Seizure Susceptibility and Epileptogenesis in Depression-Sensitive Rats Open Access
Epps, Sunshine Alisha (2013)
Published
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 31.3 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 111.3.5 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 321.5 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 49Acute pilocarpine-induced seizure susceptibility 49
Pilocarpine pharmacokinetics 49Increasing 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 784.2 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 83Seizure 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 RODENTMODEL 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 PSYCHOSTIMULANTSELF-ADMINISTRATION IN A RAT MODEL OF DEPRESSION 158
A2.1 Abstract 159 A2.2 Introduction 160 A2.3 Methods 162 A2.4 Results 167SwLo 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
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 59Figure 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 76CHAPTER 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 145Table A1.3 Differentially expressed genes with higher expression in
SwLo vs SwHi 146Figure 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 148APPENDIX 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 177Figure A2.4 Food self-administration and reinstatement in SwHi
and SwLo rats 178About this Dissertation
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