PMC:3951193 / 17890-21202 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3951193","sourcedb":"PMC","sourceid":"3951193","source_url":"http://www.ncbi.nlm.nih.gov/pmc/3951193","text":"Glucocorticoids\nThe distribution of glucocorticoid receptors (GRs) and CB1 overlap substantially in the central nervous system and other tissues, as do GRs and CB2 in immune cells. Dual activation of GRs and CBs may participate in glucocorticoid-mediated anti-inflammatory activity, immune suppression, insulin resistance, and acute psychoactive effects. In a rat model of spinal nerve injury (sciatic nerve constriction with suture loops), the GR receptor agonist dexamethasone increased CB1 density after spinal nerve injury, which suggests that CB1 is a downstream target for GR actions [50]. Glucocorticoid administration also induced CB1 expression in bone in mice [51] and rats [52].\nThe acute administration of glucocorticoids may shift AA metabolism toward eCB synthesis in parts of the brain. Electrophysiological studies of rat hypothalamic slices demonstrated that adding dexamethasone or corticosterone to slice baths caused a rapid suppression of synaptic activity, characterized as glucocorticoid-induced, eCB-mediated suppression of synaptic excitation (GSE). GSE was blocked by CB1 antagonists, indicating that eCB release mediated GSE [53]. A follow-up study demonstrated that GSE correlated with increased levels of AEA and 2-AG [54]. The same group found no changes in AEA and 2-AG after exposure of cerebellar slices to dexamethasone. In hypothalamic slices, GSE could be blocked by leptin, suggesting that GSE is a nutritional state-sensitive mechanism [55]. Dexamethasone enhanced eCB-mediated GSE by inhibiting COX2 in dorsal raphe serotonin neurons [56].\nCorticosterone administration increased AEA levels in several rat limbic structures (amygdala, hippocampus, hypothalamus), but not the prefrontal cortex. 2-AG levels were only elevated in the hypothalamus [57]. The same group conducted an ex vivo study of the rat medial prefrontal cortex (mPFC). Bath application of corticosterone to mPFC slices suppressed GABA release onto principal neurons in the prelimbic region, which was prevented by application of the CB1 antagonist AM251 [58]. This indicates local recruitment of eCB signaling, probably through 2-AG. A previous study of rats receiving a single dose of corticosterone detected no change in 2-AG and a reduction of AEA in hippocampal homogenates [59]. Corticosterone increased hippocampal levels of 2-AG in rats; the impairment of contextual fear memory by corticosterone was blocked by the CB1 antagonist AM251 [60].\nChronic exposure to glucocorticoids downregulates the eCB system. Chronic corticosterone administration decreased CB1 densities in rat hippocampus [59] and mouse hippocampus and amygdala [61]. Chronic corticosterone administration in male rats led to visceral hyperalgesia in response to colorectal distension, accompanied by increased AEA, decreased CB1 expression, and increased TRPV1 expression in dorsal root ganglia. Co-treatment with the corticoid receptor antagonist RU-486 prevented these changes [62].\nIn summary, preclinical rodent studies indicate that acute glucocorticoid administration enhances the activity of eCBs. The clinical phenomenon of acute “corticosteroid mania” may have a cannabimimetic component. Chronic exposure to glucocorticoids downregulates the eCB system, a scenario consistent with chronic stress, which we review 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