Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output

Abstract

Endocannabinoid signaling is distributed throughout the brain, regulating synaptic release of both excitatory and inhibitory neurotransmitters. The presence of endocannabinoid signaling within stress-sensitive nuclei of the hypothalamus, as well as upstream limbic structures such as the amygdala, suggests it may play an important role in regulating the neuroendocrine and behavioral effects of stress. The evidence reviewed here demonstrates that endocannabinoid signaling is involved in both activating and terminating the hypothalamic-pituitary-adrenal axis response to both acute and repeated stress. In addition to neuroendocrine function, however, endocannabinoid signaling is also recruited by stress and glucocorticoid hormones to modulate cognitive and emotional processes such as memory consolidation and extinction. Collectively, these data demonstrate the importance of endocannabinoid signaling at multiple levels as both a regulator and an effector of the stress response.

Figure 1.

A, Under steady-state conditions, AEA signaling within the BLA restrains glutamatergic signaling and helps maintain non-stress conditions. B, In response to stress, FAAH activity increases, reducing AEA content and disinhibiting glutamate release onto BLA neurons, facilitating an adequate stress response.

Figure 2.

Fast-feedback inhibition of the HPA axis via glucocorticoid-induced eCB release in the hypothalamus. Left, Stress activation of the HPA axis consists of CRH secretion from PVN neurons and CRH-evoked ACTH secretion from the pituitary, which, in turn, stimulates corticosteroid (CORT) release from the adrenal cortex and CORT feedback onto the PVN. Right, In PVN CRH neurons, CORT binds to a membrane-associated glucocorticoid receptor (mGR) (1), which causes eCB synthesis in CRH neurons (2) and retrograde eCB release (3); eCB binds to presynaptic CB1 receptors on glutamate terminals (4) and inhibits glutamate release (5) onto the CRH neurons, suppressing the excitatory synaptic drive and decreasing CRH neuron activity and CRH release (6), which suppresses HPA axis activation.

Figure 3.

A, In response to acute stress, there is little to no change in 2-AG within the BLA. B, Repeated stress exposure, however, primes 2-AG signaling within the BLA such that in response to stressor presentation, there is a phasic and limited increase in 2-AG signaling within the BLA which suppresses glutamatergic inputs to the BLA, decreasing the outflow of the amygdala and driving habituation of the stress response. A similar phenomenon may also subserve behavioral plasticity, such as fear extinction, to aversive stimuli.