With respect to the endocannabinoid system, the first studies to suggest that endocannabinoid signaling may be regulated by stress or glucocorticoids came from in vitro research from the laboratory of Jeffrey Tasker. Through a series of elegant studies, Tasker and colleagues demonstrated that within the PVN of the hypothalamus (as well as the supraoptic nucleus), glucocorticoids evoked a rapid induction of endocannabinoid synthesis and release through a non-genomic mechanism involving a Gs coupled membrane bound receptor (Di et al., 2005a; Di et al., 2003; Di et al., 2005b; Di et al., 2009; Malcher-Lopes et al., 2006). This discovery helped to clarify a long-standing set of findings of a G-protein coupled glucocorticoid receptor in the newt, Taricha granulosa (Orchinik et al., 1992; Orchinik et al., 1991). The glucocorticoid-mediated release of endocannabinoids within the PVN, in turn, resulted in the suppression of incoming excitatory neurotransmission to CRH neurosecretory cells and provided a mechanism by which glucocorticoids could exert rapid shut down of the HPA axis (Di et al., 2003). Two broader implications of these findings were that: 1) endocannabinoid signaling was capable of dampening HPA axis activity, and 2) endocannabinoid signaling within the hypothalamus could be induced by stress and glucocorticoids.
