Figure 3. Modulatory effect of the cannabinoid 1 receptor (CB1R) activity in the hypothalamic-pituitary-adrenal (HPA) axis. Under stress conditions, the HPA axis is activated to produce an adaptive defensive response to stress. To counteract excessive HPA-axis activation, CB1R activity limits the release of hypothalamic corticotropin-releasing hormone. CB1R is also present in the pituitary gland and adrenal cortex cells, where they restrict adrenocorticotropin hormone and glucocorticoid release, respectively. On the contrary, glucocorticoids induce fast increases in endocannabinoid synthesis in brain areas that shape the perception of stress. These regions include the prefrontal cortex, the hippocampus, and the amygdala. Indeed, glucocorticoids released after acute stressors promote a rapid increase in retrograde 2-arachidonoylglycerol (2-AG) signaling in these brain areas leading to decreased GABAergic release in the amygdala that induces a fast increase in anxiety-like behavior. Abbreviations: 2-AG, 2-arachidonoylglycerol; ACTH, adrenocorticotropin hormone; AMG, amygdala; CB1R, cannabinoid 1 receptor; CRH, corticotropin-releasing hormone; eCB, endocannabinoids; HPC, hippocampus; HPA, hypothalamic-pituitary-adrenal; PFC, prefrontal cortex.
