Corticotropin-releasing hormone receptors mediate consensus interferon-alpha YM643-induced depression-like behavior in mice.
Depression-like behavior induced by YM643, a consensus interferon-alpha (IFN-alpha), was evaluated with the tail-suspension test in mice and compared with depression-like behavior induced by sumiferon, a natural IFN-alpha. To investigate the mechanism of IFN-alpha-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-alpha-induced depression-like behavior were evaluated. Intravenously injected YM643 (2 x 10(8)-2 x 10(9) U/kg) and sumiferon (2 x 10(6)-2 x 10(7) I.U./kg) dose-dependently increased immobility time. Repeated s.c. injection of either YM643 (6 x 10(6)-6 x 10(8) U/kg) or sumiferon (6 x 10(4)-6 x 10(6) I.U./kg) for 7 days also dose-dependently increased immobility time. After i.c.v. injection of either YM643 (2 x 10(6) U/mouse) or sumiferon (6 x 10(4) 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 ID(50) 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-alpha 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-alpha-induced depression-like behavior, but the prostaglandin and opioid systems do not participate in this process.
Yamano
M
M
Applied Pharmacology Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Japan. yamano@yamanouchi.co.jp
Yuki
H
H
Yasuda
S
S
Miyata
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007099:Imipramine / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000928:Antidepressive Agents; C101628:CP 154526; D016898:Interferon-alpha; D009292:Narcotic Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D009270:Naloxone; D007099:Imipramine; D007213:Indomethacin