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 arousal-induced 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.

Fig. 1.

Effect of systemic CORT administration on retrieval of fear memory. (A) Systemic CORT (0.3, 1, or 3 mg/kg) treatment administered 1 h before retention testing dose-dependently impairs retrieval of contextual fear memory. Results represent mean ± SEM. **P < 0.01 vs. vehicle (n = 11–13 per group). (B) Effect of systemic CORT (3 mg/kg) treatment on freezing during retrieval of contextual fear memory analyzed in 1-min time bins. Results represent mean ± SEM. *P < 0.05, **P < 0.01 vs. vehicle (n = 11–13 per group). (C) Systemic CORT (0.3, 1, or 3 mg/kg) treatment given 1 h before retention testing does not impair retrieval of auditory fear memory. Results represent mean ± SEM (n = 8 per group). (D) Effect of systemic CORT (0.3, 1, or 3 mg/kg) administration on basal freezing levels in a nontraining context. Results represent mean ± SEM (n = 10–15 per group).

Fig. 2.

Role of the endocannabinoid system in regulating glucocorticoid effects on retrieval of contextual fear memory. (A) Hippocampal infusion of the CB1 receptor antagonist AM251 (0.35 ng in 0.5 μL) administered 1 h before retention testing blocks the impairment of retrieval of contextual fear memory induced by concurrent systemic CORT (3 mg/kg) treatment. Results represent mean ± SEM. *P < 0.05 vs. vehicle (n = 7–11 per group); #P < 0.05 vs. CORT alone. (B) Representative photomicrograph illustrating placement of cannula and needle tip in the dorsal hippocampus with subfields dentate gyrus (DG), CA1, and CA3. (C and D) Systemic CORT (0.3, 1, or 3 mg/kg) treatment dose-dependently increases hippocampal 2-AG but not AEA in the same time window of the retention test. All results represent mean ± SEM. *P < 0.05 vs. vehicle (n = 10–15 per group).

Fig. 3.

Endocannabinoid and norepinephrine interactions in the dorsal hippocampus on retrieval of contextual fear memory. (A) The CB receptor agonist WIN55,212–2 (WIN, 10 or 30 ng in 0.5 μL) infused into the hippocampus 1 h before the retention test impairs retrieval of contextual fear memory. Concurrent infusion of the β-adrenoceptor antagonist propranolol (1.25 μg) blocks this WIN55,212–2-induced memory retrieval impairment. Results represent mean ± SEM. *P < 0.05, **P < 0.001 vs. vehicle (n = 10–14 per group). (B) Intrahippocampal infusions of norepinephrine (1 or 3 μg in 0.5 μL) administered 1 h before the retention testing impair retrieval of contextual fear memory. Concurrent infusion of the CB1 receptor antagonist AM251 (0.35 ng) does not block this impairment. Results represent mean ± SEM. *P < 0.05, **P < 0.01 vs. vehicle (n = 11–15 per group).