Endocannabinoid Signaling Negatively Modulates Stress-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis

Abstract

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for the adaptation and survival of animals upon exposure to stressful stimuli, and data suggest that endocannabinoid (eCB) signaling modulates neuroendocrine function. We have explored the role of eCB signaling in the modulation of stress-induced HPA axis activation. Administration of the CB1 receptor antagonist/inverse agonist SR141716 (0.01, 0.1, 1, and 5 mg/kg, i.p.) to male mice produced a small, dose-dependent increase in the serum corticosterone (CORT) concentration. Despite this effect, the highest dose of SR141716 did not significantly increase neuronal activity within the paraventricular nucleus of the hypothalamus, as measured by the induction of Fos protein. Similarly, exposure of mice to 30 min of restraint increased serum CORT concentrations, but did not produce a consistent, statistically significant increase in Fos expression within the PVN. However, pretreatment of mice with SR141716 before restraint stress robustly potentiated restraint-induced CORT release and Fos expression within the PVN. Pretreatment of mice with either the CB1 receptor agonist CP55940, the eCB transport inhibitor AM404, or the fatty acid amide hydrolase inhibitor URB597 significantly decreased or eliminated restraint-induced CORT release. Upon exposure to acute restraint, hypothalamic 2-arachidonylglycerol content was reduced compared with the control value; however, after 5 d of restraint exposure (which resulted in an attenuated CORT response), the hypothalamic 2-arachidonylglycerol content was increased compared with the control value. These data indicate that eCB signaling negatively modulates HPA axis function in a context-dependent manner and suggest that pharmacological augmentation of eCB signaling could serve as a novel approach to the treatment of anxiety-related disorders.

Involvement of the Endocannabinoid System in the Ability of Long-Term Tricyclic Antidepressant Treatment to Suppress Stress-Induced Activation of the Hypothalamic–Pituitary–Adrenal Axis

“…Recent data have demonstrated that CB 1 receptors in the PVN of the hypothalamus gate glutamatergic fibers, which activate the HPA axis (Di et al, 2003), which suggests that the endocannabinoid system can regulate glutamate-induced activation of the HPA axis. This hypothesis has received in vivo support from experiments demonstrating that genetic deletion of the CB 1 receptor exacerbates stress-induced activation of the HPA axis, whereas enhancement of endocannabinoid signaling can attenuate stress-induced activation (Patel et al, 2004;Barna et al, 2004). Thus, the upregulation of the CB 1 receptor in the hypothalamus seen in this study is consistent with suppression of stress-induced activation of the HPA axis following desipramine treatment.…”

“…This bidirectional regulation of hippocampal CB 1 receptors by stress and antidepressants suggests that CB1 receptor/endocannabinoid signaling in the hippocampus could be relevant for the development and treatment of depression. Interestingly, long-term desipramine treatment did not affect endocannabinoid content in any brain structure examined, although brain regional endocannabinoid content is sensitive to stress exposure Patel et al, 2004Patel et al, , 2005b and is affected by acute manipulation of monoamine receptor activity (Patel et al, 2003;Giuffrida et al, 1999).…”

“…Specifically, repeated episodes of homotypic stress results in a habituation of the stress response that is accompanied by an increase in the tissue contents of endocannabinoid ligands in the limbic system and the hypothalamus, and acute treatment with a CB 1 receptor antagonist can reverse habituation to repeated homotypic stress (Patel et al, 2004(Patel et al, , 2005b. These data suggest that the endocannabinoid system acts to modulate or dampen activation of the neural stress axis (Patel et al, 2005b).…”

“…These data predict that activation of CB 1 receptors in the PVN would result in a suppression of HPA axis activity, whereas a disruption in endocannabinoid signaling would result in hyperactivity of the HPA axis. This hypothesis has received substantial support in vivo, as genetic or pharmacological disruption of endocannabinoid signaling results in exaggerated endocrine responses to stress, and conversely, inhibition of endocannabinoid uptake or metabolism attenuates stress-induced activation of the HPA axis (Patel et al, 2004;Barna et al, 2004).…”

Anxiolytic-Like Properties of the Anandamide Transport Inhibitor AM404

“…Stressful stimuli affect anandamide mobilization in brain regions that are involved in the control of emotion. In rats, for example, a single electric shock to the paw elevates anandamide levels in the midbrain (Hohmann et al, 2005), while in mice physical restraint decreases anandamide levels in the amygdala (Patel et al, 2004). Moreover, pharmacological blockade or genetic ablation of CB 1 receptors exacerbates normal reactions to acute stress, presumably by disabling an endocannabinoid modulation of these reactions (Navarro et al, 1997;Haller et al, 2004;Urigüen et al, 2004).…”