Vol. 292, Issue 1, 181-187, January 2000

Corticotropin-Releasing Hormone₁ Receptors Mediate Consensus Interferon- YM643-Induced Depression-Like Behavior in Mice

Mayumi Yamano, Hidenobu Yuki, Syuhei Yasuda and Keiji Miyata

Applied Pharmacology Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Japan

Depression-like behavior induced by YM643, a consensus interferon- (IFN-), was evaluated with the tail-suspension test in mice and compared with depression-like behavior induced by sumiferon, a natural IFN-. To investigate the mechanism of IFN--induced depression-like behavior, the effects of the tricyclic antidepressant imipramine, the cyclooxygenase inhibitor indomethacin, the opioid receptor antagonist naloxone, and the selective corticotropin-releasing hormone receptor antagonist CP-154,526 on IFN--induced depression-like behavior were evaluated. Intravenously injected YM643 (2 × 10⁸-2 × 10⁹ U/kg) and sumiferon (2 × 10⁶-2 × 10⁷ I.U./kg) dose-dependently increased immobility time. Repeated s.c. injection of either YM643 (6 × 10⁶-6 × 10⁸ U/kg) or sumiferon (6 × 10⁴-6 × 10⁶ I.U./kg) for 7 days also dose-dependently increased immobility time. After i.c.v. injection of either YM643 (2 × 10⁶ U/mouse) or sumiferon (6 × 10⁴ I.U./mouse), significant prolongation of immobility time also was observed. Pretreatment with imipramine (30 mg/kg s.c.) significantly reduced the YM643- or sumiferon-induced increases in immobility time. CP-154,526 (0.3-3 mg/kg s.c.) dose-dependently reduced YM643- or sumiferon-induced increases in immobility time with ID₅₀ values of 0.6 mg/kg against YM643 and 1.3 mg/kg against sumiferon. However, neither indomethacin (10 mg/kg s.c.) nor naloxone (3 mg/kg s.c.) had any effect on YM643- or sumiferon-induced increases in immobility time. These results suggest that IFN- centrally induces depression-like behavior in mice that can be alleviated with imipramine. The results also suggest that activation of corticotropin-releasing hormone receptors is involved in IFN--induced depression-like behavior, but the prostaglandin and opioid systems do not participate in this process.