PT - JOURNAL ARTICLE AU - Philippe Huot AU - Tom H. Johnston AU - Katie D. Lewis AU - James B. Koprich AU - M. Gabriela Reyes AU - Susan H. Fox AU - Matthew J. Piggott AU - Jonathan M. Brotchie TI - Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) Enantiomers <em>In Vitro</em> and in the MPTP-Lesioned Primate: <em>R</em>-MDMA Reduces Severity of Dyskinesia, Whereas <em>S</em>-MDMA Extends Duration of ON-Time AID - 10.1523/JNEUROSCI.1171-11.2011 DP - 2011 May 11 TA - The Journal of Neuroscience PG - 7190--7198 VI - 31 IP - 19 4099 - http://www.jneurosci.org/content/31/19/7190.short 4100 - http://www.jneurosci.org/content/31/19/7190.full SO - J. Neurosci.2011 May 11; 31 AB - l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease, but long-term l-DOPA administration is marred by the emergence of motor complications, namely, dyskinesia and a shortening of antiparkinsonian benefit (wearing-OFF). 3,4-Methylenedioxymethamphetamine (MDMA) is unique in that it exerts antidyskinetic effects and may enhance antiparkinsonian actions of l-DOPA. MDMA is composed of two enantiomers with different pharmacological profiles; here, we describe a novel enantiospecific synthesis of the two enantiomers and expand on the previous characterization of their pharmacology. R-MDMA (rectus-MDMA) is relatively selective for 5-HT2A receptors, whereas S-MDMA (sinister-MDMA) inhibits both serotonin (SERT) and dopamine transporters (DAT; SERT/DAT ratio of 10 to 1). R- or S-MDMA (1, 3, and 10 mg/kg, s.c.) was administered in combination with l-DOPA (15 mg/kg, s.c.) to six female common marmosets (Callithrix jacchus) rendered parkinsonian by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) administration. Motor disability, including parkinsonism and dyskinesia, and duration of antiparkinsonian benefit (ON-time) were evaluated. After the administration of R-MDMA (3 and 10 mg/kg), the severity of peak-dose dyskinesia was decreased (by 33 and 46%, respectively; p &lt; 0.05); although total ON-time was unchanged (∼220 min), the duration of ON-time with disabling dyskinesia was decreased by 90 min when compared to l-DOPA alone (69% reduction; p &lt; 0.05). S-MDMA (1 mg/kg) increased the total ON-time by 88 min compared to l-DOPA alone (34% increase; p &lt; 0.05), though dyskinesia were exacerbated. These data suggest that racemic MDMA exerts simultaneous effects, reducing dyskinesia and extending ON-time, by 5-HT2A antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively.