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- Title
Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) Enantiomers In Vitro and in the MPTP-Lesioned Primate: R-MDMA Reduces Severity of Dyskinesia, Whereas S-MDMA Extends Duration of ON-Time.
- Authors
Huot, Philippe; Johnston, Tom H.; Lewis, Katie D.; Koprich, James B.; Reyes, M. Gabriela; Fox, Susan H.; Piggott, Matthew J.; Brotchie, Jonathan M.
- Abstract
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 ofR-MDMA(3 and 10 mg/kg), the severity of peak-dose dyskinesia was decreased (by 33 and 46%, respectively; p < 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 <0.05). S-MDMA (1 mg/kg) increased the total ON-time by 88 min compared to L-DOPA alone (34% increase; p < 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.
- Subjects
PARKINSON'S disease; EXTRAPYRAMIDAL disorders; BRAIN diseases; PARKINSONIAN disorders; MOVEMENT disorders
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 19, p7190
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1171-11.2011