Glucocorticoid-endocannabinoid uncoupling mediates fear suppression deficits after early - Life stress

Early-life stress (ELS) creates life-long vulnerability to stress-related anxiety disorders through altering stress and fear systems in the brain. The endocannabinoid system has emerged as an important regulator of the stress response through a crosstalk with the glucocorticoid system, yet whether it plays a role in the persistent effects of ELS remains unanswered. By combining, behavioral, pharmacological and biochemical approaches in adult male rats, we examined the impact of ELS on the regulation of endocannabinoid function by stress and glucocorticoids. We employed a postnatal limited-nesting/bedding induced ELS between postnatal days 2-9 in rats. Exposure to postnatal ELS compromised the ability of both acute stress and glucocorticoid administration to mobilize the endocannabinoid ligand 2-arachidonoyl glycerol (2-AG) in the hippocampus of adult male rats. These findings suggest that ELS compromises the coupling of the glucocorticoid and endocannabinoid systems in the hippocampus. Since 2-AG signaling is essential in mediating glucocorticoid-induced suppression of fear recall, we further examined the impact of ELS on the ability of glucocorticoids to suppress fear memory recall. While ELS did not affect normative fear recall, it impaired the ability of glucocorticoids to dampen fear recall. Notably, bypassing glucocorticoids and directly amplifying hippocampal 2-AG signaling with a monoacyl glycerol lipase inhibitor produced a suppression of fear memory recall in animals exposed to ELS. These findings suggest that ELS results in an uncoupling of glucocorticoid-endocannabinoid signaling in the hippocampus, which, in turn, relates to alterations in stress regulation of memory recall. These data provide compelling evidence that ELS-induced deficits in the glucocorticoid-endocannabinoid coupling following stress could predispose susceptibility to stress-related psychopathology.