Involvement of CRFR(1) in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

Several animal and clinical studies have highlighted the ineffectiveness of fear extinction sessions delivered shortly after trauma exposure. This phenomenon, termed the immediate extinction deficit, refers to situations in which extinction programs applied shortly after fear conditioning may result in the reduction of fear behaviors (in rodents, frequently measured as freezing responses to the conditioned cue) during extinction training, but failure to consolidate this reduction in the long term. The molecular mechanisms driving this immediate extinction resistance remain unclear. Here we present evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala (BLA) in male Wistar rats. Intra-BLA microinfusion of the CRFR(1) antagonist NBI30775 enhances extinction recall, whereas administration of the CRF agonist CRF(6–33) before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser(845) and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal after treatment with the CRFR(1) antagonist indicates their dependence on CRFR(1) actions. These findings can have important implications for the improvement of therapeutic approaches to trauma, as well as furthering our understanding of the neurobiological mechanisms underlying fear-related disorders.