The effect of CRF2 receptor antagonists on rat conditioned fear responses and c-Fos and CRF expression in the brain limbic structures

The influence of intracerebroventricular-administered selective corticotropin-releasing factor receptor 2 (CRF2) antagonists (antisauvagine-30, astressin-2B), on rat anxiety-like behavior, expression levels of c-Fos and CRF, and plasma corticosterone levels were examined in the present study. In fear-conditioned animals, both CRF receptor antagonists enhanced a conditioned freezing fear response and increased the conditioned fear-elevated concentration of serum corticosterone. Exogenously administered antisauvagine-30 increased the aversive context-induced expression of c-Fos in the 1 and 2 areas of the cingulate cortex (Cg1, Cg2), the central amygdala (CeA) and parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN), and it enhanced the effect of conditioned fear in the secondary motor cortex (M2) and medial amygdala (MeA). Immunocytochemistry demonstrated an increase in CRF expression in the Cg1, M2 areas of the cortex, and pPVN, and it revealed the effect of conditioned fear in the CeA 35 min after antisauvagine-30 administration and 10 min after the conditioned fear test. Furthermore, astressin-2B, another CRF2 receptor antagonist, enhanced expression of c-Fos and CRF in the CeA and pPVN, and revealed the effect of conditioned fear in the Cg1. These data support a model in which an excess in CRF1 receptor activation, combined with reduced CRF2 receptor signaling, may contribute to stronger expression of anxiety-like responses.

► CRF2 receptor antagonists enhanced a conditioned freezing fear response. ► CRF2 receptor antagonists increased the conditioned fear-elevated concentration of serum corticosterone. ► CRF2 receptor antagonists enhanced the conditioned fear-elevated expression of c-Fos and CRF in the CeA and pPVN.