The Nature of 3, 4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonergic Dysfunction: Evidence for and Against the Neurodegeneration Hypothesis.

High doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") have been well-documented to reduce the expression of serotonergic markers in several forebrain regions of rats and nonhuman primates. Neuroimaging studies further suggest that at least one of these markers, the plasma membrane serotonin transporter (SERT), may also be reduced in heavy Ecstasy users. Such effects, particularly when observed in experimental animal models, have generally been interpreted as reflecting a loss of serotonergic fibers and terminals following MDMA exposure. This view has been challenged, however, based on the finding that MDMA usually does not elicit glial cell reactions known to occur in response to central nervous system (CNS) damage. The aim of this review is to address both sides of the MDMA-neurotoxicity controversy, including recent findings from our laboratory regarding the potential of MDMA to induce serotonergic damage in a rat binge model. Our data add to the growing literature implicating neuroregulatory mechanisms underlying MDMA-induced serotonergic dysfunction and questioning the need to invoke a degenerative response to explain such dysfunction.