Modulators of behavioral sensitivity to cocaine following dopamine β-hydroxylase (DBH) inhibition Open Access

Gaval, Meriem (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/qf85nc12g?locale=en
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Abstract

Abstract
Modulators of behavioral sensitivity to cocaine following dopamine β-hydroxylase (DBH) inhibition

Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE), playing a direct role in determining the DA/NE ratio in noradrenergic neurons. DA and NE are both involved in the modulation of reward and reinforcement of natural stimuli and drugs of abuse. Recent evidence from human laboratory studies and animal studies suggests that DBH inhibition results in alterations in behavioral responses to psychostimulants. Here, we discuss the individual contributions of DA and NE to psychostimulant-induced behaviors in animal models, as well as the functional interactions between the dopaminergic and noradrenergic system that may underlie the altered responses to psychostimulants following DBH inhibition. The experiments described in this dissertation describe the changes in cocaine-induced behaviors following pharmacological and genetic DBH inhibition as well as examine the molecular and cellular consequences of this manipulation, which may underlie the behavioral effects on psychostimulant-induced behaviors.

Modulators of behavioral sensitivity to cocaine following dopamine β-hydroxylase (DBH) inhibition
By
Meriem Gaval
Doctor of Philosophy
Graduate Division of Biological and Biomedical Sciences
Neuroscience
Advisor: David Weinshenker, PhD
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of
Doctor of Philosophy in Neuroscience
2011

Table of Contents

TABLE OF CONTENTS

I. GENETIC AND PHARMACOLOGICAL MODULATORS OF COCAINE SENSITIVITY: IMPLICATIONS FOR ADDICTION THERAPIES...1

1.1 Abstract...2
1.2 Cocaine addiction...3
1.3 Catecholamines and cocaine addiction...4

1.3.1 Dopamine and psychostimulant-induced behaviors...4
1.3.2 Norepinephrine and psychostimulant-induced behaviors...15

1.4 Dopamine and norepinephrine interactions...22
1.5 DBH inhibition animal models...24
1.6 Experimental design and rationale...26

II. CHRONIC GENETIC OR PHARMACOLOGICAL REDUCTION OF NORADRENERGIC TONE LEADS TO BEHAVIORAL HYPERSENSITIVITY TO COCAINE...34

2.1 Abstract...35
2.2 Introduction...36
2.3 Materials and methods...38
2.4 Results...41
2.5 Discussion...43

III. MOLECULAR AND CELLULAR CHANGES FOLLOWING DBH INHIBITION...55

3.1 Abstract...56
3.2 Introduction...57
3.3 Materials and methods...59
3.4 Results...66
3.5 Discussion...69

IV. THE ROLE OF DBH INHIBITION IN THE MECHANISM OF ACTION OF DISULFIRAM...86

4.1 Abstract...87
4.2 Introduction...89

4.2.1 Cocaine addiction...89
4.2.2 Disulfiram as a pharmacotherapy for alcohol and cocaine addiction...90

4.3 Materials and methods...96
4.4 Results...99
4.5 Discussion...102

V. DISCUSSION...119

5.1 Introduction...120
5.2 Dopamine β-Hydroxylase inhibition and cocaine-induced behaviors...121
5.3 Dopamine receptor signaling...124

5.3.1 Changes in dopamine signaling proteins following selective dopamine β-hydroxylase inhibition...127
5.3.2 β-arrestin2 and dopamine-dependent behaviors...128
5.3.3 Changes in nucleus accumbens cellular responses following selective dopamine β-hydroxylase inhibition...129
5.3.4 β-arrestin2 and nucleus accumbens cellular responses...130

5.4 Putative mechanism of action of disulfiram...131
5.5 Conclusion...134

VI. REFERENCES...138

VII. APPENDICES...197

A1. EFFECTS OF DISULFIRAM AND DOPAMINE β-HYDROXYLASE GENOTYPE ON COCAINE-INDUCED SEIZURES...197

A1.1 Abstract...198
A1.2 Introduction...199
A1.3 Methods...201
A1.4 Results...204
A1.5 Discussion...206
A1.6 References...217

A2. DISULFIRAM ATTENUATES DRUG-PRIMED REINSTATEMENT OF COCAINE-SEEKING VIA INHIBITION OF DOPAMINE β-HYDROXYLASE...225

A2.1Abstract...226
A2.2 Introduction...227
A2.3 Methods...229

A2.4 Results...237
A2.5Discussion...241
A2.6 References...253

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