Identification of Mechanisms Underlying the Reduction of Cocaine Seeking by Exercise Open Access

Ogbonmwan, Yvonne (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/pz50gw22z?locale=en
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Abstract

Relapse represents one of the most significant problems in the long-term treatment of drug addiction. The current standard of care for substance use disorder combines behavioral and pharmacological treatments. Behavioral treatments provide some modest efficacy for addiction but more effective treatment is needed to significantly improve the outcomes of individuals diagnosed with substance use disorder. In recent human and animal studies, chronic exercise has shown to be a promising adjunct therapy for drug addiction. Additionally, while there are many pharmacological treatments for several classes of drugs of abuse, there are no FDA-approved pharmacotherapies to treat addiction to cocaine or other psychostimulants. The experiments described in this dissertation assess changes in drug-seeking behavior using an animal model of relapse and reinstatement, in response to chronic exercise or galanin receptor activation. We assessed the efficacy of chronic exercise as an interventional therapy in an animal model of cocaine addiction for both cocaine-primed and stress-induced reinstatement. We also investigated galanin receptor activation as a novel target for the treatment of cocaine addiction. Using rodent cocaine self-administration we show how galanin receptor activation alters responses to drugs of abuse. We also describe how galanin receptor activation alters extracellular levels of cocaine in the mesocorticolimbic brain circuit, which may underlie the behavioral effect of galanin receptor activation on responses to cocaine during reinstatement.


Table of Contents

CHAPTER 1: BEHAVIORAL AND PHAMRACOLOGICAL TREATMENTS FOR COCAINE ADDICTION………….1

1.1 Abstract…………………………………………….…………………………………………………………………..………………………….......2

1.2 Introduction…………………………………………….……………………………………………………......…..…………………………........3

1.3 Animal Models of Drug Addiction………………………………………….…………………………….…..…………………………........3

1.4 Effect Of Cocaine on the Mesocorticolimbic Circuitry……………………………………………..…………………………........7

1.5 Treatments………………………………...…………………………...……………………………………….....…..………………………….....10

1.5.1 Pharmacotherapies………………………………...…………………………………………….….......…..………………………….....10

1.5.2 Behavioral Therapies….………………………………...……………………………...…………......………..…………………………...19

1.6 The Protective Effects of Exercise…………………...…………………………………………………..…..…………………………...21

1.6.1 Therapeutic Effects of Exercise on Psychiatric Illnesses……………………...….….…..……………..…..………………21

1.6.2 Exercise Induced Molecular Changes………………………….……………………...….…..…......……………..…..…………23

1.7 Experimental Design and Rationale………………………….………………………………..………….....…....……………..…..……28

CHAPTER 2: THE EFFECTS OF POST-EXTINCTION EXERCISE ON COCAINE-PRIMED AND STRESS-INDUCED REINSTATEMENT OF COCAINE SEEKING IN RATS…………………………..…..……………..…..………………33

2.1 Abstract…………………………………………….………………………………………………………..……………………..…..……………………34

2.2 Introduction…………………………………………………………………………………………………………………..…..……………………36

2.3 Materials and Methods………………………………………………………………….………………………………..…..…………………………39

2.4 Results…………………………………………………………………………………………………………………..…..………………………….......46

2.5 Discussion………………………………………………………………………………………………………………..…...…..……………......49

2.6 Acknowledgement……………………………………………………………………………………………………………...........................54

CHAPTER 3: THE GALANIN RECEPTOR AGONIST, GALNON, ATTENUATES COCAINE-INDUCED REINSTATEMENT AND DOPAMINE OVERFLOW IN THE FRONTAL CORTEX…………………………………………........………………………….…59

3.1 Abstract…………………………………………….……………………………………………………………………………………………60

3.2 Introduction…………………………………………………………………………………………………………………………………61

3.3 Materials and Methods………………………………………….………………………………………………………………………62

3.4 Results………………………………………………………………………………………………………………………………………………70

3.5 Discussion………………………………………….……………………………………………………….……..…………………………………......75

3.6 Acknowledgement ………………………………………….……………………………………………....………………………....…….....……83

CHAPTER 4: CONCLUSIONS AND FUTURE DIRECTIONS………….……….……………………………….…..……….94

4.1 Summary…………………………………………….…………………………………………………………....…………………….…..………95

4.2 Exercise as an Interventional Therapy for Cocaine Dependence……………………………...………….…..………96

4.3 Potential Design for Future Clinical Studies Assessing Exercise as a Treatment for Cocaine Addiction…………………………………………………….…………………………………………………………....…………………….…..……105

4.4 Molecular Mechanisms Underlying the Ability of Exercise to Attenuate Relapse-Like Behavior: Focus on Galanin……………………………………………….…………………………………………………………....…………………….…..………...107

4.4.1 Drug Responses………….……….…………………………………………………….……………….………………………………107

4.4.2 Exercise increases Galanin mRNA in the LC………….……….………………………...………………………………108

4.5 Galnon And Cocaine-Primed Reinstatement………….……….…………………..…………………………………….………109

4.6 Neuroanatomical and Neurochemical Substrates Underlying the Effect of Galanin Signaling on Cocaine-Primed Reinstatement..…………………………………………….………………………………………………....……………………....…………….…………....110

4.7 Linking Exercise-Induced Increases in Galanin mRNA in the LC to Attenuation of Cocaine-Primed Reinstatement…………………………………………………….…………………………………………………………....………………………….113

4.7.1 Stress-Induced Reinstatement………….……….…………………..…………………………………….…………………………...115

4.8 Galanin Receptors Contributing to Reinstatement…………..………………………………………………………………....116

4.9 BDNF and Neurogenesis as Possible Mechanisms That May Account for Attenuation of Reinstatement by Exercise…………………………………………………….…………………………………………………………....…………………….…..….119

4.10 Potential Side effects of Pharmacotherapies that Target Galanin……………………………………………………...120

4.11 Conclusion………….……….…………………..…………………………………………………………………………………………….....125

REFERENCES. …………………………………………….…………………………………………………….……………………………....129

APPENDIX: DISULFIRAM ATTENUATES DRUG-PRIMED REINSTATEMENT OF COCAINE SEEKING VIA INHIBITION OF DOPAMINE Β-HYDROXYLASE…………………………….…....……………....……………………………………………………………….174

A.1 Abstract…………………………………………….……………………………………………………..………………………..……….....175

A.2 Introduction…………………….………………………………………………………………….………........……………………........176

A.3 Materials and Methods……………………………………………………………….……………………......…………........………..179

A.4 Results……………………………………………………………….…………………………………………...............................…..187

A.5 Discussion………………………………………………………………………………….………………………………........……………191

A.6 Disclosure/Conflict of Interest…………………………………………………………………………………………........………….195

A.7 Acknowledgement……………………………………………………………………………………………………………........………….196

A.8 References…………………………………………………………………………………………………….……………………........……….205

Tables & Figures

CHAPTER 1: BEHAVIORAL AND PHAMRACOLOGICAL TREATMENTS FOR COCAINE ADDICTION

Figure 1.1 Self-Administration Model ………………………….………………………………………………………………........30

Figure 1.2 Mesocorticolimbic Circuit………………………….………………………………………………………………........……….31

Figure 1.3 Effect of Cocaine on Monoamine Transmission………………………………………........…………………….32

CHAPTER 2: THE EFFECTS OF POST-EXTINCTION EXERCISE ON COCAINE-PRIMED AND STRESS-INDUCED REINSTATEMENT OF COCAINE SEEKING IN RATS

Figure 2.1 Voluntary wheel running after cocaine self-administration and extinction……………………………..55

Figure 2.2 Post-extinction exercise attenuates cocaine-primed reinstatement……...............……………..……56

Figure 2.3 Exercise has no effect on foot shock-induced reinstatement …………………………………..……….....57

Figure 2.13 Exercise increases galanin mRNA in the LC but not A2……………………………………..……….....…...58

CHAPTER 3: THE GALANIN RECEPTOR AGONIST, GALNON, ATTENUATES COCAINE-INDUCED REINSTATEMENT AND DOPAMINE OVERFLOW IN THE FRONTAL CORTEX

Figure 3.1 Galnon reduces cocaine-induced hyperactivity………………………………………...……..……….....…....84

Figure 3.2 Galnon attenuates cocaine-induced increases in dopamine overflow in the frontal cortex……….85

Figure 3.3 Galnon does not alter cocaine-induced increases in dopamine overflow in the nucleus accumbens…………………………………………………………………………………………………….……………………........……….86

Figure 3.4 Galnon has no effect on cocaine self-administration…………………………………………………………...…….87

Figure 3.5 Galnon attenuates cocaine-primed reinstatement………………………………………………………………...….88

Figure 3.6 Galnon has no effect on food self-administration………………………………………………………...…………89

Figure 3.7 Effects of galnon on the pattern of cocaine self-administration……………….……………...……………90

Figure 3.8 Effects of galnon on the pattern of food self-administration……………….…………...……………………91

Figure 3.9 Galnon attenuates food-primed reinstatement……………….…………………………...…………………………92

Figure 3.10 How galnon may be reducing cocaine-induced behaviors……………….………...…………………………93

CHAPTER 4: CONCLUSIONS AND FUTURE DIRECTIONS

Figure 4.1 Proposed exercise-induced reduction of norepinephrine transmission via galanin. ………….……127

APPENDIX: DISULFIRAM ATTENUATES DRUG-PRIMED REINSTATEMENT OF COCAINE SEEKING VIA INHIBITION OF DOPAMINE B-HYDROXYLASE

Figure A1.1 Catecholamine biosynthetic pathway…………………………………………………….……….…………………..…197

Figure A1.2 Effect of disulfiram on catecholamine levels in the rat prefrontal cortex…………………..…..…..198

Figure A1.3 Disulfiram does not affect maintenance of cocaine self-administration………………..……………..199

Figure A1.4 Disulfiram blocks cocaine-primed reinstatement………………………………….……………..…………………200

Figure A1.5 Effect of nepicastat on catecholamine levels in the rat prefrontal cortex……..………………………201

Figure A1.6 Nepicastat does not affect maintenance of cocaine self-administration………..………………………202

Figure A1.7 Nepicastat blocks cocaine-primed reinstatement……………………………………..…………………..........203

Figure A1.8 Nepicastat does not affect food-primed reinstatement………………..………………………………….…....204

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