Differential involvement of 5-HT1A and 5-HT1B/1D receptor in human interferon -induced immobility

Although Interferon-alpha (IFN-α) is a powerful drug in treating several viral infections and certain tumors, a considerable amount of neuropsychiatry side-effects such as depression and anxiety are unavoidable consequence. Combination with selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine significantly improved the situation. However, the potential 5-HT1A receptorand 5-HT1B receptor-signals, involved in the antidepressant effects are still unclear. Here we analyzed the effects of 5-HT1A receptorand 5-HT1B receptorsignals by using mouse forced swimming test (FST), a predictive test of antidepressant-like action. The present results indicate that: (1) fluoxetine (administrated intragastrically, 30 mg/kg; not subactive dose: 15 mg/kg) significantly reduced IFN-α-induced increase of the immobility time in the forced swimming test; (2) 5-HT1A receptorand 5-HT1B receptor-ligands along or combination have no effects on IFN-α-induced increase of the immobility time in the FST; (3) surprisingly, WAY 100635 (5-HT1A receptor antagonist) and 8-OH DPAT(5-HT1A receptor agonists) markedly enhanced the antidepressant effect of fluoxetine at subactive dose (15 mg/kg, i.g.) on the IFN-α-treated mice in the FST respectively; Further investigations showed that fluoxetine combined with WAY 100635 and 8-OH DPAT failed to produce antidepressant effects in the FST. (4) Co-application of CGS 12066A or GR 127935 with fluoxetine has no synergistic effects on the IFN-α induced increase of immobility time in FST. (5) Interestingly, co-administration of GR 127935, WAY 100635 and fluoxetine significantly reduced the IFN-α induced increase in immobility time of FST, which is more effective than that produced by the coadministration of WAY 100635 and fluoxetine. All results suggest that: (1) compared to 5-HT1B receptor, 5-HT1A receptor signal plays the dominant role in improving the anti-immobility effect of fluoxetine in the IFN-α-induced depression; (2) synergistic effect of 5-HT1B receptor with 5-HT1A receptor depends on fluoxetine-elevated basal level of serotonin in IFN-α-treated mice.