Chronic stimulation of corticotropin-releasing factor receptor 1 enhances the anxiogenic response of the cholecystokinin system.

Corticotropin-releasing factor (CRF) and cholecystokinin (CCK), two highly colocalized neuropeptides, have been linked to the etiology of stress-related anxiety disorders. Recent evidence points to the possibility that some of the anxiogenic effects of the central CCK system take place through interplay with the CRF system. The aim of the present study was to examine the effects of chronic, mild activation of CRF receptor 1 (CRF(1)) on the central CCK system of the C57BL/6J mouse. As shown by in situ hybridization, real-Time PCR and immunohistochemistry, 5 days of intracerebroventricular (i.c.v.) injections of a subeffective dose (2.3 pmol) of cortagine, a CRF(1)-selective agonist, resulted in an increase in CCK mRNA levels and CCK(2) receptor immunoreactivity in several brain regions, such as amygdala and hippocampus, known to be involved in the regulation of anxiety. Mice with elevated endogenous central CCK tone exhibited significantly higher anxiety-like behaviors in the open-field task and elevated plus maze, and enhanced conditioned fear. These behavioral changes were reversed by i.c.v. administration of the CCK(2)-selective antagonist LY225910, after 5 days of priming with cortagine. Under the same conditions, the intraperitoneal administration of the CRF(1) antagonist antalarmin was ineffective. This result indicated that once the CCK system was sensitized by prior CRF(1) activation, it exhibited its anxiogenic effects, without influence by CRF(1), possibly because of its observed downregulation. In sum, our results provide a novel model for the interaction of the CRF and CCK systems contributing to the development of hypersensitive emotional circuitry.