Cannabinoid Receptor Activation in the Basolateral Amygdala Blocks the Effects of Stress on the Conditioning and Extinction of Inhibitory Avoidance

Despite the efficacy of behavior therapy for human anxiety disorders, extinction-like treatments require repeated cue exposures and are vulnerable to reversal by a number of environmental factors, particularly stress. The endocannabinoid system has recently emerged as important in the regulation of extinction learning and in the regulation of the hypothalamic-pituitary-adrenal axis. Here, we aimed to examine the involvement of the cannabinoid CB1 receptor in the basolateral amygdala (BLA) in inhibitory avoidance (IA) conditioning and extinction and to test whether cannabinoid activation would reverse the effects of stress on these memory processes. The synthetic full agonist of the CB1/CB2 receptor WIN55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl) methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate] (5 mu g/0.5 mu l) microinjected into the BLA had no effect on IA conditioning or extinction by itself. However, microinjecting WIN55,212-2 into the BLA before exposing the rats to a stressor reversed the enhancing effects of the stressor on IA conditioning and its impairing effects on IA extinction. Importantly, WIN55,212-2 microinjected into the BLA reduced stress-induced elevations in corticosterone levels. Control experiments demonstrated the following: (1) the effects of WIN55,212-2 could not be attributed to sensorimotor deficits, because these parameters seemed unchanged by WIN55,212-2 microinjected into the BLA; and (2) the CB1 receptor in the BLA is crucially involved in the extinction of IA, because the CB1 receptor antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (6 ng/0.5 mu l) microinjected into the BLA significantly blocked extinction. Together, our findings may support a wide therapeutic application for cannabinoids in the treatment of conditions associated with the inappropriate retention of aversive memories and stress-related disorders.