Putative role of endocannabinoid signaling in the etiology of depression and actions of antidepressants.

In the last few years, there have been several advances in the determination of the role of the endocannabinoid system in the etiology of depression and the functional actions of antidepressant drugs. Specifically, a deficiency in endocannabinoid signaling is sufficient to produce a "depressive-like" phenotype at the preclinical level (including changes in rewarding, emotional and cognitive behavior and biological changes such as increased HPA axis activity, impaired stress adaptation, reduced neurogenesis and altered serotonin negative feedback), and capable of inducing symptoms of depression in humans at a clinical level. In line with these findings, clinical populations diagnosed with depression are found to have reduced levels of circulating endocannabinoids and preclinical models of depression reveal a deficit in central endocannabinoid signaling. Moreover, facilitation of endocannabinoid signaling is sufficient to produce all of the behavioral and biochemical effects of conventional antidepressant treatments. Further, many forms of antidepressant treatments significantly alter endocannabinoid signaling, and in some of these cases this recruitment of endocannabinoid signaling is involved in the neuroadaptive effects of these treatments. Ultimately, these data present a compelling picture of the putative role of the endocannabinoid system in the processes subserving both the development and treatment of depression.