The corticotropin-releasing factor (CRF)(1) receptor antagonists CP154,526 and DMP695 inhibit light-induced phase advances of hamster circadian activity rhythms

Abstract

The circadian activity of corticotropin releasing factor (CRF) and the hypothalamic-pituitary-adrenal axis is controlled by the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus. However, the reciprocal influence of CRF and the hypothalamic-pituitary-adrenal axis upon the circadian pacemaker is less well established. Therefore, in the present study, we tested two nonpeptidergic antagonists at CRF(1) receptors for their ability to modulate photic resetting of pacemaker time (phase). CP154,526 dose dependently and significantly inhibited light-induced phase advances in hamster circadian activity rhythms late in the subjective night by approximately 60% at a maximally effective dose of 20 mg/kg delivered intraperitoneally. Likewise, a further CRF(1) receptor antagonist, DMP695, inhibited phase advances by approximately 40% at a dose of 10 mg/kg. The attenuation of phase shifts by CP154,526 was specific to phase advances as light-induced phase delays of the circadian pacemaker achieved early in the subjective night were not affected by CP154,526 (20 mg/kg). We also tested one of the CRF(1) receptor antagonists for its potential ability to reset the pacemaker in the absence of light and found that CP154,526 did not elicit a nonphotic phase shifts in circadian activity rhythms at circadian times (CT) 2, 8, 14, 18, or 22. In conclusion, CRF(1) receptor antagonists selectively modulate the effect of light on the circadian pacemaker late at night. These novel data emphasize the suspected critical link between CRF and the hypothalamic-pituitary-adrenal axis, on the one hand, and stress (including stress caused by jet-lag) and depression on the other. These results also suggest that CRF(1) antagonists may not only improve affect but also counter the circadian disruption associated with depression and other stress-related disorders.