Direct central effects of acute methylenedioxymethamphetamine on serotonergic neurons

Acute peripheral administration of either the (+) or (-) stereoisomer of methylenedioxymethamphetamine (MDMA) to rats results in a rapid loss of tryptophan hydroxylase (TPH) activity in several brain regions. This decline in enzyme activity precedes a decrease in serotonin (5-HT) concentrations in the same areas. An initial rise in the concentration of 5-hydroxyindole acetic acid after drug administration suggests that an increase in the turnover of 5-HT is an early event in the development of these changes. Unsuccessful attempts to reproduce the in vivo effects of MDMA on TPH activity using in vitro preparations such as cortical slices or the mouse mastocytoma cell line, P-815, suggested a requirement for an intact neuronal system or metabolism of the drug. Injection of MDMA directly into several brain regions also had no effect on TPH activity or 5-HT concentrations. However, when brain concentrations of MDMA were maintained using a constant i.c.v. infusion, TPH activity declined as observed following peripheral administration. The results, therefore, indicate that the acute effect of MDMA on 5-HT synthesis is a direct central effect of the drug which may be triggered by a sustained increase in transmitter turnover.