3,4-methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates

Abstract

Ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] was shown to prolong the action of L-3,4-dihydroxyphenylalanine (L-DOPA) while suppressing dyskinesia in a single patient with Parkinson's disease (PD). The clinical basis of this effect of MDMA is unknown but may relate to its actions on either dopaminergic or serotoninergic systems in brain. In normal, drug-naive common marmosets, MDMA administration suppressed motor activity and exploratory behavior. In 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, L-DOPA-primed common marmosets, MDMAtransiently relieved motor disability but over a period of 60 min worsened motor symptoms. When given in conjunction with L-DOPA, however, MDMA markedly decreased dyskinesia by reducing chorea and to a lesser extent dystonia and decreased locomotor activity to the level observed in normal animals. MDMA similarly alleviated dyskinesia induced by the selective dopamine D2/3 agonist pramipexole. The actions of MDMA appeared to be mediated through 5-HT mechanisms because its effects were fully blocked by the selective serotonin reuptake inhibitor fluvoxamine. Furthermore, the effect of MDMA on L-DOPA-induced motor activity and dyskinesia was partially inhibited by 5-HT1a/b antagonists. The ability of MDMA to inhibit dyskinesia results from its broad spectrum of action on 5-HT systems. Serotoninergic receptors appear to play an important modulatory role in L-DOPA-induced dyskinesia, and this study may provide a framework for the use of serotoninergic agents in the treatment of L-DOPA-induced dyskinesia.