The role of prefrontal cortex CB1 receptors in the modulation of fear memory

Understanding the mechanism of how fear memory can be extinguishedcould provide potential therapeutic strategies for the treatmentof posttraumatic stress disorders. Here we show that infusionof CB1 receptor antagonist into the infralimbic (IL) subregionof the medial prefrontal cortex (mPFC) retarded cue-alone–inducedreduction of fear-potentiated startle. Conversely, cannabinoidagonist WIN55212-2 (WIN) facilitated the extinction. Unexpectedly,administration of WIN without cue-alone trials reduced startlepotentiation in a dose-dependent manner. The effect of cannabinoidagonists was mimicked by endocannabinoid uptake or fatty acidamide hydrolase inhibitors. Rats were trained with 10 conditionedstimulus (CS⁺) (yellow light)–shock pairings. Extinctiontraining with CS⁺ (yellow light)-alone but not CS^– (bluelight)-alone trials decreased fear-potentiated startle. Intra-ILinfusion of WIN before CS^–-alone trials decreased startlepotentiation, suggesting that the cannabinoid agonist decreasedconditioned fear irrespective of whether the rats underwentCS⁺- or CS^–-alone trials. Cannabinoid agonists activatedextracellular signal-regulated kinases (ERKs) in mPFC slices,and ERK inhibitor blocked the effect of cannabinoid agonistson fear-potentiated startle. These results suggest that CB1receptors acting through the phosphorylation of ERK are involvednot only in the extinction of conditioned fear but also in theadaptation to aversive situations in general.