5-HT2 antagonists stereoselectively prevent the neurotoxicity of 3,4-methylenedioxymethamphetamine by blocking the acute stimulation of dopamine synthesis: reversal by L-dopa.
C. J. Schmidt, Vicki L. Taylor, Gina M. Abbate, T. Nieduzak
Journal of Pharmacology and Experimental Therapeutics 1990 DOI: 10.1016/s0022-3565(25)23084-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rodents (implied by in vivo neurochemistry methods) |
| Interventions | MDL 11 MDMA nomifensine L-dopa |
| Duration | One week follow-up |
| Topics | MDMA |
| Key findings | The R-(+) stereoisomer of MDL 11,939 reversed MDMA's acute increase in striatal dopamine synthesis and prevented the one-week deficit in forebrain 5-HT. The authors suggest that this acute dopamine synthesis is a compensatory response to carrier-mediated dopamine efflux, and that it is a prerequisite for MDMA-induced neurotoxicity; L-dopa co-administration reversed the protection. |
Abstract
The active and inactive stereoisomers of the serotonin (5-HT2) antagonist, MDL 11,939, were used to examine the relationship between the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on the dopaminergic system and its long-term effects on the serotonergic system. Only the R-(+) stereoisomer of MDL 11,939 both reversed the acute stimulation of striatal dopamine synthesis by MDMA and prevented the deficit in forebrain 5-HT concentrations measured one week later. This acute activation of striatal dopamine synthesis by MDMA is a compensatory response to the carrier-mediated efflux of transmitter as shown by its sensitivity to the dopamine uptake inhibitor, nomifensine. It is suggested that in the absence of this enhanced synthesis, the dopaminergic neuron cannot sustain the carrier-mediated dopamine release which is a prerequisite for the development of MDMA-induced neurotoxicity. This hypothesis is supported by the observation that the administration of the dopamine precursor, L-dopa, with MDMA reverses the protective effects of 5-HT2 receptor antagonists.