Neuropharmacology of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and its stereoisomers

Racemic 3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that is widely abused as the street drug "ecstasy". MDMA abuse is a high risk behavior that has been associated with severe deleterious consequences including acute lethality and brain changes indicative of long-term damage. MDMA produces complex biological effects consistent with a mixture of psychomotor-stimulant-like effects and hallucinogen-like effects. Previous studies have shown that the stereoisomers of MDMA may produce qualitatively different effects, suggesting a parsimonious mechanism for these complex effects. In the present experiments, we have sought to further explore the neuropharmacology of MDMA and its stereoisomers. In Chapter 2, we resolved some of the discrepancies and vagaries of the existing literature on the behavioral effects of MDMA by determining---using non-invasive measurements of sleep architecture and drug-discrimination---that the stereoisomers of MDMA engender qualitatively different behavioral and interoceptive effects. Furthermore, we determined that antagonism of the serotonin 5-HT 2A receptor attenuates MDMA-elicited sleep disruption. In Chapter 3, we determined---using in vivo microdialysis and enzyme linked immunosorbent plasma analysis---that the stereoisomers of MDMA concomitantly elicited qualitatively different neurochemical and endocrine effects. Analogous to Chapter 2, additional experiments demonstrated some of these effects are attenuated by antagonism of the 5-HT2A receptor whereas others are attenuated by pretreatment with a selective serotonin reuptake inhibitor (SSRI). In Chapter 4, we determined---using functional magnetic resonance imaging (fMRI)---that the systems level neuropharmacological effects of MDMA and its stereoisomers are also qualitatively different. Collectively, this work strongly supports the hypothesis that qualitative differences in the effects of its stereoisomers mediate the complex biological effects of MDMA. Furthermore, this work supports the continued development of 5-HT 2A receptor antagonists and SSRIs as novel pharmacotherapeutics for treating MDMA abuse. As such, these studies represent an important expansion of our understanding of the neuropharmacology of MDMA and its complex biological effects.