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

Abstract

Abstract
Neuropharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy")
and its stereoisomers
By
Kevin Sean Murnane

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-HT2A 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-HT2A 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.

Table of Contents

Table of Contents

Chapter 1: General Introduction

History of MDMA...1-4
Epidemiology of MDMA abuse...4-7
In vivo pharmacology of psychomotor-stimulants...8-12

In vivo pharmacology of hallucinogens...12-19
Interoceptive and behavioral effects of MDMA...19-23
Mechanism of action of MDMA...23-30
Summary and study aims...30-31

Chapter 2: Interoceptive and behavioral effects of MDMA
Introduction...34-40
Materials and methods...41-49
Results...50-56
Discussion...57-67

Chapter 3: Endocrine and neurochemical effects of MDMA
Introduction...76-81
Materials and methods...81-88
Results...89-100
Discussion...100-112

Chapter 4: Neuroactivational effects of MDMA
Introduction...128-131
Materials and methods...132-144
Results...144-148
Discussion...148-156

Chapter 5: General discussion
Summary of findings...167-170
Relevance for the study of MDMA...170-185


List of Tables and Figures
Chapter 1: General Introduction
Figure 1-1 Chemical structure of MDMA...32

Chapter 2: Interoceptive and behavioral effects of MDMA
Figure 2-1 Chemical structure of substituted compounds...69
Figure 2-2 Tests of amphetamine substitution...69
Figure 2-3 Tests of cocaine substitution...70
Figure 2-4 Tests of 2C-T-7 substitution...70
Figure 2-5 Tests of DPT substitution...71
Figure 2-6 Effects of amphetamine on sleep...71
Figure 2-7 Effects of MDMA and its stereoisomers on sleep...72

Figure 2-8 Pretreatment time dependence of M100907...72
Figure 2-9 Effects of M100907 on sleep disruption by S,R(+/-)-MDMA...73
Figure 2-10 Effects of M100907 on sleep disruption by S(+)-MDMA...73
Figure 2-11 Effects of M100907 on sleep disruption by R(-)-MDMA...74

Chapter 3: Endocrine and neurochemical effects of MDMA
Table 3-1 Basal endocrine and neurohemical levels...113
Figure 3-1 Chemical structure of test compounds...114
Figure 3-2 Amphetamine and mCPP-elicited prolactin secretion...115
Figure 3-3 Correlation between 5-HT release and prolactin secretion...116
Figure 3-4 Prolactin secretion elicited by MDMA or its stereoisomers...117
Figure 3-5 Dopamine release elicited by MDMA or its stereoisomers...118
Figure 3-6 5-HT release elicited by MDMA or its stereoisomers...119
Figure 3-7 5-HT release elicited by R(-)-MDMA at 3 mg/kg...119
Figure 3-8 Determination of an in vivo interaction of the stereoisomers on dopamine release...120
Figure 3-9 Effects of M100907 on basal dopamine levels...120
Figure 3-10 Effects of M100907 on dopamine release by amphetamine...121
Figure 3-11 Effects of M100907 on dopamine release by S(+)-MDMA...122
Figure 3-12 Effects of fluoxetine on prolactin secretion by S,R(+/-)-MDMA...123
Figure 3-13 Effects of fluoxetine on prolactin secretion by R(-)-MDMA...124
Figure 3-14 Effects of fluoxetine on serotonin release by R(-)-MDMA...125
Figure 3-15 Effects of M100907 on prolactin secretion by R(-)-MDMA....125
Figure 3-15 Effects of a combination of M100907 and fluoxetine on prolactin secretion by R(-)-MDMA...126


Chapter 4: Neuroactivational effects of MDMA
Table 4-1 Translational and rotational spatial movements...157
Figure 4-1 Pictorial representation of the custom imaging apparatus...158
Figure 4-2 Physiological parameters of subjects...159
Figure 4-3 Effects of field map correction on imaging data...160
Figure 4-4 Translational and rotational spatial movements...161
Figure 4-5 BOLD fMRI response to visual stimulation...162
Figure 4-6 BOLD fMRI response to cocaine...162
Figure 4-7 Dose-effect determination of BOLD response to S,R(+/-)-MDMA...163
Figure 4-8 Figure 4-7 reploted in sagital section...164
Figure 4-9 Figure 4-6 reploted as group data and in sagital section....165
Figure 4-10 BOLD fMRI response to S(+)-MDMA....166
Figure 4-11 Dose-effect determination of BOLD response to R(-)-MDMA...166

Chapter 5: General discussion
Table 5-1 Novel receptor affinity determinations for each form of MDMA...186

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
Parola chiave	MDMA Neuropharmacology Rhesus Discrimination fMRI Sleep microdialysis
Committee Chair / Thesis Advisor	Howell, Leonard, Emory University
Committee Members	Votaw, John R, Emory University Keilholz, Shella D, Emory University Smith, Yoland, Emory University Zola, Stuart M, Emory University

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