Neuropharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and its stereoisomers Open Access
Murnane, Kevin (2010)
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
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