Resumo

Objective: Fear conditioning is useful to study aversive memories, which play a role in anxiety disorders such as the posttraumatic stress. In contextual fear conditioning, the animal is shocked in a conditioning chamber, so that context re-exposure elicits freezing behavior. Repeated non-reinforced context re-exposures results in progressive decrease of freezing (i.e. fear extinction). Previous evidence suggests that endocannabinoids are released in the brain during fear extinction. Glucocorticoid hormones are relased by adrenal glands during stress events. It is suggested that glucocorticoids may trigger the release of endocannabinoids in the brain. Hence, our objective was to investigate whether the interaction between these neuromodulatory systems contributes to the contextual fear extinction. We investigated the effects of the blockade of CB1 receptors on glucocorticoid-induced facilitation of fear extinction and the effects of the inhibition of glucocorticoid synthesis on the endocannabinoid-induced facilitation of fear extinction. Methods: Male Wistar rats were implanted with a guide cannulae aimed at the lateral ventriculae. After 7 days, the rats were placed into the conditioning chamber and 3 min later received an electric-footshock (1.5 mA, 1 s). Subsequently, they were re-exposed to the chamber for 9 min in 3 consecutive days. The CB1 antagonist SR141716A (0.2 mg/kg, i.p.), or vehicle was administered 20 min before the synthetic corticosteroid dexamethasone (0.1; 0.5; 1.0 ug/ul, i.c.v.).The inhibitor of corticosterone synthesis metyrapone (25 mg/kg, i.p.) was injected 90 min before the inhibitor of endocannabinoid uptake AM404 (1.0 ug/ul, i.c.v.) or vehicle. I.c.v. treatments were performed 5 min before each extinction trial. A 3-min drug-free test of contextual memory was performed 24 h after the last extinction session to investigate lasting effects. The percentage of freezing was used as an index of fear memory. Results: Dexamethasone (0.5 ug/ul, i.c.v.) facilitated extinction of contextual fear memory in a CB1-dependent fashion (Dexa: 14,48±1,79; 8,66±1,56/N=9 X SR/Dexa: 28,43±3,98; 19,65±2,35/N=9 X Ctrl: 35,60±4,09; 24,58±2,71/N=8). The enhancement of endocannabinoid levels by AM404 also facilitated fear extinction, which was prevented by the inhibition of corticosteroid synthesis by metyrapone (AM404: 17,61±1,88; 8,24±1,48/N=10 X MET/AM404: 29,48±3,83; 27,75±3,05/N=10 X Ctrl: 31,71±2,92; 22,57±2,78/N=12). Both effects proved to be persistent when tested in drug-free test. Conclusion: Our present findings show an interdependency of the corticosteroid and endocannabinoid systems as a mechanism for contextual fear extinction. It’s suggested that stress-related glucocorticoids drive the release of endocannabinoid in the brain, with a final impact on the extinction of aversive memories.