Regulation of endocannabinoid signaling by stress: implications for stress-related affective disorders

The endocannabinoid system is a widely distributed, neuromodulatory system which serves an integral role in regulating synaptic transmission. The presence of this system in stress-responsive neural circuits suggests that it may play a critical role in regulating neuroendocrine and behavioral responses to stress. Endocannabinoid content in limbic structures which regulate activation of the hypothalamic-pituitary-adrenal (HPA) axis is dynamically regulated by stress. Under conditions of acute stress, the endocannabinoid system tonically constrains activation of the HPA axis. During repeated exposure to aversive stimuli, the endocannabinoid system up-regulates in limbic structures, resulting in dampened neural activity in stress circuits, which could contribute to stress habituation. Disrupted endocannabinoid signaling, on the other hand, is associated with an inability to adapt to chronic stress. Therapeutically, these data suggest that the endocannabinoid system could be dysregulated in affective disorders, such as depression, which are characterized by maladaptive stress coping. In this review, we discuss the evidence demonstrating that the endocannabinoid system is affected by and can oppose the effects of prolonged stress and, as such, represents a potential target for the development of novel antidepressant agents.