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

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-HT(2A) 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 < 0.05); although total ON-time was unchanged (approximately 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-HT(2A) antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively.

Figure 1.

Synthesis of MDMA enantiomers.

Figure 2.

A, Time course of dyskinesia in marmosets treated with l-DOPA and R-MDMA (1, 3, and 10 mg/kg) or vehicle. R-MDMA (3 and 10 mg/kg) significantly reduced the severity of l-DOPA-induced dyskinesia during the first 2 h of treatment, compared to l-DOPA vehicle treatment (p < 0.001 from 0–60 min; p < 0.01 from 60–120 min) and l-DOPA 1 mg/kg R-MDMA treatment (p < 0.05 for 10 mg/kg R-MDMA from 0–60 min, and p < 0.01 for 3 and 10 mg/kg R-MDMA from 60–120 min). Each time point represents the cumulated dyskinesia score for every 5 min observation period during the preceding 60 min. The maximal possible score (most severe disability) was 24. On the y-axis, 6 is mild, 12 is moderate, 18 is marked, and 24 is severe. The crosses on the graph indicate time points for which there is significance. B, Time course of dyskinesia in marmosets treated with l-DOPA and S-MDMA (1, 3, 10 mg/kg) or vehicle. S-MDMA (1 mg/kg) significantly increased the severity of dyskinesia from 300–360 min when compared to l-DOPA vehicle (p < 0.05). The severity of dyskinesia was also significantly higher when 1 mg/kg S-MDMA was compared to 3 and 10 mg/kg S-MDMA (both p < 0.05). Each time point represents the cumulated dyskinesia score for every 5 min observation period during the preceding 60 min. The maximal possible score (most severe disability) was 24. On the y-axis, 6 is mild, 12 is moderate, 18 is marked, and 24 is severe. The cross on the graph indicates a time point for which there is significance. C, Time course of parkinsonism in marmosets treated with l-DOPA and R-MDMA (1, 3, 10 mg/kg) or vehicle. R-MDMA had no effect on the antiparkinsonian action of l-DOPA (p > 0.05). Each time point represents the cumulated parkinsonism score for every 5 min observation period during the preceding 60 min. The maximal possible score (most severe disability) was 216. On the y-axis, 54 is mild, 108 is moderate, 162 is marked, and 216 is severe. D, Time course of parkinsonism in marmosets treated with l-DOPA and S-MDMA (1, 3, 10 mg/kg) or vehicle. Each time point represents the cumulated parkinsonism score for every 5 min observation period during the preceding 60 min. The maximal possible score (most severe disability) was 216. On the y-axis, 54 is mild, 108 is moderate, 162 is marked, and 216 is severe. *p < 0.05 when compared to l-DOPA vehicle; **p < 0.01 when compared to l-DOPA vehicle; ***p < 0.001 when compared to l-DOPA vehicle; ^#p < 0.05 when compared to l-DOPA 1 mg/kg R-MDMA or S-MDMA; ^##p < 0.01 when compared to l-DOPA 1 mg/kg R-MDMA or S-MDMA; ^§ 0.05 when compared to l-DOPA 3 mg/kgR-MDMA or S-MDMA; ^†p < 0.05 when compared to l-DOPA 10 mg/kgR-MDMA or S-MDMA. The values represent the median score for parkinsonism/dyskinesia at each time point.

Figure 3.

A, Peak-dose dyskinesia (60–150 min after l-DOPA administration) in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA (3 and 10 mg/kg) significantly reduced the severity of peak-dose dyskinesia when compared to l-DOPA vehicle (both p < 0.05). B, Peak-dose dyskinesia (60–150 min after l-DOPA administration) in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA did not significantly alter the severity of peak-dose dyskinesia (p > 0.05). *p < 0.05 when compared to l-DOPA vehicle. The bars represent the median score for dyskinesia, and the dots represent the individual score of each animal. The maximal possible score (most severe disability) was 36. On the y-axis, 9 is mild, 18 is moderate, 27 is marked, and 36 is severe.

Figure 4.

A, Peak-dose parkinsonism (60–150 min after l-DOPA administration) in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA did not alter the peak antiparkinsonian action of l-DOPA (p > 0.05). B, Peak-dose parkinsonism (60–150 min after l-DOPA administration) in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA did not alter the peak antiparkinsonian action of l-DOPA (p > 0.05). The bars represent the median score for parkinsonism, and the dots represent the individual score of each animal. The maximal possible score (most severe disability) was 144. On the y-axis, 36 is mild, 72 is moderate, 108 is marked, and 144 is severe.

Figure 5.

A, Duration of ON-time in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA had no effect on the duration of ON-time (p > 0.05). B, Duration of ON-time with disabling dyskinesia in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA (3 and 10 mg/kg) significantly reduced the duration of ON-time with disabling dyskinesia when compared to l-DOPA vehicle (both p < 0.01). C, Duration of ON-time with nondisabling dyskinesia in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA (3 and 10 mg/kg) significantly increased the duration of ON-time with nondisabling dyskinesia when compared to l-DOPA vehicle (both p < 0.01). D, Duration of ON-time in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA (1 mg/kg) significantly increased duration of ON-time when compared to l-DOPA vehicle (p < 0.01). This extension of ON-time was not maintained when higher doses of S-MDMA (3 and 10 mg/kg) were administered (p < 0.01 when 1 mg/kg S-MDMA was compared to 3 mg/kg S-MDMA; p < 0.001 when 1 mg/kg S-MDMA was compared to 10 mg/kg S-MDMA). E, Duration of ON-time with disabling dyskinesia in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA had no significant effect on duration of ON-time with disabling dyskinesia (p > 0.05). F, Duration of ON-time with nondisabling dyskinesia in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA had no effect on duration of ON-time with nondisabling dyskinesia (p > 0.05). **p < 0.01 when compared to l-DOPA-vehicle; ^††p < 0.01 when 1 mg/kg S-MDMA is compared to 3 mg/kg S-MDMA; ^###p < 0.001 when 1 mg/kg S-MDMA is compared to 10 mg/kg S-MDMA. The values represent the mean ± SEM ON-time duration.

Figure 6.

A, Duration of ON-time with psychosis-like behavior in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA had no effect on the duration of ON-time with psychosis-like behavior (p > 0.05). B, Duration of ON-time with disabling psychosis-like behavior in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA (3 and 10 mg/kg) significantly decreased the duration of ON-time with disabling psychosis-like behavior when compared to l-DOPA vehicle (p < 0.01 for 3 mg/kg R-MDMA; p < 0.05 for 10 mg/kg R-MDMA). C, Duration of ON-time with nondisabling psychosis-like behavior in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA (3 mg/kg) significantly increased the duration of ON-time with nondisabling psychosis-like behavior when compared to l-DOPA vehicle (p < 0.01). D, Duration of ON-time without psychosis-like behavior in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA (3 mg/kg) significantly increased the duration of ON-time without psychosis-like behavior when compared to l-DOPA vehicle (p < 0.05). E, Duration of ON-time without disabling psychosis-like behavior in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA (3 and 10 mg/kg) significantly increased the duration of ON-time without disabling psychosis-like behavior when compared to l-DOPA vehicle (p < 0.001 for 3 mg/kg R-MDMA; p < 0.05 for 10 mg/kg R-MDMA). F, Peak-dose psychosis-like behavior (60–150 min after l-DOPA administration) in marmosets treated with l-DOPA and R-MDMA (1, 3, or 10 mg/kg) or vehicle. R-MDMA did not significantly alter the severity of peak-dose dyskinesia (p > 0.05). G, Duration of ON-time with psychosis-like behavior in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA had no effect on the duration of ON-time with psychosis-like behavior (p > 0.05). H, Duration of ON-time with disabling psychosis-like behavior in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA had no effect on the duration of ON-time with disabling psychosis-like behavior (p > 0.05). I, Duration of ON-time with nondisabling psychosis-like behavior in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA had no effect on the duration of ON-time with nondisabling psychosis-like behavior (p > 0.05). J, Duration of ON-time without psychosis-like behavior in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. Duration of ON-time without psychosis-like behavior was significantly longer in the 1 mg/kg S-MDMA treatment when compared to the 10 mg/kg S-MDMA treatment (p < 0.05). K, Duration of ON-time without disabling psychosis-like behavior in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA had no effect on the duration of ON-time without disabling psychosis-like behavior (p > 0.05). L, Peak-dose psychosis-like behavior (60–150 min after l-DOPA administration) in marmosets treated with l-DOPA and S-MDMA (1, 3, or 10 mg/kg) or vehicle. S-MDMA did not significantly alter the severity of peak-dose dyskinesia (p > 0.05). Data are presented as the mean ± SEM ON-time duration (A–E, G–K). F, L, Bars represent the median score for psychosis-like behavior, and the dots represent the individual score of each animal; the maximal possible score (most severe disability) was 36. For graphs F and L, on the y-axis, 9 is mild, 18 is moderate, 27 is marked, and 36 is severe. *p < 0.05; **p < 0.01; ***p < 0.001.