Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

Abstract

There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousalinduced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3-3 mg/kg) to male Sprague-Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal β-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212-2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences.cannabinoid receptor | norepinephrine | emotional arousal | fear conditioning | posttraumatic stress disorder I t is well-established that glucocorticoid (GC) hormones, released from the adrenal cortex during stressful episodes, can modulate different memory processes (1-4). Although most studies focused on GC effects on the acquisition and consolidation of memory, extensive evidence also indicates that acutely elevated GC levels at the time of retention testing impair the retrieval of memory of spatial and contextual training (5-9). Because a glucocorticoid receptor (GR) agonist infused into the hippocampus before retention induces comparable memory retrieval impairment (10, 11), such findings suggest that GC effects on memory retrieval depend, at least in part, on activation of GRs in the hippocampus. Findings of studies of human subjects are consistent with the findings of animal studies and indicate that exogenous GC administration or exposure to a psychosocial stressor shortly before retention testing impairs retrieval of declarative (mostly episodic) information (7, 12, 13) and reduces hippocampal activity (14). Moreover, previous findings indicate that emotionally arousing information is especially sensitive to the retrieval-impairing effects of GCs (8) and that emotional arousal during the test situation enables GC effects on memory retrieval (15). Findings of recent clinical studies suggest that the administration of stress doses of GCs may have therapeutic v...

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