Endocannabinoid signaling modulates HPA axis activity in the mouse – implications for depression disorders

Hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity is associated with major depressive disorders. We further elucidated the role of cannabinoid type 1 (CB1) receptors in the regulation of basal and stress-induced HPA axis activity by genetic and pharmacological means. Male CB1 receptor knock-out (ko) mice showed increased basal corticosterone levels as compared to wild-type (wt) littermates. The selective CB1 receptor antagonist SR141716 dose-dependently elevated basal corticosterone levels in male C57BL/6N mice. Both male and female CB1 ko mice showed increased forced swim stress-induced corticosterone levels 10min, 30min, but not 120min after stressor onset. This effect was mimicked by SR141716 administration in C57BL/6N and CB1 wt mice, but not in CB1 ko, indicating that SR141716 mediated its effect on HPA regulation via CB1 receptors. SR141716 also elevated corticosterone secretion in response to a psychological stressor, social defeat. Chronic SR141716 administration induced antidepressant-like behavioral responses in the forced swim test (FST), but did not lead to tolerance to its acute stimulatory effects on FST-induced corticosterone secretion. Finally, antidepressant-like behavioral effects of desipramine in the FST were compromised in male CB1 ko mice, but desipramine attenuated FST stress-induced corticosterone secretion in both CB1 ko and CB1 wt. We conclude that CB1 receptor signaling tightly controls corticosterone secretion in the mouse.