Noradrenergic regulation of cocaine-seeking behaviors 公开

Schmidt, Karl (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/vx021f71t?locale=zh
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Abstract

Noradrenergic regulation of cocaine-seeking behaviors

By Karl T. Schmidt

Norepinephrine (NE) has been shown in human and laboratory studies to modulate relapse-like behaviors of drugs of abuse. The neuroanatomy and receptor subtypes mediating these effects are not as well characterized. Here, we discuss the contributions of noradrenergic signaling to psychostimulant-induced behaviors in animal models. The experiments in this dissertation focus on noradrenergic projections from the locus coeruleus to mesocorticolimbic brain regions and how these circuits influence drug-seeking and other operant behaviors. Alpha 1 adrenergic receptors in the medial prefrontal cortex, but not ventral tegmental area or nucleus accumbens, are necessary for drug-primed reinstatement, but not sufficient to reinstate in the absence of cocaine. Furthermore, blockade of all noradrenergic signaling prevents cocaine induced glutamate release in the prefrontal cortex. Stimulating NE neurons in the locus coeruleus with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) drives drug-seeking behaviors, but only when tested under conditions commonly used to test stress-induced reinstatement. Finally, selective activation of the locus coeruleus with optogenetics reinforces operant behavior at levels matching identical stimulation of dopamine neurons in the ventral tegmental area. Overall, these studies identify regions of noradrenergic influence important in relapse-like behavior and other motivated behaviors.

Table of Contents

TABLE OF CONTENTS


CHAPTERS PAGE

I. INTERACTIONS BETWEEN NORADRENERGIC SYSTEM AND PSYCHOMOTOR STIMULANTS 1

1.1Abstract 2

1.2 Cocaine Prevalence and Abuse in Society 3

1.3 Psychostimulants and Catecholamines 4

1.4 Adrenergic Receptor Subtypes 5

1.5 Compounds Targeting Adrenergic Receptors 7

1.6 Animal Models of Psychomotor Stimulant Effects 9

1.6.1 Locomotor Activity 9

1.6.2 Place Preference and Aversion 10

1.6.3 Anxiety 11

1.6.4 Drug Discrimination 12

1.6.5 Self-Administration 13

1.7 Norepinephrine Alteration of Psychostimulant-Induced

Behaviors 14

1.7.1 Locomotor Activity 14

1.7.2 Place Preference and Aversion 16

1.7.3 Anxiety 20

1.7.4 Drug Discrimination 22

1.7.5 Self-Administration 24

1.8 Optogenetic/Chemogenetic Control of Noradrenergic Neurons 31

1.9 Summary 34

II. NOREPINEPHRINE REGULATES COCAINE-PRIMED

REINSTATEMENT VIA α1-ADRENERGIC RECEPTORS IN THE MEDIAL PREFRONTAL CORTEX 37

2.1 Abstract 38

2.2 Introduction 40

2.3 Materials and Methods 43

2.4 Results 49

2.5 Discussion 53

III. CHEMOGENETIC MODULATION OF THE LOCUS COERULEUS ALONE OR IN COMBINATION WITH DRUG PRIME DURING REINSTATEMENT OF COCAINE SEEKING 64

3.1 Abstract 65

3.2 Introduction 66

3.3 Materials and Methods 69

3.4 Results 73

3.5 Discussion 75

IV. OPTOGENETIC ACTIVATION OF THE LOCUS COERULEUS AS A PRIMARY REINFORCER 85

4.1 Abstract 86

4.2 Introduction 87

4.3 Materials and Methods 91

4.4 Results 94

4.5 Discussion 97

V. DISCUSSION 106

5.1 Introduction 107

5.2 Norepinephrine and reinstatement of cocaine seeking 107

5.3 Clinical implications 113

5.4 Chemogenetic and optogenetic tools to study the noradrenergic system

and reinstatement 116

5.5 Conclusion 118

REFERENCES 123

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