Endocannabinoids and stress.
Endogenous cannabinoids play an important role in the physiology and behavioral expression of stress responses. Activation of the hypothalamic-pituitary-adrenal (HPA) axis, including the release of glucocorticoids, is the fundamental hormonal response to stress. Endocannabinoid (eCB) signaling serves to maintain HPA-axis homeostasis, by buffering basal activity as well as by mediating glucocorticoid fast feedback mechanisms. Following chronic stressor exposure, eCBs are also involved in physiological and behavioral habituation processes. Behavioral consequences of stress include fear and stress-induced anxiety as well as memory formation in the context of stress, involving contextual fear conditioning and inhibitory avoidance learning. Chronic stress can also lead to depression-like symptoms. Prominent in these behavioral stress responses is the interaction between eCBs and the HPA-axis. Future directions may differentiate among eCB signaling within various brain structures/neuronal subpopulations as well as between the distinct roles of the endogenous cannabinoid ligands. Investigation into the role of the eCB system in allostatic states and recovery processes may give insight into possible therapeutic manipulations of the system in treating chronic stress-related conditions in humans.
Stress regulates endocannabinoid-CB1 receptor signaling.
The CB1 cannabinoid receptor is a G protein coupled receptor that is widely expressed throughout the brain. The endogenous ligands for the CB1 receptor (endocannabinoids) are N-arachidonylethanolamine and 2-arachidonoylglycerol; together the endocannabinoids and CB1R subserve activity dependent, retrograde inhibition of neurotransmitter release in the brain. Deficiency of CB1 receptor signaling is associated with anhedonia, anxiety, and persistence of negative memories. CB1 receptor-endocannabinoid signaling is activated by stress and functions to buffer or dampen the behavioral and endocrine effects of acute stress. Its role in regulation of neuronal responses is more complex. Chronic variable stress exposure reduces endocannabinoid-CB1 receptor signaling and it is hypothesized that the resultant deficiency in endocannabinoid signaling contributes to the negative consequences of chronic stress. On the other hand, repeated exposure to the same stress can sensitize CB1 receptor signaling, resulting in dampening of the stress response. Data are reviewed that support the hypothesis that CB1 receptor signaling is stress responsive and that maintaining robust endocannabinoid/CB1 receptor signaling provides resilience against the development of stress-related pathologies.
Low-frequency stimulation evokes serotonin release in the nucleus accumbens and induces long-term depression via production of endocannabinoid.
The nucleus accumbens (NAc), a major component of the mesolimbic system, is involved in the mediation of reinforcing and addictive properties of many dependence-producing drugs. Glutamatergic synapses within the NAc can express plasticity, including a form of endocannabinoid (eCB)-long-term depression (LTD). Recent evidences demonstrate cross talk between eCB signaling pathways and those of other receptor systems, including serotonin (5-HT); the extensive colocalization of CB1 and 5-HT receptors within the NAc suggests the potential for interplay between them. In the present study, we found that 20-min low-frequency (4 Hz) stimulation (LFS-4Hz) of glutamatergic afferences in rat brain slices induces a novel form of eCB-LTD in the NAc core, which requires 5-HT2 and CB1 receptor activation and L-type voltage-gated Ca(2+) channel opening. Moreover, we found that exogenous 5-HT application (5 μM, 20 min) induces an analogous LTD (5-HT-LTD) at the same synapses, requiring the activation of the same receptors and the opening of the same Ca(2+) channels; LFS-4Hz-LTD and 5-HT-LTD were mutually occlusive. Present results suggest that LFS-4Hz induces the release of 5-HT, which acts at 5-HT2 postsynaptic receptors, increasing Ca(2+) influx through L-type voltage-gated channels and 2-arachidonoylglycerol production and release; the eCB travels retrogradely and binds to presynaptic CB1 receptors, causing a long-lasting decrease of glutamate release, resulting in LTD. These observations might be helpful to understand the neurophysiological mechanisms underlying drug addiction, major depression, and other psychiatric disorders characterized by dysfunction of 5-HT neurotransmission in the NAc.
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.
Endogenous cannabinoid signaling is essential for stress adaptation.
Secretion of glucocorticoid hormones during stress produces an array of physiological changes that are adaptive and beneficial in the short term. In the face of repeated stress exposure, however, habituation of the glucocorticoid response is essential as prolonged glucocorticoid secretion can produce deleterious effects on metabolic, immune, cardiovascular, and neurobiological function. Endocannabinoid signaling responds to and regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis that governs the secretion of glucocorticoids; however, the role this system plays in adaptation of the neuroendocrine response to repeated stress is not well characterized. Herein, we demonstrate a divergent regulation of the two endocannabinoid ligands, N-arachidonylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), following repeated stress such that AEA content is persistently decreased throughout the corticolimbic stress circuit, whereas 2-AG is exclusively elevated within the amygdala in a stress-dependent manner. Pharmacological studies demonstrate that this divergent regulation of AEA and 2-AG contribute to distinct forms of HPA axis habituation. Inhibition of AEA hydrolysis prevented the development of basal hypersecretion of corticosterone following repeated stress. In contrast, systemic or intra-amygdalar administration of a CB(1) receptor antagonist before the final stress exposure prevented the repeated stress-induced decline in corticosterone responses. The present findings demonstrate an important role for endocannabinoid signaling in the process of stress HPA habituation, and suggest that AEA and 2-AG modulate different components of the adrenocortical response to repeated stressor exposure.