Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Abstract

Abstract3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative and a popular drug of abuse that exhibits mild hallucinogenic and rewarding properties and engenders feelings of connectedness and openness. The unique psychopharmacological profile of this drug of abuse most likely is derived from the property of MDMA to promote the release of dopamine and serotonin (5-HT) in multiple brain regions. The present review highlights primarily data from studies employing in vivo microdialysis that detail the actions of MDMA on the release of these neurotransmitters. Data from in vivo microdialysis experiments indicate that MDMA, like most amphetamine derivatives, increases the release of dopamine in the striatum, n. accumbens and prefrontal cortex. However, the release of dopamine evoked by MDMA in each of these brain regions appears to be modulated by concomitantly released 5-HT and the subsequent activation of 5-HT2A/C or 5-HT2B/C receptors. In addition to its stimulatory effect on the release of monoamines, MDMA also enhances the release of acetylcholine in the striatum, hippocampus and prefrontal cortex, and this cholinergic response appears to be secondary to the activation of histaminergic, dopaminergic and/or serotonergic receptors. Beyond the acute stimulatory effect of MDMA on neurotransmitter release, MDMA also increases the extracellular concentration of energy substrates, e.g., glucose and lactate in the brain. In contrast to the acute stimulatory actions of MDMA on the release of monoamines and acetylcholine, the repeated administration of high doses of MDMA is thought to result in a selective neurotoxicity to 5-HT axon terminals in the rat. Additional studies are reviewed that focus on the alterations in neurotransmitter responses to pharmacological and physiological stimuli that accompany MDMA-induced 5-HT neurotoxicity.

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain

“…Increases in MDMA-induced dopamine and 5-HT release, and the neurotoxicity of 5-HT by MDMA, suggest the involvement of MDMA metabolites (Escobedo et al, 2005;Erives et al, 2008;Colad et al, 2004) and the formation of reactive oxygen species (Erives et al, 2008;Gudelsky and Yamamoto, 2008;Quinton and Yamamoto, 2006). Clarification of the mechanism of drug interactions with MDMA, especially with respect to metabolism and the formation of reactive oxygen species, will require further study.…”

Longitudinal Examination of Learning and Memory in Rats Following Adolescent Exposure to 3,4-Methylenedioxymethamphetamine or 5-Methoxy-N,N-Diisopropyltryptamine

“…In this study, the effects were observed inde- stimulates acetylcholine release, although this reported effect appears to be minor in comparison to its effects on 5-HT and dopaminergic receptors [115].…”

Sleep apnea in young abstinent recreational MDMA (“ecstasy”) consumers

“…However, we have previously found reductions of brain serotonin transporters, as measured by PET, to be significantly associated with self-reported lifetime MDMA exposure. 19 Finally, concerns regarding the role of other drugs of abuse in the present findings are mitigated by the relationship between extent of prior MDMA exposure and sleep apnea and hypopnea in the current study, the known dose-related neurotoxic effects of MDMA toward brain serotonin neurons, [15][16][17][18] and the fact that serotonin has been previously implicated in OSA. 8 Additional research will be necessary to determine whether sleep abnormalities in MDMA users play a role in subtle cognitive deficits and impulsivity that have previously been identified in this population.…”

“…15,16 Studies in animals, including nonhuman primates, have demonstrated that MDMA leads to lasting dose-related and protracted reductions in a variety of brain serotonin axonal markers, and neuroanatomical studies with immunochemical markers suggest that losses of axonal markers are secondary to a distal axotomy of serotonin neurons. 17,18 PET imaging studies using radioligands that bind to serotonin transporters provide evidence that MDMA is also neurotoxic in humans.…”