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A pharmacokinetic analysis of 3,4-methylenedioxymethamphetamine effects on monoamine concentrations in brain
M Hiramatsu1, E DiStefano, A S Chang
1Department of Pharmacology, UCLA School of Medicine 90024-1735.
Abstract:
Interpretation of the in vivo actions of 3,4-methylenedioxymethamphetamine (MDMA) is complicated by the formation of the active metabolite, 3,4-methylenedioxyamphetamine (MDA). This study evaluates the role of MDA in the dopamine releasing actions of (+)-MDMA. In the study, rats were given subcutaneous doses of (+)-MDMA and concentrations of monoamines and their metabolites in striatal dialysate were measured at 15 min intervals. In parallel experiments, plasma concentrations of (+)- and (-)-MDMA and MDA were determined by GC/MS procedures. The time course of MDMA levels was comparable for the two isomers as were their bioavailabilities. In contrast, the plasma levels of MDA were about three times higher after (+)-MDMA. (+)-MDMA caused a rapid increase in striatal dialysate levels of dopamine and decreased extracellular levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). There was a significant correlation between dopamine concentration in striatal dialysate and plasma MDMA concentration, but not with plasma MDA. These results indicate that MDMA itself has stereoselective actions on dopamine neurons. However, the higher plasma MDA levels after (+)-MDMA may account for part of the enantiomeric differences in the behavioral and neurotoxicological effects of MDMA.
Insights
3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) affect dopamine release. This study shows MDMA itself has stereoselective dopamine actions, though MDA may contribute to behavioral differences.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- The interpretation of 3,4-methylenedioxymethamphetamine (MDMA) in vivo effects is complicated by its active metabolite, 3,4-methylenedioxyamphetamine (MDA).
- Understanding the distinct roles of MDMA and MDA is crucial for elucidating MDMA's neurochemical and behavioral outcomes.
Purpose of the Study:
- To evaluate the specific role of MDA in the dopamine-releasing effects of (+)-MDMA.
- To differentiate the actions of MDMA from its metabolite MDA on dopamine neurotransmission.
Main Methods:
- Rats received subcutaneous doses of (+)-MDMA.
- Striatal dialysate monoamine and metabolite concentrations were measured. Plasma concentrations of MDMA isomers and MDA were determined using GC/MS.
Main Results:
- Plasma MDA levels were approximately three times higher following (+)-MDMA administration compared to other conditions.
- (+)-MDMA significantly increased striatal dopamine and decreased DOPAC and HVA levels.
- Dopamine levels correlated with plasma MDMA, not MDA, suggesting direct MDMA action.
Conclusions:
- MDMA exhibits stereoselective effects on dopamine neurons.
- Elevated MDA levels after (+)-MDMA may partially explain enantiomeric differences in behavioral and neurotoxicological effects.