Acute administration of methylenedioxymethamphetamine: comparison with the neurochemical effects of its N-desmethyl and N-ethyl analogs.

The acute and long-term neurochemical effects of three methylenedioxyamphetamine analogs were examined in the serotonergic system of the rat brain. Methylenedioxymethamphetamine as well as its N-desmethyl and N-ethyl derivatives depleted cortical serotonin (5HT) concentrations to less than 30% of control 3 h after drug administration. All three compounds were also very similar in their effects on [3H]5HT release from superfused rat striatal slices. Increasing the size of the N-alkyl substituent did appear to reduce the potency of the agent for inducing [3H]dopamine release. One week following drug administration cortical 5HT concentrations had returned to control levels in animals treated with the N-ethyl derivative while the other two analogs produced persistent depletions in transmitter concentrations. The effects of the latter two drugs were correlated with a significant decrease in whole brain synaptosomal [3H]5HT uptake indicating serotonergic nerve terminal damage. N-ethyl-methylenedioxyamphetamine had no effect on synaptosomal 5HT uptake at one week. The (+) stereoisomer of methylenedioxyamphetamine was slightly more potent than the (-) enantiomer at producing the long-term 5HT depletion as previously shown for its N-methyl derivative suggesting similar mechanisms may be responsible for their neurotoxic effects.