Disruption of Tonic Endocannabinoid Signaling Triggers the Generation of a Stress Response

Endocannabinoid (eCB) signaling gates many aspects of the stress response, including the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is controlled by corticotropin-releasing hormone (CRH) producing neurons in the paraventricular nucleus of the hypothalamus (PVN). Disruption of eCB signaling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood. Using an array of cellular, endocrine, and behavioral readouts associated with the activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signaling to the generation of a stress response. The CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243, and NAPE PLD inhibitor LEI401 all uniformly increased c-fos in the PVN, unmasked stress-linked behaviors, such as grooming, and increased circulating CORT, recapitulating the effects of stress. Similar effects were also seen after direct administration of AM251 into the PVN, while optogenetic inhibition of PVN CRH neurons ameliorated stress-like behavioral changes produced by disruption of eCB signaling. These data indicate that under resting conditions, constitutive eCB signaling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN. ### Competing Interest Statement The authors have declared no competing interest.