The most likely receptor target of the effects of augmented anandamide in the BLA is CB1R, which is highly expressed in this region.5 To confirm that CB1R activation mediated the extinction-facilitating effect of AM3506, we repeated our experiment above, in which mice were systemically injected with AM3506 before extinction, but co-treated half of the AM3506-treated mice with 1 mg/kg of the CB1R antagonist SR141716 (Rimonabant). Neither SR141716 nor AM3506 altered baseline, pre-CS, freezing or CS-induced freezing during extinction training (ANOVA effect of treatment: P>0.05) (Supplementary Figure S6a). Replicating our earlier finding, fear measured at the 10-day retrieval test was significantly lower, relative to vehicle, in mice treated with AM3506 (ANOVA effect of treatment: F3,41 = 3.14, P<0.05, followed by post hoc tests, n = 9–12) (Figure 3a). By contrast, mice treated with SR141716+AM3506 were no different from vehicle controls, thereby indicating that systemic CB1R antagonism had blocked the extinction-facilitating effect of AM3506.
