The Role of Norepinephrine in Cocaine-Induced Reward, Anxiety, andRelapse Open Access

Abstract

Cocaine is a widely abused psychostimulant that acts by blocking monoamine transporters, thus increasing extracellular availability of dopamine (DA), norepinephrine (NE), and serotonin. DA and NE are synthesized in the same enzymatic pathway, with DA being converted to NE by the enzyme dopamine β-hydroxylase (DBH). Although DA is generally thought of as the primary neurotransmitter underlying the behavioral effects of psychostimulants, a role for NE signaling is now increasingly recognized. Furthermore, disulfiram, a non-specific DBH inhibitor, is efficacious at decreasing cocaine use in human addicts. Using mice with a genetic knockout of the Dbh gene that completely lack NE (Dbh -/- mice), and by administering disulfiram, we explored how DBH and NE modulate responses to cocaine. First, we found that Dbh -/- mice were more sensitive than control mice to the locomotor stimulating effects of cocaine, and this increased psychomotor response was associated with an increased density of high affinity-state striatal DA receptors. We then explored cocaine-induced reward behavior and found that Dbh -/- mice were more sensitive to both the rewarding and aversive properties of cocaine. However, in spite of this increased cocaine aversion, Dbh -/- mice exhibit a paradoxical insensitivity to acute cocaine-induced anxiety. This behavioral phenotype was mimicked in control mice following pretreatment with disulfiram or the β-adrenergic receptor antagonist propranolol. Interestingly, we found that while propranolol blocked cocaine-induced anxiety-like behavior in control mice, the α1-adrenergic receptor antagonist prazosin blocked the expression of cocaine-induced place preference. These results suggest a dissociation between the anxiogenic and rewarding properties of cocaine, and distinguish the specific adrenergic signaling pathways involved in these behaviors. Finally, we used the rat self-administration paradigm to assess whether pretreatment with disulfiram could alter cocaine-seeking behavior. Administration of disulfiram had no effect on the maintenance phase of cocaine self-administration behavior, but completely blocked the expression of cocaine-primed reinstatement. Understanding the mechanism of action by which disulfiram attenuates cocaine use will increase our knowledge about the role of NE in drug addiction, and will help identify novel targets for future exploration in medication development for drug dependence.

Table of Contents

CHAPTER 1: INTRODUCTION 1

1.1 Cocaine Abuse 2

1.2 Basic Characteristics of Norepinephrine and Dopamine Systems in the Brain 4

1.3 Norepinephrine and Dopamine Interactions 6

1.4 Disulfiram, Cocaine Abuse, and Dopamine Beta-Hydroxylase 8

1.5 Potential Mechanisms for Disulfiram Action on Cocaine Abuse 11

1.6 Dopamine β-Hydroxylase Knockout Mouse: A Novel Tool for Studying the Role of Norepinephrine and DBH in Drug Addiction 15

1.7 Rodent Behavioral Testing Paradigms 17

1.8 Summary 21

CHAPTER 2: DOPAMINE β-HYDROXYLASE KNOCKOUT MICE HAVE ALTERATIONS IN DOPAMINE SIGNALING AND ARE HYPERSENSITIVE TO COCAINE 25

2.1 Abstract 26

2.2 Introduction 27

2.3 Materials and Methods 29

2.4 Results 37

Basal and amphetamine-induced DA release is attenuated in Dbh -/- mice 37

Increased density of striatal high-affinity state DA receptors in Dbh -/- mice 38

Dbh -/- mice are hypersensitive to cocaine-induced locomotion 39

Altered cocaine reward and aversion in Dbh -/- mice 41

Prazosin blocks the expression of cocaine-induced place preference 42

2.5 Discussion 42

CHAPTER 3: NOREPINEPHRINE SIGNALING THROUGH β-ADRENERGIC RECEPTORS IS CRITICAL FOR THE EXPRESSION OF COCAINE-INDUCED ANXIETY 66

3.1 Abstract 67

3.2 Introduction 68

3.3 Materials and Methods 69

3.4 Results 73

Cocaine-induced anxiety is abolished in Dbh -/- mice 73

Pharmacological restoration of NE alters anxiety behavior in Dbh -/- mice 74

The DBH inhibitor disulfiram abolishes cocaine-induced anxiety in control mice 75

Blockade of β-adrenergic receptors attenuates cocaine-induced anxiety in Dbh +/- mice 75

Blockade of β-adrenergic receptors attenuates cocaine-induced anxiety in wildtype C57BL/6J mice 77

3.5 Discussion 77

CHAPTER 4: DISULFIRAM INHIBITS COCAINE-INDUCED REINSTATEMENT OF DRUG SEEKING BEHAVIOR IN RATS 92

4.1 Abstract 93

4.2 Introduction 95

4.3 Materials and Methods 98

4.4 Results 106

Intragastric injection of disulfiram has no effect on catecholamine levels 106

Intraparitoneal disulfiram injection decreases NE to DA ratio in rat brain tissue 107

Disulfiram has no effect on maintenance of cocaine self-administration 108

Disulfiram blocks the expression of cocaine-induced reinstatement 109

4.5 Discussion 110

CHAPTER 5: CONCLUSIONS AND FUTURE DIRECTIONS 126

5.1 The Role of Norepinephrine in Cocaine-Induced Reward, Anxiety, and Relapse 127

5.2 Implications for Disulfiram Mechanism of Action on Cocaine Abuse 129

5.3 Future Directions 133

5.4 Specific DBH inhibition 135

REFERENCES 141

APPENDIX 1: CONTINUOUS MINIPUMP DELIVERY OF DOPAMINE β-HYDROXYLASE INHIBITORS ALTERS COCAINE-INDUCED LOCOMOTION 153

A1.1 Abstract 154

A1.2 Introduction 155

A1.3 Materials and Methods 156

A1.4 Results 163

Chronic disulfiram does not lead to significant weight change 163

Chronic disulfiram attenuates cocaine-induced locomotion 163

Chronic nepicastat increases cocaine-induced locomotion 164

Chronic disulfiram and nepicastat do not alter cocaine-induced anxiety 165

The effect of chronic nepicastat on cocaine-induced place preference 165

Chronic disulfiram does not alter catecholamine levels 166

A1.5 Discussion 166

A1.6 References 185

APPENDIX 2: REDUCED ANTICONVULSANT EFFICACY OF VALPROIC ACID IN DOPAMINE β-HYDROXYLASE KNOCKOUT MICE 187

A2.1 Abstract 188

A2.2 Introduction 189

A2.3 Materials and Methods 191

A2.4 Results 194

Effects of acute VPA administration on flurothyl-induced seizures in Dbh +/- and Dbh -/- mice 194

The effects of reboxetine/VPA coadministration on flurothyl-induced seizures 196

The effects of chronic VPA administration on flurothyl-induced seizures in Dbh +/- and Dbh -/- mice 197

A2.5 Discussion 198

A2.6 References 209

About this Dissertation

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Keyword	Self-Administration Cocaine Dopamine Beta-Hydroxylase Disulfiram Norepinephrine Anxiety Reward
Committee Chair / Thesis Advisor	Weinshenker, David, Emory University
Committee Members	Miller, Gary W, Emory University Hall, Randy A, Emory University Holmes, Philip, University of Georgia Howell, Leonard, Emory University

Last modified

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	The Role of Norepinephrine in Cocaine-Induced Reward, Anxiety, andRelapse ()	2018-08-28 15:28:01 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions