UBC Theses and Dissertations

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UBC Theses and Dissertations

The endocannabinoid system as a novel target in the pathophysiology and treatment of depressive illness Hill, Matthew Nicholas


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 C1B 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 C1B receptor activity contributed to the stress-attenuating effects of desipramine, as pharmacological antagonism of the C1B 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 C1B 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 C1B receptor binding is increased. Concurrent treatment with the antidepressant imipramine was capable of reversing some, 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.

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