This thesis reviews the literature on, and describes experimental work carried out with, the drug rimonabant, an antagonist at the cannabinoid CBI receptor. -, Rimonabant was licensed in Europe for the treatment of obesity in 2006, however it <- was withdrawn from the market in 2008, because of unacceptable psychiatric side effects, notably depression and anxiety. The mechanism( s) by which CB 1 antagonists produce such symptoms is unclear. The Introduction to this thesis reviews the literature on clinical depression, with special reference to endocannabinoids, and concludes that there are several plausible neurobiological mechanisms linking CB 1 antagonism to the symptoms of this disease. These include inhibition ofphasic dopamine firing elicited by reward, leading to anhedonia; disinhibition ofthe hypothalamo-pituitary stress axis; interference with the extinction of negative emotional memories; and interference with hippocampal neurogenesis. The remainder of the thesis describes the methods and results of four studies in which healthy volunteers were given rimonabant in double-blind, placebo- , controlled experiments. This work was intended to elucidate possible mechanisms by which rimonabant produces depression, with the twin goals of advancing the understanding ofthe endocannabinoid system, and contributing to our knowledge of the neurobiology of clinical depression. Two studies made use of cognitive psychological tasks in order to investigate the impact of rim on ab ant on responses to positive and negative emotional stimuli. The other two studies used functional magnetic resonance imaging (fMRI) to probe the neural effects of CBI antagonism on various functions ofthe brain. Taken together, the results of these four investigations suggest that rimonabant causes depression via interference with the brain's response to positive stimuli and enhancement ofthe response to negative ones. I conclude by discussing the key role of endocannabinoids in mood. The important implications for our understanding of the pathophysiology of clinical depression are explained.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:589615 |
| Date | January 2010 |
| Creators | Horder, Jamie |
| Contributors | Harmer, Catherine ; Cowen, Philip |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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