Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response

Abstract

Background and PurposeEndocannabinoid (eCB) signalling 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 signalling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood.Experimental ApproachUsing an array of cellular, endocrine and behavioral readouts associated with activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signaling to the generation of a stress response.Key ResultsThe CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243, and NAPE PLD inhibitor LEI401 all uniformly increased 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.Conclusions and ImplicationsThese data indicate that under resting conditions, constitutive eCB signaling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN.

Presynaptic nanoscale components of retrograde synaptic signaling

“…Endocannabinoids are important tonic regulators of neurotransmitter release in a circuit-wide manner under specific physiological or pathological conditions ( 16 – 19 , 40 ). Accordingly, bath application of JZL184, an inhibitor of the 2-AG–degrading enzyme monoacylglycerol lipase (MAGL), robustly increased 2-AG levels by ~250% and concomitantly decreased IPSC amplitudes and successful synaptic events in WT mice.…”

“…While AEA can be synthesized through complex enzymatic pathways in biochemical preparations ( 72 ), NAPE-PLD is known to be the primary enzyme responsible for the synthesis of AEA in vivo ( 37 , 38 ). Accordingly, recent evidence showed that NAPE-PLD is responsible for the AEA tone in the stress response ( 19 , 38 ). However, we found that the synaptic cannabinoid tone is unaffected in NAPE-PLD KO mice.…”

“…The mechanistic diversity of CB 1 R-dependent forms of retrograde synaptic signaling makes functional division of labor possible and demonstrates the parsimonious nature of how synapses exploit the limited number of molecular players. Considering the large-scale volumetric spread of AEA and 2-AG signaling in vivo, the AEA/2-AG tones may be ideal for the lasting control of neurotransmitter release at a circuit-wide level in association with specific physiological and pathological states ( 16 – 19 , 38 , 40 ).…”