Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Major depression currently afflicts approximately 17% of individuals and is estimated to cost the Canadian government over $14.4 billion each year. Our laboratory and others have recently shown that the endocannabinoid system, a major neuromodulatory system in the brain, may be dysfunctional in depression and that augmentation of this system may represent a novel form of pharmacotherapy. Notably, studies have confirmed that endocannabinoid activity is increased in the prefrontal cortex (PFC) of depressed suicide victims and animals exposed to chronic stress. However, it has yet to be determined whether this change is a negative consequence of major depression, or rather, an adaptive coping mechanism engaged to compensate for other neurochemical imbalances that arise from a life of chronic stress. The current research proposes three experiments that will help to clarify the functional role of these changes in PFC endocannabinoid activity in rats exposed to chronic unpredictable stress. The first experiment will determine whether these changes are occurring mostly on excitatory or inhibitory neurons in the PFC following chronic stress exposure. The second experiment will determine whether activating these new cannabinoid receptors in the PFC following 21 days of chronic stress will produce an exaggerated antidepressant response in rats. The last experiment will then reveal whether activation of cannabinoid receptors in the PFC following chronic stress correlates with neuronal activation in the dorsal raphé, the major serotonin-producing cell body in the brain, thus providing a mechanism by which increased endocannabinoid activity in the PFC produces an antidepressant response. As a whole, this research will delineate the role of prefrontal cannabinoid receptors in the pathophysiological development of depression and outline a functional role for this system in the development of more effective antidepressants.