THE RELATIONSHIP BETWEEN THE DEGREE OF NEURODEGENERATION OF RAT-BRAIN5-HT NERVE-TERMINALS AND THE DOSE AND FREQUENCY OF ADMINISTRATION OF MDMA (ECSTASY)

The effect of varying the dose and frequency of administration of 3,4- methylenedioxymethamphetamine (MDMA or 'ecstasy') on both the acute hy perthermic response and the long term neurodegeneration of 5-hydroxytr yptamine (5-HT) nerve terminals in the brain has been studied in Dark Agouti rats. A single injection (4-15 mg/kg i.p.) of MDMA produced imm ediate dose-related hyperthermia and a dose-related decrease in 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and [H-3]paroxetine binding in reg ions of the brain 7 days later, with a dose of 4 mg/kg having no degen erative effect. This dose was also without effect when given once dail y for 4 days, but produced a marked loss of [H-3]paroxetine binding an d indole concentration (approximate to 55%) when given twice daily for 4 days. When a dose of 4 mg/kg was given twice weekly for 8 weeks it had no effect on these serotoninergic markers, despite a clear anorect ic effect of the drug being seen. These data demonstrate that MDMA-ind uced neurodegeneration is related to both the dose and frequency of ad ministration and indicate that damage to 5-HT neurones can occur in th e absence of a hyperthermic response to the drug. We suggest that dama ge occurs when endogenous free radical scavenging mechanisms become ov erwhelmed or exhausted. (C) 1998 Elsevier Science Ltd. All rights rese rved.