Ryan J. McLaughlin, Matthew N. Hill, Boris B. Gorzalka

The prefrontal cortex (PFC) provides executive control of the brain in humans and rodents, coordinating cognitive, emotional, and behavioral responses to threatening stimuli and subsequent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. The endocannabinoid system has emerged as a fundamental regulator of HPA axis feedback inhibition and an important modulator of emotional behavior. However, the precise role of endocannabinoid signaling within the PFC with respect to stress coping and emotionality has only recently been investigated. This review discusses the current state of knowledge regarding the localization and function of the endocannabinoid system in the PFC, its sensitivity to stress and its role in modulating the neuroendocrine and behavioral responses to aversive stimuli. We propose a model whereby steady-state endocannabinoid signaling in the medial PFC indirectly regulates the outflow of pyramidal neurons by fine-tuning GABAergic inhibition. Local activation of this population of CB1 receptors increases the downstream targets of medial PFC activation, which include inhibitory interneurons in the basolateral amygdala, inhibitory relay neurons in the bed nucleus of the stria terminalis and monoamine cell bodies such as the dorsal raphe nucleus. This ultimately produces beneficial effects on emotionality (active coping responses to stress and reduced anxiety) and assists in constraining activation of the HPA axis. Under conditions of chronic stress, or in individuals suffering from mood disorders, this system may be uniquely recruited to help maintain appropriate function in the face of adversity, while breakdown of the endocannabinoid system in the medial PFC may be, in and of itself, sufficient to produce neuropsychiatric illness. Thus, we suggest that endocannabinoid signaling in the medial PFC may represent an attractive target for the treatment of stress-related disorders.