Abstract
The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA) along with a lower binding of specific ligands to the 5-HT transporters (SERT). Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration.
Highlights
Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species
Concern over its increasing abuse and its possible neurotoxicity in humans led to the assignment of MDMA as a Schedule I agent by the U.S Drug Enforcement Agency in 1985 [12]
MDMA can cause long-lasting changes in neurochemical and histological markers of serotonergic function in brains of rats [18,19,55], primates [56,57] and, possibly, humans [58]. Such effect is evidenced by the decline in the activity of tryptophan hydroxylase [59]; a decrease in the content of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA) [18,19,22,60,61]; a lower density of [3H]paroxetine-labelled 5-HT transporters (SERT) [20,62] along with the loss of specific ligands to the 5-HT transporters (SERT) protein in several regions of the brain [63,64]; and long-term altered responses to 5-HT agonists or 5-HT releasing drugs in rats, non-human primates and MDMA users [65,66,67,68,69]
Summary
3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a phenylpropanolamine with structural similarities to both amphetamine and mescaline (Figure 1). Nichols [10] proposed the term ‘‘Entactogen’’ to describe the effects of MDMA and related compounds. This definition is based on the claimed ability of MDMA to allow therapists and patients to access and deal with repressed painful emotional issues [11]. Due to these unique psychological effects, never marketed for this purpose, MDMA was used in the 70s and 80s by U.S psychotherapists [4]. Whether the neurotoxic findings seen after single or repeated high doses of MDMA in experimental animals are relevant for humans [18,19,20,21,22,23]
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