Cannabinoid receptor type 1 (CB1) affects hypothalamic-pituitary-adrenal (HPA) axis activity at cerebral and pituitary level

Abstract

The endogenous cannabinoid system (ECS) is involved in the stress-related behaviors, typically characterized by the activation of the HPA axis. However, the precise role of the ECS in this context is not yet well defined. We previously reported that cannabinoid receptor type 1 (CB1) is expressed in ACTH producing cells of the normal and tumoral pituitaries[1] and that CB1 mRNA is co-localized with Corticotropin Releasing Hormone (CRH) mRNA in the paraventricular nucleus of murine hypothalamus[2]. Therefore, we have further evaluated the co-localization between CB1 and CRH mRNAs in other brain regions involved in stress response. Our data show that CB1 mRNA is co-expressed with CRH mRNA in the cortex, piriform cortex, bed nucleus stria terminalis and amygdala of CB1+/+ mice, all areas known to be consistently involved in modulating the stress-related behavior. By using primary pituitary cell culture tool, we have shown that cells derived from CB1–/– mice are characterized by a basal ACTH hypersecretion in vitro as compared to cultures from CB1+/+ mice. Moreover, in CB1–/–-derived cells, ACTH response to CRH and forskolin challenges is significantly higher when compared to that obtained from CB1+/+ -derived cells. Altogether, these experiments clearly suggest that CB1 is able to affect HPA axis activity at various levels, either at hypothalamic and supra-hypothalamic structures or at the pituitary site by directly modulating ACTH secretion.