Paradoxical activational effects of a corticotropin-releasing factor-binding protein "ligand inhibitor" in rat brain

The corticotropin-releasing factor-binding protein is distinct from known c orticotropin-releasing factor receptors, but can bind the peptide and neutr alize its biological actions. Recent interest has centered about the therap eutic potential of "ligand inhibitors" of binding protein action, synthetic corticotropin-releasing factor fragments which are inactive at corticotrop in-releasing factor receptors, but can displace the peptide from the bindin g protein, thereby increasing levels of free corticotropin-releasing factor . To identify sites of action of such ligands, the distribution of Fos expr ession seen following intracerebroventricular administration of rat/human c orticotropin-releasing factor(6-33) (5-50 mug) was charted in relation to c orticotropin-releasing factor-binding protein and receptor expression. It w as expected that Fos induction would mimic aspects of the distribution of t he two known corticotropin-releasing factor receptors, but the far greater correspondence was seen with that of the binding protein itself. This inclu ded neurons in the isocortex, the olfactory system, amygdala and a number o f discrete brainstem cell groups; many Fos-immunoreactive neurons in each w ere found to co-express corticotropin-releasing factor-binding protein mess enger RNA. Subsets of activated neurons co-expressed Type 1 corticotropin-r eleasing factor receptor messenger RNA, though these were largely limited t o cell groups that also express the corticotropin-releasing factor-binding protein, and where binding protein immunoreactivity and Type 1 receptor tra nscripts were found to co-exist. Responsive neurons displaying Type 2 corti cotropin-releasing factor receptor message were seen reliably only in the l ateral septal nucleus. These findings support only a limited capacity of the ligand inhibitor to a ctivate neurons bearing corticotropin-releasing factor receptors. The more pervasive activation seen among neurons that express the corticotropin-rele asing factor-binding protein may be indicative of an unexpected role for th is protein in signaling by corticotropin-releasing factor-related peptides. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.