| dc.description.abstract | The study of endogenous and phyto- cannabinoids share a rich and intertwined history, with the discovery of the endogenous cannabinoid (eCB) system occurring serendipitously during efforts to elucidate the biological mechanisms subserving the psychoactive effects of Cannabis. The research presented in this thesis provides novel insights into both of these areas of study, collectively under the theme of the central actions of cannabinoids. Chapter II outlines the identification of opposing retrograde and astrocyte-dependent eCB signaling mechanisms that regulate lateral habenula synaptic transmission, providing a framework for eCB function in this area of the brain. These findings address unknown questions regarding the actions of cannabinoids in the lateral habenula, which have been shown to produce behavioral effects that are paradoxically opposite to those elicited by systemic cannabinoid manipulations. The results of the studies in Chapter II may have broad implications for the biology of and treatment of neuropsychiatric disorders and potentially the aversive subjective effects of high-dose Cannabis and cannabinoids. In Chapter III, previously unknown actions of cannabidiol, the non-psychoactive constituent of Cannabis, on amygdala physiology are described. Given the emerging potential for cannabidiol in treating stress-related neuropsychiatric disorders, such as anxiety and posttraumatic stress disorder, a mechanistic understanding of the effects of cannabidiol on limbic brain structures, including the amygdala, will have significant implications for understanding its therapeutic utility. Chapter III details physiological mechanisms by which cannabidiol may reduce amygdala activity, which would be predicted to have anxiolytic effects and could provide a mechanistic framework for future studies of cannabidiol in the treatment of stress-related pathology. In summary, the work presented in this thesis advances our understanding of cannabinoid physiology and pharmacology in the central nervous system with broad translational implications. | |
