Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis

Sachin Patel, Craig T. Roelke, David J. Rademacher, William E. Cullinan, Cecilia J. Hillard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

405 Scopus citations


Activation of the hypothalamic-pituitary-adrenal (HDPA) 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 SB141716 (0.01, 0.1, 1, and 5 mg/kg, ip) 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 UKB597 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 contest-dependent manner and suggest that pharmacological augmentation of eCB signaling could serve as a novel approach to the treatment of anxiety-related disorders.

Original languageEnglish (US)
Pages (from-to)5431-5438
Number of pages8
Issue number12
StatePublished - Dec 2004
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology


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