Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4‐methylenedioxymethamphetamine): Assessment using quantitative autoradiography

MDMA (ecstasy) causes long-lasting damage to serotonin neurons in the brain. Using a rat model, researchers measured serotonin transporter density—a marker of healthy serotonin neurons—after four days of MDMA treatment. Within 24 hours, many brain regions showed marked decreases in serotonin transporters, including the cortex, hippocampus, and caudate nucleus. These reductions persisted for at least two weeks. Some regions, like the dorsal striatum, showed greater damage at two weeks than immediately after treatment, while others, such as the endopiriform nucleus, showed partial recovery. Regions containing serotonin cell bodies (raphe nuclei) and axons of passage were unaffected. Catecholamine neurons were not damaged, indicating MDMA's selectivity for serotonin terminals.

Study at a glance

Abstract

Abstract The Widely abused “designer” durg MDMA (3,4‐methylenedioxymethamphetamine) has been shown to caused marked and long‐lasting changes in brain serotonergic systems. The present study uses quantitative in vitro autoradiography of 3 H‐paroxetine labeled 5‐HT uptake sites to assess the time‐dependent effects of MDMA on 5‐HT neurons in specific neuroanatomic loci. Following treatment with MDMA (20 mg/kg, b.i.d. for 4 days), marked decreases in 5‐HT uptake sites were observed in a number of brain regions known to receive projections of ‐5HT neurons. These regions included cerebral cortex, caudate nucleus, hippocampus, nucleus accumbens, olfactory tubercle, superior and inferior colliculi, geniculate nuclei, and most thalamic nuclei. In contrast, other areas such as the septal nuclei and some thalamic nuclei which also receive 5‐HT projections were not substantially affected by this drug. In most regions, decreases in 5‐HT uptake sites occurred within 24 hours of the last dose of MDMA and persisted at the 2 week time point. Some regions such as dorsal striatum exhibited a time‐dependent reduction with greater reductions occurring at 2 weeks rather than immediately following the MDMA treatment regimen. The density of 5‐HT uptake sites in other regions such as endopiriform nucleus and substantia nigra at the 2 week versus 18 hour time point indicated some degree of region‐specific recovery. Regions which demonstrated no significant reduction in 5‐HT uptake sites included the dorsal and median raphe nuclei, ventral tegmental area, central grey, interpeduncluar nucleus, locus coerulus, pontine reticular formation and cerebellum. Likewise, region containing 5‐HT axons of passage (e.g., indusium griseum and lateral hypothalamus) appeared to be insensitive to the neurotoxic effects of MDMA on 5‐HT neurons. Furthermore, the neurotoxic effects of MDMA showed specificity in that the catecholamine neurons labeled by 3 H‐mazindol were unaffected by the treatment regimen. These data indicate that the preferential degeneration of serotonergic neurons by MDMA is mediated primarily at 5‐HT terminal regions, whereas regions containg 5‐HT perikarya and axons of passage remain relatively unaffected. In addition, the observed time‐dependent reductions and recovery of 5‐HT uptake sites which were detected within 2 weeks of the treatment regimen in certain brain regions suggest region‐specific differences in recovery of 5‐HT systems from MDMA‐induced lesion.