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The Endocannabinoid System As a Novel Target in The THE ENDOCANNABINOID SYSTEM AS A NOVEL TARGET IN THE PATHOPHYSIOLOGY AND TREATMENT OF DEPRESSIVE ILLNESS by MATTHEW NICHOLAS HILL B.Sc., The University of British Columbia, 2002 M.A., The University of British Columbia, 2004 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Psychology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2008 © Matthew Nicholas Hill, 2008 ( / ABSTRACT The endocannabinoid system is a neuromodulatory system which has recently gained attention in the pathophysiology and treatment of depressive illness. However, to date, the research investigating these relationships has been sparse. This dissertation aimed to further this understanding by examining the extent to which the activity of the endocannabinoid system (1) responds to a variety of regimens which reduce depression, (2) responds in an animal model of depression, and (3) differs in humans diagnosed with major depression. In Chapter 2 it was demonstrated that the cannabinoid CB1 receptor is upregulated in the hippocampus and hypothalamus following long-term treatment with the tricyclic antidepressant desipramine. In addition, it was also found that this increase in CB1 receptor activity contributed to the stress-attenuating effects of desipramine, as pharmacological antagonism of the CB1 receptor prevented the ability of desipramine treatment to suppress activation of the hypothalamic-pituitary-adrenal axis in response to stress. In Chapter 3, it was found that providing rodents with free access to a running wheel for 8 days resulted in a robust increase in hippocampal endocannabinoid signaling. This increase in endocannabinoid activity was, in turn, required for voluntary exercise to increase the proliferation of progenitor cells in the dentate gyms of the hippocampus. In Chapter 4 it was revealed that repeated exposure of rodents to electroconvulsive shock evokes a coordinate sensitization of amygdalar CB1 receptor signaling with a suppression of prefrontal cortical endocannabinoid activity. In Chapter 5 it was demonstrated that subcortical endocannabinoid activity is dampened in the chronic unpredictable stress model of depression, while prefrontal cortical CB1 receptor binding is increased. Concurrent treatment with the antidepressant imipramine was capable of reversing some, 11 but not all, of these changes. In Chapter 6, it was found that the circulating content of the endocannabinoid 2-arachidonoylglycerol was significantly reduced in women diagnosed with major depression. These data collectively provide evidence for the hypothesis that deficient endocannabinoid signaling may be involved in the etiology of depression, and that pharmacological augmentation of endocannabinoid neurotransmission may be a suitable target for the development of novel antidepressants. 111 TABLE OF CONTENTS Abstract ii Table of Contents iv List of Tables vi List of Figures viii Abbreviations x Acknowledgements xii Co-authorship Statement xiv CHAPTER 1 General Introduction 1 1.1 Current Status of Antidepressant Treatments: Focus on Monoaminergic Neurotransmission 2 1.2 Neurobiological Theories of Depression: The Hypothalamic-Pituitary-Adrenal Axis, Neuroplasticity and the Hippocampus 5 1.3 The Endocannabinoid System: Physiology and Biochemistry 9 1.4 The Endocannabinoid System: Evidence for a Role in Emotional Regulation and Affective Disease 13 1.5 Overview and Objectives 19 1.6 References 24 CHAPTER 2 Involvement of the Endocannabinoid System in the Ability of Long-term Tricyclic Antidepressant Treatment to Suppress Stress-induced Activation of the Hypothalamic-Pituitary-Adrenal Axis 35 2.1 Introduction 35 2.2 Methods 37 2.3 Results 43 2.4 Discussion 49 2.5 References 54 CHAPTER 3 Endogenous Cannabinoid Signaling is Required for Voluntary Exercise- induced Enhancement of Progenitor Cell Proliferation in the Hippocampus 58 3.1 Introduction 58 3.2 Methods 61 3.3 Results 66 3.4 Discussion 73 3.5 References 79 iv CHAPTER 4 Electroconvulsive Shock Treatment Differentially Modulates Cortical and Subcortical Endocannabinoid Activity 85 4.1 Introduction 85 4.2 Methods 88 4.3 Results 90 4.4 Discussion 97 4.5 References 106 CHAPTERS Regional Alterations in the Endocannabinoid System in an Animal Model of Depression: Effects of Concurrent Antidepressant Treatment 109 5.1 Introduction 109 5.2 Methods 113 5.3 Results 116 5.4 Discussion 126 5.5 References 135 CHAPTER 6 Circulating Endocannabinoid Content is Altered in Depressive Illness.. 140 6.1 Introduction 140 6.2 Methods 143 6.3 Results 147 6.4 Discussion 151 6.5 References 156 CHAPTER 7 General Discussion 159 7.1 Towards an Endocannabinoid Theory of Depression 160 7.2 Enhancement of Endocannabinoid Signaling is a Novel Therapeutic Target for the Pharmacotherapy of Depression 171 7.3 Conclusion 179 7.4 References 181 Appendix: UBC Ethics Board Certificate of Approval 191 V LIST OF TABLES Table 2.1 Effect of chronic desipramine treatment (10 mg/kg) on brain regional endocannabinoid content (data presented as mean values +1- SEM) 45 Table 2.2 Effect of chronic desipramine treatment (10 mg/kg) and acute pharmacological 1 receptor, using the CB1 blockade of the cannabinoid CB receptor antagonist AM251 (1 mg/kg) on plasma corticosterone levels under basal conditions and following exposure to swim stress (data presented as mean values +/- SEM) 46 Table 3.1 The effects of voluntary exercise on the dissociation constant (Kd) of 3H- CP5 5940, a cannabinoid CB1 receptor agonist, from the CB1 receptor in the hippocampus and prefrontal cortex (data presented as mean values +/- SEM) 66 Table 3.2 The effects of voluntary exercise on the maximal hydrolytic activity (Vmax) and the binding affinity (Km) of fatty acid amide hydrolase for anandamide in the hippocampus (data presented as mean values +/- SEM) 69 Table 3.3 The effects of voluntary exercise and administration of the cannabinoid CB1 receptor antagonist AM251 (1 mg/kg) on the volume of the granule cell layer and hilus of the dentate gyrus (data presented as mean values +/- SEM) 71 Table 4.1 The effects of electroconvulsive shock treatment on CB1 receptor-mediated 35S- GTPyS binding in discrete brain regions (data presented as mean values +/- SEM) 92 Table 4.2 The effects of electroconvulsive shock treatment on the tissue content of the two primary endocannabinoid ligands anandamide and 2-arachidonoylglycerol (data presented as mean values +/- SEM) 93 Table 5.1 The effects of exposure to chronic, unpredictable stress on parameters of male sexual behavior (data presented as mean values +/- SEM) 117 Table 5.2 The effects of exposure to chronic, unpredictable stress and/or concurrent treatment with the antidepressant imipramine (10 mg/kg) on the dissociation constant 3H-CP55940 from the cannabinoid CB1 receptor (data presented as mean values (Kd) of +/-SEM) 119 Table 5.3 The effects of exposure to chronic, unpredictable stress and/or concurrent treatment with the antidepressant imipramine (10 mg/kg) on the tissue content of the endocannabinoid 2-arachidonoylglycerol (data presented as mean values +/- SEM) 123 Table 5.4 The effects of exposure to chronic, unpredictable stress and/or concurrent treatment with the antidepressant imipramine (10 mg/kg) on the binding affinity (Km) of fatty acid amide hydrolase for anandamide (data presented as mean values +/- SEM) ..126 vi Li” I (g -/+ aqrnam qoa jo anpm. ueaw s pawasaad wp) uoipindod aiduws Jo S3flSIJ3flJfl{3 3NdJOWaG 9 ajqj LIST OF FIGURES Figure 1.1 The synthetic and metabolic pathways of 2-arachidonoylglycerol 11 Figure 1.2 The synthetic and metabolic pathways of anandamide 12 Figure 2.1 The effect of chronic desipramine (10 mg/kg) treatment on the maximal binding the cannabinoid CB1 receptor as measured [3H]CP55940 binding in (Bmax) of by corticolimbic structures (data presented as mean values +1- SEM) 44 Figure 2.2 The effect of chronic administration of desipramine (10 mg/kg), and the influence of acute cannabinoid CB1 receptor blockade through administration ofAM25l (1 mg/kg), on both basal and stress-induced elevations in total number of fos immunoreactive-like cells in the medial parvocellular population of the paraventricular nucleus of the hypothalamus (data presented as mean values +7- SEM) 47 Figure 2.3 Representative photomicrographs of fos immunoreactivity in the paraventricular nucleus of the hypothalamus under both basal conditions and in response to swim stress exposure 48 Figure 3.1 The effect of engagement in voluntary exercise on the maximal binding (Bmax) of the cannabinoid CB1 receptor in the hippocampus and the prefrontal cortex (data presented as mean values +/- SEM) 67 Figure 3.2 The effect of engagement in voluntary exercise on the EC5O and the maximal 1 receptor-mediated 35S- GTPyS binding in the stimulation (Emax) of cannabinoid CB hippocampus, elicited by the CB1 receptor agonist WIN 55,212-2 (data presented as mean values +/- SEM) 67 Figure 3.3 The effect of engagement in voluntary exercise on the tissue content of the endocannabinoid ligands anandamide and 2-arachidonoylglycerol in the hippocampus and the prefrontal cortex (data presented as mean values +/- SEM) 68 Figure 3.4 The effect of engagement in voluntary exercise, administration of the cannabinoid CB1 receptor antagonist AM251 (1 mg/kg), or both treatments combined, on the total estimated number of proliferating cells expressing the endogenous cell cycle protein Ki67 within the granule cell layer or the hilus of the dentate gyms (data presented as mean
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