Stereospecificity of the prosocial and neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) in mice Public

Abstract

3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that became popular as a recreational drug (ecstasy) and therapeutic tool during the late 1970's and early 1980's. Escalating recreational use led to its prohibition, but scientific interest in the drug has persisted due to its unique prosocial effects. Under clinical observation, volunteers report that MDMA increases feelings of closeness towards others, empathy, and sociability. In addition to these acute effects, there is accumulating evidence that MDMA can have powerful and enduring therapeutic benefits. Recent clinical trials have observed that MDMA is effective in treating post-traumatic stress disorder and social anxiety in adults with autism. Large Phase III clinical trials are moving forward despite no clear mechanistic understanding of why MDMA is therapeutically useful. An appropriate animal model with which to evaluate the neurobiological mechanisms of MDMA-induced prosocial behavior and therapeutic-like effects is needed. A more complete understanding of MDMA is especially important because of its widespread illicit use and the risk of serious adverse effects that may accompany its use. MDMA is neurotoxic and can produce potentially lethal hyperthermia even at moderate doses. There is thus significant impetus to isolate the mechanisms of MDMA's prosocial and therapeutic effects so that new therapeutics can be developed that have fewer side effects and lower potential for abuse. To probe the pharmacological mechanisms of MDMA, a mouse model was developed using repeated intermittent drug treatments to elicit robust prosocial behaviors. To determine if these effects are stereospecific, the two enantiomers of MDMA were tested using this paradigm. Although less potent, (-)-MDMA recapitulated the prosocial effects of racemic MDMA, without any locomotor stimulant side effects. (-)-MDMA and racemic MDMA stimulated oxytocinergic neurons; release of this neuropeptide has been suggested as an important factor underlying the unique social effects of MDMA. In contrast, (+)-MDMA, which has previously been considered the active isomer because of its higher potency, had no significant prosocial effects and did not significantly stimulate oxytocinergic neurons. To determine if (-)-MDMA could be a safer therapeutic option than traditional MDMA, markers of neurotoxicity were evaluated postmortem. In comparison to racemic MDMA, (-)-MDMA produced no evidence of neurotoxicity and did not produce hyperthermia, even at very high doses. These results indicate that the prosocial effects of MDMA are separable from the stimulant, neurotoxic, and thermogenic effects of the drug, and suggest that (-)-MDMA could be a more viable therapeutic option than racemic MDMA.

Table of Contents

Table of Contents

Chapter 1. Introduction

A. The History and Current Use of MDMA…………………………………………..1

B. Pharmacology of MDMA………………………………………………………….5

C. Prosocial Effects and Therapeutic Use of MDMA………………………………..8

D. Lethality and Toxicity of MDMA………………………………………………..15

E. Summary and Experimental Rationales…………………………………………..26

F. Figures………………………………...…………………………………………..29

Chapter 2. Sensitization to the prosocial effects of MDMA

A. Introduction……………………………………………………………………….31

B. Methods…………………………………………………………………………..35

C. Results……………………………………………………………………………41

D. Discussion……………………………………………………………………..…45

E. Figures……………………………………………………………………………53

Chapter 3. Stereoselectivity of MDMA-induced prosocial behavior

A. Introduction………………………………………………………………………60

B. Methods…………………………………………………………………………..63

C. Results……………………………………………………………………………66

D. Discussion…………………………………………………………………………68

E. Figures ……………………………………………………………………………77

Chapter 4. Separating the Agony from Ecstasy

A. Introduction……………………………………………………………………….81

B. Methods……………………………………………………………………………84

C. Results ………………………………………………………………………….…88

D. Discussion…………………………………………………………………………89

E. Figures………………………………………………………………………….…95

Chapter 5. Conclusions
A. Key Findings……………………………………………………………………...99

B. Future Directions…………………………………………………………………103

C. Overcoming Prohibition…………………………………………………………105

D. The Hope for MDMA …………………………………………………………..111

Acknowledgments…………………………………………………………………………..113

Appendix A…………………………………………………………………………………115

References…………………………………………………………………………………..120

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience Health Sciences, Pharmacology
Mot-clé	MDMA Ecstasy
Committee Chair / Thesis Advisor	Howell, Leonard, Emory University
Committee Members	Walker, Lary C, Emory University Hall, Randy A, Emory University Weinshenker, David, Emory University Young, Larry J, Emory University Gourley, Shannon L, Emory University

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