Fig. 5.

Working model for eCB modulation of LC following chronic stress.

Cannabinoid type 1 receptor (CB1r) has been localized to excitatory and inhibitory corticotropin-releasing factor (CRF) afferents in the locus coeruleus (LC), and anterograde tract tracing has found CB1r specifically on excitatory amygdalar-CRF afferents, the main source of CRF to the LC. A. Following a stressor, CRF is released in the LC, where it binds to corticotropin-releasing factor receptor type 1 (CRFr1). This causes postsynaptic depolarization of LC-norepinephrine (NE) neurons, leading to an increase in activity and NE efflux in the medial prefrontal cortex (mPFC). B. CRF-induced depolarization and influx in intracellular calcium (Ca²⁺) stimulates diacylglycerol lipase (DGL) to synthesize and release 2-arachidonlyglycerol (2-AG) into the synaptic cleft. 2-AG then crosses the synapse and binds to CB1r. This inhibits the continued release of CRF, attenuating the CRF-induced increases in LC-NE activity and NE efflux, and helping to diminish the stress response. C. Chronic stress, especially in vulnerable female subpopulations, results in high DGL expression. Increased DGL would suggest greater production of 2-AG, which could bind to CB1r on neighboring synapses, causing inhibition of GABAergic interneurons and non-CRF releasing afferents. This dysregulation synaptic activity and disinhibition could further excite LC-NE neurons can cause aberrant NE release in the mPFC, and could contribute to the increased propensity for females to develop stress-induced psychiatric disorders.