Critical role of the endocannabinoid system in mediating rapid glucocorticoid effects on memory for emotionally arousing experiences

Abstract

Rationale : 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 arousal-induced noradrenergic activity, the neurobiological 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. Methods : For all three experiments, male Sprague-Dawley rats were trained on a hippocampus-dependent contextual fear-conditioning (CFC) task and retention was tested 24 h later. All drugs were administered 60 min before retention testing. Results : Systemic injections of corticosterone (3.0 mg/kg) impaired memory retrieval of CFC training (P < 0.05) whereas lower doses (0.3 or 1.0 mg/kg) were ineffective. The retrieval-impairing dose of corticosterone significantly increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) (p<0.05), but not anandamide, whereas an intra-hippocampal infusion of the cannabinoid receptor type 1 (CB1) antagonist AM251 (0.35 ng) prevented the corticosterone-induced memory retrieval impairment. We further found that an intra-hippocampal infusion of the CB1 receptor agonist WIN55,212-2 (10 ng) impaired memory retrieval of CFC training (p<0.001), and that this impairment was blocked by co-administration of the β-adrenoceptor antagonist propranolol (1.25 µg). In contrast, blockade of hippocampal CB1 transmission with AM251 failed to attenuate memory retrieval impairment induced by concurrent infusions of norepinephrine (1–3 µg). Conclusion : These findings indicate that glucocorticoid-induced memory retrieval impairment depends on functional interactions between the endocannabinoid and noradrenergic systems.

Keywords

• Glucocorticoid
• endocannabinoid
• anadamide
• 2-arachidonoylglycerol
• CB1 receptor
• memory