In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain

Abstract

A single high dose of methylenedioxymethamphetamine, a psychedelic agent, produced a rapid and persistent depletion of striatal indoles similar to that observed following administration of the serotonergic neurotoxin p-chloroamphetamine. The drug had little effect on dopaminergic variables. Like p-choloroamphetamine, methylenedioxymethamphetamine was found to be a relatively selective agent for inducing [ 3H]serotonin release in vitro. The serotonin uptake inhibitor, citalopram, blocked both [ 3H]serotonin release in vitro and striatal serotonin depletion in vivo, indicating that both processes were carrier dependent. In vivo comparisons of the stereoisomers of methylenedioxymethamphetamine indicated two phases of serotonin depletion similar to those reported for p-chloroamphetamine. Although both the (+)- and (−)-stereoisomers produced an acute (3 hr) decrease in striatal indoles, the long-term effects of the drug showed stereoselectivity in that the (+)-enantiomer produced the most dramatic serotonin depletion. Comparison of the effects of the stereoisomers of methylenedioxymethamphetamine and its n-desmethyl analog, methylenedioxyamphetamine, on [ 3H]serotonin and [ 3H]dopamine release in vitro showed the (+)-enantiomer of both drugs to be the more potent releasing agent. In spite of its reported lack of hallucinogenic activity, (+)methylenedioxyamphetamine was found to be of a potency similar to that of (+)methylenedioxymethamphetamine in inducing [ 3H]serotonin release in vitro. The results are discussed in terms of the neurochemical similarities between methylenedioxy-methamphetamine and p-chloroamphetamine as well as the proposed role of serotonin release in the behavioral effects of methylenedioxymethamphetamine.