rat 6-OHDA model is related to increased synchronization of afferent activity to the basal ganglia output nuclei (Meissner et al, 2006).…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…However, in contrast to the studies cited above, chronic administration of the selective and long-acting D 1 agonist A-77,636 led to a gradual reduction in dyskinesia severity, in the primed MPTP-lesioned common marmoset (Pearce et al, 1999). Although that last study was not a de novo study, it highlights the importance of pulsatile dopamine receptor stimulation in the pathophysiology of LID.…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…Short-acting D1 and D2 receptor ago-nists have both been shown to induce dyskinesia in animal models of parkinsonism. 303 However, in MPTP monkeys the pure D1 agonists A-86929 and A-77636 provide motor benefits with reduced dyskinesia, 1032,1033 and there is renewed interest in studying these agents in patients with PD. Recent studies have implicated the D3 receptor in the induction of dyskinesia, 305 and the partial D3 agonist BP897 ([N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide) has been shown to provide antiparkinsonian effects and reversal of dyskinesia in both macaque and squirrel monkeys.…”