R278995/CRA0450, a corticotropin-releasing factor (CRF(1)) 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 CRF(1) receptor antagonist R278995/CRA0450 (3 and 10mg/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 3mg/kg, R278995/CRA0450 produced minor changes in sleep behaviour, while an overall reduction in power spectra was observed during deep slow wave sleep. At 10mg/kg, R278995/CRA0450 consistently reduced rapid eye movement (REM) sleep (-75.4%) and increased the REM sleep onset latency (+67%, 92.1±4.9min for vehicle vs. 153.8±24min 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 CRF(1) 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.
Janssen Research & Development, Dept. of Neurosciences, Johnson & Johnson Pharmaceutical Companies, Turnhoutseweg 30, B-2340 Beerse, Belgium. aahnaou@prd.jnj.com
Abdallah
A
Ahnaou
Thomas
T
Steckler
Annick
A
Heylen
Ludo
L
Kennis
Atsuro
A
Nakazato
Shigeyuki
S
Chaki
Wilhelmus H I M
WH
Drinkenburg
D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology*; D004569:Electroencephalography / Q000379:methods; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D012895:Sleep, REM / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects; D000099052:CRF Receptor, Type 1
C491550:1-(8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate; D000928:Antidepressive Agents; D001557:Benzenesulfonates; D011804:Quinolines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1