R278995/CRA0450, a corticotropin-releasing factor (CRF1) receptor antagonist modulates REM sleep measures in rats: Implication for therapeutic indication

Abnormalities in the regulation of the hypothalamic stress hormone corticotropin-releasing factor (CRF) are thought to play a critical role in mood disorders. Consequently, CRF receptor antagonists have been proposed as potential novel therapeutic agents of these conditions. Sleep disturbance is common in depressed patients and changed sleep-wake architecture is considered as potential predictor or surrogate marker of response to treatment. The aim of our study was to characterise the effects of oral administration of the corticotropin-releasing factor CRF1 receptor antagonist R278995/CRA0450 (3 and 10 mg/kg) on sleep-wake organization and electroencephalographic (EEG) components in Sprague-Dawley rats, and to determine whether the changes observed in the sleep-EEG pattern resemble those seen with antidepressants. At 3 mg/kg, R278995/CRA0450 produced minor changes in sleep behaviour, while an overall reduction in power spectra was observed during deep slow wave sleep. At 10 mg/kg, R278995/CRA0450 consistently reduced rapid eye movement (REM) sleep (− 75.4%) and increased the REM sleep onset latency (+ 67%, 92.1 ± 4.9 min for vehicle vs. 153.8 ± 24 min for R278995/CRA0450), in the absence of systematic changes in spectral EEG pattern, which are characteristic anti-depressant-like effects. These findings in rats indicate that the corticotropin-releasing factor CRF1 receptor antagonist R278995/CRA0450 is centrally active under standard conditions as it inhibits REM sleep and promotes wakefulness. The characteristic changes found in the sleep EEG model further support the hypothesis that R278995/CRA0450 could exert a non-sedative, antidepressant-like action.