REVIEWSIs there a role for the endocannabinoid system in the etiology and treatment of melancholic depression?Hill, M. N.; Gorzalka, B. B. Author Information Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada Sponsorship: Financial support for the authors during the writing of this paper was provided by a Natural Sciences and Engineering Research Council of Canada (NSERC) Operating Grant to B.B.G. and a NSERC Postgraduate Scholarship and a Michael Smith Foundation for Health Research Trainee Award to M.N.H. Correspondence and requests for reprints to Dr Boris Gorzalka, 2136 West Mall, Vancouver, BC, Canada V6T 1Z4 E-mail: [email protected] Received 31 March 2005 Accepted as revised 14 June 2005 Behavioural Pharmacology: September 2005 - Volume 16 - Issue 5-6 - p 333-352 Buy Abstract With advances in basic and clinical neuroscience, many gaps have appeared in the traditional monoamine theory of depression that have led to reformulation of the hypotheses concerning the neurobiology of depression. The more recent hypotheses suggest that melancholic depression is characterized by central glucocorticoid resistance that results in hypercortisolemia, which in turn leads to down-regulation of neurotrophins and subsequent neurodegeneration. Examining the neurobiology of depression from this perspective suggests that the endocannabinoid system may play a role in the etiology of melancholic depression. Specifically, pharmacological and genetic blockade of the cannabinoid CB1 receptor induces a phenotypic state that is analogous to melancholic depression, including symptoms such as reduced food intake, heightened anxiety, increased arousal and wakefulness, deficits in extinction of aversive memories and supersensitivity to stress. These similarities between melancholic depression and an endocannabinoid deficiency become more interesting in light of recent findings that endocannabinoid activity is down-regulated by chronic stress and possibly increased by some antidepressant regimens. We propose that an endocannabinoid deficiency may underlie some of the symptoms of melancholic depression, and that enhancement of this system may ultimately be a novel form of pharmacotherapy for treatment-resistant depression. © 2005 Lippincott Williams & Wilkins, Inc.