Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

Abstract

Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN55,212-2 (5-50 ng per 0.2 microL per side), infused bilaterally into the BLA of male Sprague-Dawley rats immediately after inhibitory avoidance training, induced dose-dependent enhancement of 48-h retention. Conversely, the CB1 receptor antagonist AM251 (0.07-0.28 ng per 0.2 microL per side) administered after training into the BLA induced inhibitory avoidance retention impairment. Furthermore, intra-BLA infusions of a low and nonimpairing dose of AM251 (0.14 ng per 0.2 microL per side) blocked the memory enhancement induced by concurrent administration of WIN55,212-2. Delayed infusions of WIN55,212-2 or AM251 administered into the BLA 3 h after training or immediate posttraining infusions of these drugs into the adjacent central amygdala did not significantly alter retention performance. Last, intra-BLA infusions of a low and otherwise nonimpairing dose of AM251 (0.14 ng per 0.2 microL per side) blocked the memory-enhancing effect induced by systemic administration of corticosterone (3 mg/kg, s.c.). These findings indicate that endocannabinoids in the BLA enhance memory consolidation and suggest that CB1 activity within this brain region is required for enabling glucocorticoid effects on memory consolidation enhancement.

Fig. 1.

Effects of WIN55,212-2 on retention of an inhibitory avoidance response. Step-through latencies (mean and SEM) on a 48-h retention test. (A) Immediate posttraining intra-BLA infusions of the cannabinoid agonist WIN55,212-2 (WIN; 5, 10, 50 ng per 0.2 μL) enhanced memory consolidation. *, P < 0.05 vs. vehicle (Veh; n = 10–11 per group). (B) Delayed infusions of WIN55,212-2 (WIN; 50 ng per 0.2 μL) administered into the BLA 3 h after training did not enhance memory consolidation (n = 11–12 rats per group). (C) Immediate posttraining infusions of WIN55,212-2 (WIN 50 ng per 0.2 μL) into the CeA did not enhance memory consolidation (n = 7 rats per group).

Fig. 2.

Effects of AM251 on retention of an inhibitory avoidance response. Step-through latencies (mean and SEM) on a 48-h retention test. (A) Immediate posttraining intra-BLA infusions of the cannabinoid antagonist AM251 (0.07, 0.14, 0.28 ng per 0.2 μL) impaired memory consolidation. *, P < 0.05 vs. vehicle (Veh; n = 9–11 per group). (B) Delayed infusions of AM251 (0.28 ng per 0.2 μl) administered into the BLA 3 h after training did not impair memory consolidation (n = 10–11 rats per group). (C) Immediate posttraining infusions of AM251 (0.28 ng per 0.2 μL) into the CeA did not impair memory consolidation (n = 5–6 rats per group).

Fig. 3.

Effects of intra-BLA infusions of WIN55,212-2, either alone or together with AM251, on an inhibitory avoidance response. Step-through latencies (mean and SEM) on a 48-h retention test. Immediate posttraining infusions of AM251 (0.14 ng per 0.2 μL) blocked the memory-enhancing effects of concurrently administered WIN55,212-2 (WIN; 50 ng) into the BLA. **, P < 0.01 compared with the corresponding vehicle (Veh) group; ♦, P < 0.05 compared with the corresponding AM251 group (n = 14–15 per group).

Fig. 4.

Effects of intra-BLA administered AM251 on systemic corticosterone-induced enhancement of an inhibitory avoidance response. Step-through latencies (mean and SEM) on a 48-h retention test. Immediate posttraining infusions of AM251 (0.14 ng per 0.2 μL) into the BLA blocked the memory enhancement induced by s.c. injections of corticosterone (CORT; 3.0 mg/kg; n = 10–12 per group). *, P < 0.05 compared with the corresponding vehicle (Veh) group; ♦, P < 0.05 compared with the corresponding CORT group.

Fig. 5.

(A) Diagram of the rat BLA, CeA, and adjacent structures (62). (B) Representative photomicrograph (Microscope Nikon 801, original magnification ×20) of a needle track terminating in the BLA. (C) Diagrams of the rat brain sections (62) showing 40 infusion needle termination sites randomly selected from rats included in the final analyses. Only data from animals that had needle tracks terminating in the BLA and had no lesions in the surrounding BLA tissue were included in the analyses.