Figure 2.

Endocannabinoid regulation of the stress response. Without a stressor (No Stress) basal AEA tone maintains CB₁ signaling constraint of the stress response and a cool, calm, collected, and happy state. Acute presentation of a stressor (Acute Stress) elevates FAAH hydrolysis of AEA, reducing CB₁ signaling and permitting activation of the stress response [13,15,32,39]. Secretion of cortisol by the stress response provides Negative Feedback by increasing 2-AG production, which increases CB₁ signaling and terminates the stress response [15]. Repeated presentation of the same stressor progressively increases 2-AG levels, possibly by reduced MAGL expression and degradation of 2-AG, which causes progressively higher CB₁ signaling and Habituation to the stress response [4,15]. Chronic Stress causes a downregulation of CB₁ that impairs feedback inhibition and facilitates persistence of the stress response and high cortisol levels, which precipitates or exacerbates illness (complications) [5,15,40].