Fast Feedback Inhibition of the HPA Axis by Glucocorticoids Is Mediated by Endocannabinoid Signaling

Abstract

Glucocorticoid hormones are secreted in response to stimuli that activate the hypothalamo-pituitary-adrenocortical (HPA) axis and self-regulate through negative feedback. Negative feedback that occurs on a rapid time scale is thought to act through nongenomic mechanisms. In these studies, we investigated fast feedback inhibition of HPA axis stress responses by direct glucocorticoid action at the paraventricular nucleus of the hypothalamus (PVN). Local infusion of dexamethasone or a membrane-impermeant dexamethasone-BSA conjugate into the PVN rapidly inhibits restraint-induced ACTH and corticosterone release in a manner consistent with feedback actions at the cell membrane. The dexamethasone fast feedback response is blocked by the cannabinoid CB1 receptor antagonist AM-251, suggesting that fast feedback requires local release of endocannabinoids. Hypothalamic tissue content of the endocannabinoid 2-arachidonoyl glycerol is elevated by restraint stress, consistent with endocannabinoid action on feedback processes. These data support the hypothesis that glucocorticoid-induced fast feedback inhibition of the HPA axis is mediated by a nongenomic signaling mechanism that involves endocannabinoid signaling at the level of the PVN.

Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats

“…These findings complement a growing body of evidence suggesting a role for 2-AG in the Endocannabinoid modulation of long-term anxiety J Lim et al modulation of emotional responses to stress (Evanson et al, 2010;Hill et al, 2011;Sciolino et al, 2011;Sutt et al, 2008). For example, studies have shown that cat odor exposure causes rapid changes in the expression of enzymes involved in the biosynthesis and degradation of 2-AG in various rat brain regions, including amygdala and periaqueductal gray area, immediately after odor exposure (Sutt et al, 2008).…”

“…Indeed, FAAH inhibitors are currently under investigation as potential treatment for anxiety disorders and secondary prevention for PTSD (Finn, 2010). In addition to anandamide, changes in 2-AG have also been implicated in the regulation of stress-induced responses (Evanson et al, 2010;Hill et al, 2011;Sciolino et al, 2011;Sutt et al, 2008). However, a systematic investigation of the longterm impact of trauma-induced stress on 2-AG-mediated signaling is still lacking.…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Genetic manipulations that impede CB 1 R activation are anxiogenic [35], and individuals with eCB system gene polymorphisms that reduce eCB tonefor example, FAAH gene polymorphisms-exhibit physiological, psychological, and neuroimaging features consistent with impaired fear regulation [36]. Reduction of AEA-CB 1 R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone [37], and CB 1 R activation is essential to negative feedback of the neuroendocrine stress response, and protects against the adverse effects of chronic stress [38,39]. Finally, chronic stress impairs eCB signaling in the hippocampus and amygdala, leading to anxiety [40,41], and people with PTSD show elevated CB 1 R availability and reduced peripheral AEA, suggestive of reduced eCB tone [42].…”

Evidence to Support The Non-Genomic Modulation of The HPA Axis

“…Concurrently, Johnson et al [18] demonstrated the presence of membrane GR in pre-and postsynaptic terminals within the lateral amygdala, providing direct evidence for the existence of membrane GR. The in vivo functional consequences of the feedback inhibition model was shown through inhibition of plasma ACTH and plasma corticosterone responses to restraint stress in rats treated with cellimpermeable dexamethasone (a preferential GR agonist) and reversal of the inhibition with co-administration of a selective cannabinoid receptor inhibitor [19].In summary, the classical genomic effects of GR and MR mediated by corticosterone are relevant to chronic changes in electrophysiological or morphological properties of neurons within the stress-axis. However, there is considerable evidence, that the rapid response to corticosterone is mediated by membrane GR/MR in a…”

“…Concurrently, Johnson et al [18] demonstrated the presence of membrane GR in pre-and postsynaptic terminals within the lateral amygdala, providing direct evidence for the existence of membrane GR. The in vivo functional consequences of the feedback inhibition model was shown through inhibition of plasma ACTH and plasma corticosterone responses to restraint stress in rats treated with cellimpermeable dexamethasone (a preferential GR agonist) and reversal of the inhibition with co-administration of a selective cannabinoid receptor inhibitor [19].…”