Control of glucocorticoid secretion is accomplished by multiple mechanisms. The first line of defense is rapid shut-off of ACTH release by glucocorticoids secreted in response to stress. Rapid inhibition is almost certainly non-genomic, and is mediated in part by direct feedback onto PVN CRH neurons and at the pituitary (John et al., 2004; Tasker and Herman, 2011). At the PVN, so-called “fast feedback” is mediated by membrane actions of glucocorticoids, which cause local mobilization of endocannabinoids and subsequent inhibition of excitatory afferent input (Di et al., 2003; Evanson et al., 2010). Fast feedback inhibits ACTH release within minutes, and affects the amplitude of the stress response (Keller-Wood and Dallman, 1984). Glucocorticoids also act via the MR to rapidly enhance the excitability of hippocampal and basolateral amygdala neurons via a non-genomic mechanism. Both regions are upstream of the PVN, and thus binding via the MR may impact HPA drive via synaptic mechanisms (Pasricha et al., 2010). The eventual shut-off of the HPA axis stress response (return to baseline) is thought to be mediated by feedback working through limbic circuitry (Jacobson and
