The CRH1 receptor antagonist R121919 attenuates stress-elicited sleep disturbances in rats, particularly in those with high innate anxiety

Excessive corticotropin-releasing hormone (CRH) secretion in limbic and prefrontal brain areas has been postulated to underly stress-related clinical conditions. Studies in mice with deleted or pharmacologically compromized CRH type 1 receptors (CRH-R1) point to a key role of the CRH/CRH-R1 signaling cascade as a potential drug target. Therefore, we compared the effect of a selective high affinity CRH-R1 antagonist (R121919) on sleep-wake behavior in two rat lines selectively bred for either high or low innate anxiety. We found that the subcutaneous injection of the solvent of R121919, a citrate buffer solution, transiently increased circulating levels of the stress hormones ACTH and corticosterone and reduced sleep, especially in high-anxiety animals. When R121919 was added to the solvent, hormone levels and sleep patterns returned to baseline and were indistinguishable between the rat lines. This finding is in accord with previous observations from a clinical trial in depressed patients and studies in rats with high innate anxiety that suggested major effects of CRH-R1 antagonism in the presence of a pathological (i.e. CRH hypersecretion) condition only.