Seizure Susceptibility and Epileptogenesis in Depression-Sensitive Rats Público

Abstract

A bi-directional comorbidity between depression and epilepsy has been established clinically, with patients with epilepsy being at an increased risk of developing depression, and patients with depression having an elevated incidence of epilepsy. Despite this bi-directionality, animal models of this comorbidity have primarily focused on epilepsy-related depression. Much less attention has been given to depression-related epilepsy, even though this direction of the comorbidity also has a negative impact on quality of life, treatment efficacy, and prognosis for the patient. In order to better understand this direction of the comorbidity, we assessed seizure- and epilepsy-related behaviors in a rat line selectively bred for a depression-like phenotype, the Swim Low-Active rat (SwLo). SwLo rats were selectively bred based on a depression-susceptible phenotype in the forced swim test (increased floating), and demonstrate other anhedonic-like phenotypes as well. Their counterparts, the Swim High-Active rats (SwHi), were selectively bred for a depression-resistant phenotype (increased struggling on the forced swim test). We have here demonstrated increased susceptibility to chemically- and electrically-induced seizures in the SwLo rats, as well as elevated susceptibility to the development of epilepsy (i.e. epileptogenesis) in certain parameters of the electrical kindling paradigm. We have thus validated these rats as a rodent model of comorbid epilepsy and depression from the direction of depression-related epilepsy, making them the first model of this kind. An additional goal in generating an animal model of this comorbidity was to provide a tool for screening novel therapies for safety and efficacy in treating comorbid epilepsy and depression. We have therefore assessed chronic aerobic exercise for antidepressant and anticonvulsant effects in the SwLo rats, allowing us to demonstrate the safety, efficacy, and selectivity of this therapeutic strategy in the comorbidity. These studies have characterized a rodent model of depression-related epilepsy, the first model of its kind, providing a novel tool for uncovering the mechanisms underlying this comorbidity and screening novel therapeutics for safety and efficacy in treating comorbid epilepsy and depression.

Table of Contents

Table of Contents CHAPTER 1: RHYTHM AND BLUES: ANIMAL MODELS OF

EPILEPSY AND DEPRESSION COMORBIDITY 1

1.1 Abstract 2 1.2 Introduction 3

1.3 Existing animal models of depression and epilepsy comorbidity 5

1.3.1 Paradigms 5 1.3.2 Chemical convulsant-induced seizures 7 1.3.3 Electrically induced seizures 9 1.3.4 Genetic/selective breeding models 11

1.3.5 Limitations of animal models 14

1.4. Potential mechanisms and therapeutic targets 16

1.4.1 Neurotransmitters of interest 16 1.4.2 Other mechanisms of interest 25 1.4.3 Brain regions of interest 31 1.4.4 Non-pharmacological therapies 32

1.5 Conclusion 34

1.6 Acknowledgements 37 CHAPTER 2: SEIZURE SUSCEPTIBILITY AND EPILEPTOGENESIS IN A RAT MODEL OF EPILEPSY AND DEPRESSION COMORBIDITY 40 2.1 Abstract 41 2.2 Introduction 42 2.3 Methods 44 2.4 Results 49

Acute pilocarpine-induced seizure susceptibility 49

Pilocarpine pharmacokinetics 49

Increasing current electroshock seizures 50

Pilocarpine-induced spontaneous seizures 50

Electrical kindling 51 2.5 Discussion 51 2.6 Acknowledgements 57 CHAPTER 3: ANTIDEPRESSANT AND ANTICONVULSANT EFFECTS OF EXERCISE IN A RODENT MODEL OF EPILEPSY AND DEPRESSION COMORBIDITY 61 3.1 Abstract 62 3.2 Introduction 63 3.3 Methods 65 3.4 Results 67 3.5 Discussion 68 3.6 Acknowledgements 73 CHAPTER 4: CONCLUSIONS AND FUTURE DIRECTIONS 77 4.1 Summary 78

4.2 Seizure susceptibility and epileptogenesis in the SwLo rat line 79

4.3 Antidepressant and anticonvulsant effects of exercise in SwLo rats 81

4.4 Future directions 83

Seizure susceptibility and epileptogenesis in the SwLo rat line 84

Antidepressant and anticonvulsant effects of exercise in SwLo rats 87

REFERENCES 91 APPENDIX 1: mRNA EXPRESSION ANALYSIS OF A RODENT

MODEL OF EPILEPSY AND DEPRESSION COMORBIDITY 128

A1.1 Abstract 129 A1.2 Introduction 130 A1.3 Methods 134 A1.4 Results 137 A1.5 Discussion 139 A1.6 Acknowledgements 143 A1.7 References 149 APPENDIX 2: OPERANT PSYCHOSTIMULANT

SELF-ADMINISTRATION IN A RAT MODEL OF DEPRESSION 158

A2.1 Abstract 159 A2.2 Introduction 160 A2.3 Methods 162 A2.4 Results 167

SwLo rats have decreased amphetamine-induced locomotion 167

Amphetamine- and cocaine-seeking behavior during progressive ratio 168

and reinstatement responding is attenuated in SwLo rats

Food-primed reinstatement of food seeking is reduced in SwLo rats 169

A2.5 Discussion 169 A2.6 Acknowledgements 174 A2.7 Conflict of Interest 174 A2.8 References 179

Tables & Figures CHAPTER 1: RHYTHM AND BLUES: ANIMAL MODELS OF EPILEPSY AND DEPRESSION COMORBIDITY Table 1.1 Characterization of animal models of epilepsy and depression comorbidity 38

CHAPTER 2: SEIZURE SUSCEPTIBILITY AND EPILEPTOGENESIS

IN A RAT MODEL OF EPILEPSY AND DEPRESSION COMORBIDITY

Figure 2.1 SwLo rats have a shorter latency to pilocarpine-induced seizures

than SwHi rats that is independent of pilocarpine pharmacokinetics 58

Figure 2.2 SwLo rats are more susceptible to electrically-induced seizures

than SwHi rats 59

Figure 2.3 Kindling parameters in SwLo and SwHi rats 60

CHAPTER 3: ANTIDEPRESSANT AND ANTICONVULSANT EFFECTS

OF EXERCISE IN A RODENT MODEL OF EPILEPSY AND

DEPRESSION COMORBIDITY

Figure 3.1 Average daily voluntary exercise in SwLo and SwHi rats 74

Figure 3.2 Antidepressant effects of exercise on FST struggling in SwLo rats 75

Figure 3.3 Anticonvulsant effects of exercise on latency to pilocarpine-induced

seizure in SwLo rats 76

CHAPTER 4: CONCLUSIONS AND FUTURE DIRECTIONS

Figure 4.1 Epilepsy- and depression-related phenotypes of the SwLo rat 90

APPENDIX 1: mRNA EXPRESSION ANALYSIS OF A RODENT

MODEL OF EPILEPSY AND DEPRESSION COMORBIDITY

Table A1.1 Primer sequences used for qRT-PCR 144

Table A1.2 Differentially expressed genes with higher expression in

SwHi vs. SwLo 145

Table A1.3 Differentially expressed genes with higher expression in

SwLo vs SwHi 146

Figure A1.1 Differential genetic expression of SwHi and SwLo rats 147

Figure A1.2 Normalized C(t) analysis of candidate gene expression in

SwLo and SwHi rats 148

APPENDIX 2: OPERANT PSYCHOSTIMULANT

SELF-ADMINISTRATION IN A RAT MODEL OF DEPRESSION

Figure A2.1 Amphetamine-induced locomotion is reduced in SwLo rats 175

Figure A2.2 Amphetamine self-administration in SwHi and SwLo rats 176

Figure A2.3 Cocaine self-administration and reinstatement in SwHi

and SwLo rats 177

Figure A2.4 Food self-administration and reinstatement in SwHi

and SwLo rats 178

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Palabra Clave	Epilepsy Rat Depression Comorbidity Exercise Genetics
Committee Chair / Thesis Advisor	Weinshenker, David, Emory University
Committee Members	Palmer, Abraham, University of Chicago Williams, Katherine A, Emory University Weiss, Jay M, Emory University Escayg, Andrew, Emory University Ressler, Kerry, Emory University

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