Mind and body medicine: chronic stress
Chronic or repeated stress results in a chronic elevation of endogenous corticosterone via the hypothalamic-pituitary-adrenocortical (HPA) axis. Chronic stress (repeated restraint) reduced AEA levels throughout the corticolimbic stress circuit in rodents [99], [196], [197]. In contrast, 2-AG levels decrease or increase, depending upon the nature of the stressor: Hill et al. [198] found reduced 2-AG content within rat hippocampus following the CUS protocol. But in the hypothalamus and midbrain, 2-AG increased in the same testing paradigm [99]. Elevations in 2-AG appear after chronic restraint stress within the amygdala [196], [199], hypothalamus [200], and medial prefrontal cortex [58].
CB1 expression decreased in rat hippocampus following the CUS protocol [198], whereas CB1 expression increased in the prefrontal cortex in the same testing paradigm [99]. The same paradigm decreased hippocampal CB1 expression in male rats, but increased CB1 expression in female rats [201]. Social isolation stress decreased CB1 density in the supraoptic nucleus of rats [202]. Immobilization/acoustic stress increased CB1 mRNA and protein expression in the prefrontal cortex of mice [203]. A chronic mild stress protocol (subjecting rats to cage soiling with water, group housing in a confined space, water and/or food deprivation, intermittent lighting, reversal of light/dark cycle, cage tilting to 45°, exposure to loud white noise and strobe lights) increased CB1 mRNA in the prefrontal cortex and decreased CB1 in the midbrain [204].
Adult rats exposed to chronic restraint stress increased CB1 binding of [3H]CP55,940 in the prefrontal cortex (PFC) with a decrease in the hippocampus. A 40-day recovery period resulted in normalization of CB1 in the PFC, and a pronounced upregulation of CB1 density in the hippocampus, possibly indicative of a rebound effect. Adolescent rats did not show any change in hippocampal CB1 density, but exhibited an upregulation in both the PFC and amygdala. They also exhibited a rebound in the hippocampus after 40 days [205].
Chronic water avoidance stress in male rats increased serum corticosterone levels and visceral hyperalgesia in response to colorectal distension, accompanied by increased AEA, decreased CB1 expression, and increased TRPV1 expression in the dorsal root ganglia [62]. Co-treatment with the corticoid receptor antagonist RU-486 prevented these changes [206]. Seven daily sessions of social defeat stress in mice decreased AEA levels in the hypothalamus and hippocampus, but not in the striatum or the frontal cortex; 2-AG levels increased after the last, but not the first, session in the hypothalamus, hippocampus, and frontal cortex [207]. Fear expression after the sessions was prolonged in mice receiving rimonabant and in CB1 −/− knockouts. Conditional knockouts lacking CB1 in two defined neuronal subpopulations—glutamatergic neurons and GABAergic neurons—indicated that the former CB1 subpopulation was responsible for the fear responses.
Electrophysiological studies confirm the effects of chronic stress upon the eCB system: Chronic social defeat stress in mice (exposure to aggression) impaired GABAergic synapse sensitivity to eCBs (probably 2-AG) mobilized by group I metabotropic glutamate receptor stimulation [208]. The CUS protocol attenuated eCB-mediated DSE, LTD, and depression of field excitatory postsynaptic potentials [96]. Chronic restraint stress attenuated eCB-mediated DSI in rat hippocampus [209]. These chronic stressors also desensitized CB1 to exogenous cannabinoids: they reduced electrophysiological responses to HU210 in mouse striatum [208], and to WIN55,212-2 in mouse striatum [96]. Chronic immobilization stress in rats impaired retrograde eCB signaling at GABAergic synapses, and a functional downregulation of CB1 in the paraventricular nucleus of the hypothalamus [210].
Acute restraint challenge in rats induces corticosterone release in the paraventricular nucleus of the hypothalamus (PVN). This is inhibited by dexamethasone, a response blocked by the CB1 antagonist AM251—suggesting that fast feedback requires local release of eCBs. Indeed, PVN content of 2-AG is elevated by the restraint challenge [200].
Acute footshock stress increased 2-AG and AEA levels in the periaqueductal gray and contributed to stress-induced analgesia (SIA) in male rats. SIA enhancement by a MAGL inhibitor and not by a FAAH inhibitor indicated that 2-AG was the primary eCB responsible for SIA [211]. SIA was modulated via CB1 receptors in the basolateral nucleus of the amygdala (BLA); microinjection of SR141716A into the BLA suppressed SIA [212]. Glucocorticoid enhancement of memory consolidation in the acute footshock stress is dependent upon CB1 activation in male rats; WIN55,212-2 infused into the amygdala enhances memory in an inhibitory avoidance apparatus, and AM251 impairs the response [213]. Acute handling stress in male newts increased serum cortisol levels and induced behavioral changes (less sexual behavior); the latter was blocked by a cannabinoid antagonist, AM281, indicating dependence upon CB1 activation [214].
Acute restraint stress in male rats increases hippocampal content of 2-AG and enhanced eCB-dependent modulation of GABA release measured by whole-cell voltage clamp of inhibitory post-synaptic currents (IPSCs) in hippocampal CA1 cells [215]. Responses in female rats are much more complex, because eCB levels fluctuate across the estrous cycle [216]. The eCB system has been implicated in cycle-dependent changes in pressure pain thresholds in human females [217].
In summary, chronic stress impairs the eCB system, via decreased levels of AEA and 2-AG. Changes in CB1 expression are more labile. Stress management may reverse the effects of chronic stress on eCB signaling, although few studies exploring this possibility have been performed to date. Clinical anecdotes suggests that stress-reduction techniques, such as meditation, yoga, and deep breathing exercises impart mild cannabimimetic effects [218].
Rossi et al. [208] found that mice given access to a running wheel recovered their chronic stress-induced synaptic defects. Accordingly, social play in rats increased CB1 phosphorylation (a marker of CB1 activation) in the amygdala and enhanced AEA levels in the amygdala and nucleus accumbens [219]. The effects of exercise on the eCB system are elaborated below. Grooming behavior, which is a stress-reduction behavior in rodents, increased in response to SR141716A administration [220].