Gender disparity of depression: The role of endocannabinoids and noradrenergic function

Abstract

Depression is a common and potentially debilitating psychiatric disorder, and is twice as prevalent in women as in men. The traditional monoamine hypothesis of depression provides one perspective into the biological basis of depression, but it is unable to explain all facets of this disease. The reason for the sex difference is currently unclear. The endocannabinoid system, a major neuromodulatory system in the brain, interacts with multiple neurotransmitter and hormone systems, including the monoamine neurotransmitter norepinephrine. Increased endocannabinoid signaling appears to cause greater levels of noradrenergic activation in the locus coeruleus and in axons projecting into other parts of the brain. Dysfunctions in both the endocannabinoid system and the noradrenergic system have been linked to the physiology of depression, with the hypothalamic-pituitary-adrenal (HPA) axis stress response being a major area of interaction. Norepinephrine acts as a gatekeeper to the body's stress response, mobilizing the HPA axis to react to stressors. The endocannabinoid system is also a gatekeeper to this response, preventing maladaptive HPA hyperactivation and potentially protecting the noradrenergic system from entering into a burn-out state in the face of chronic stress. Sexual dimorphism in both systems, as well as in how cells of the locus coeruleus respond to stress, may contribute to some of the sex differences seen in depression. Disruptions to these systems may underlie some cases of depression, and provide potential targets for novel antidepressant treatments.