The cannabinoid CB1 receptor has been shown to be critically involved in the extinction of fear memory. Systemic injection of a CB1 receptor antagonist prior to extinction training blocked extinction. Conversely, administration of the cannabinoid uptake inhibitor AM404 facilitated extinction in a dose-dependent manner. Here we show that bilateral infusion of CB1 receptor agonists into the amygdala after memory reactivation blocked reconsolidation of fear memory measured with fear-potentiated startle. The effect was dose-dependent and could be blocked by AM251, a specific CB1 receptor antagonist. In contrast, the effect of CB1 agonists on reconsolidation was no longer seen if memory reactivation was omitted. Concomitant with block of reconsolidation, CB1 agonist-treated animals did not exhibit shock-induced reinstatement or spontaneous recovery of fear. The absence of recovery was not attributable to permanent damage to the amygdala in WIN-treated rats, nor did the effect result from alteration of baseline startle or shock reactivity. These results suggest that CB1 agonists could impair fear memory via blocking reconsolidation.
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