Serotonin neurotoxins — past and present

Abstract

Autoxidation pathways and redox reactions of dihydroxytryptamines (5,6- and 5,7-DHT) and of 6-hydroxydopamine (6-OH-DA) are illustrated, and their potential role in aminergic neurotoxicity is discussed. It is proposed that certain aspects of the cytotoxicity of 6-OH-DA and of the DHTs, namely redox cycling of their quinone- and quinoneimine-intermediates as a source of free radicals, may also apply to quinoidal reactive intermediates and to glutathionyl- or cysteinyl conjugates ("thioether adducts") of o-dihydroxylated (catechol-like) metabolites of certain substituted amphetamines (of methylenedioxymethamphetamine (MDMA) and of methylenedioxyamphetamine (MDA)). Despite similarities in their primary interaction with the plasmalemmal (serotonergic transporter/dopamine transporter, SERT/DAT) and vesicular monoamine transporters (VMAT2), MDMA and fenfluramine (N-ethyl-meta-trifluoromethamphetamine, Fen) differ substantially in many aspects of their metabolism, pharmacokinetics, pharmacology, and neurotoxicology profile; the consequences of these differences for neuronal response patterns and long-term survival prospects are not yet fully understood. However, sustained hyperthermia appears to be a critical factor in these differences. Methodological requirements for adequate detection and description of pre- and postsynaptic forms of drug-induced neurotoxicity are exemplified using recently published accounts. The inclusion of microglial markers into research strategies has widened contemporary pathogenetic concepts on methamphetamine (MA)-induced neurotoxicity as an example of inflammatory neurodegeneration, thus complementing the traditional ROS and RNS-dependent stress models. Amphetamine-type neurotoxicity studies may assist in elaborating of preventive strategies for human neurodegenerative disorders.

Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

“…The purpose of the present studies was to further evaluate lasting effects of MDMA and other substituted amphet amines on SERT protein expression and other markers of brain 5-HT neurons, and compare their effects to those of 5,7-dihydroxytryptamine (5,7-DHT), an established 5-HT neurotoxin (Jonsson, 1980;Baumgarten and Lachenmayer, 2004). Specifically, using two different anti-SERT polysera, we sought to establish the validity and sensitivity of Western blot methods for detecting drug-induced changes in SERT protein expression, and to test the hypothesis that serotonergic deficits after substituted amphetamines represent neuroadaptive responses in 5-HT metabolism secondary to SERT sequestration (trafficking).…”

Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

“…Much has been speculated that such deficits are related with the monoaminergic system (103,104). It is possible that, as PrP Sc begins to propagate, early loss of function of PrP C at the neuronal surface may interfere with monoaminergic signaling by modulating G-protein-coupled receptor responses.…”

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

“…The effects of experimenter-administered MDMA on monoamines have been reviewed previously (most recently in Itzhak and Achat-Mendes 2004;Baumgarten and Lachenmayer 2004;Reneman 2003;Green et al 2003;Gudelsky and Yamamoto 2003;Lyles and Cadet 2003) and generally describe a profile consisting of extensive and persistent depletions of central 5-HT, reduced SERT expression, and inhibition of 5-HT synthesis in the absence of effects on other monoamines. Effects consistent with gliosis, however, may or may not be discussed.…”