N-methyl-D-aspartate receptor antagonists decrease interferon-alpha induced depressive behavior in mice model of despair

Abstract

Introduction: Treatment with interferon-alpha (IFNa) can induce depression that is likely the result of its effect on the tryptophan-kynurenine pathway. Kynurenine passes through the blood–brain barrier and breaks to neurotoxic metabolites, such as quinolinic acid, with agonistic effect on N-methyl-D-aspartate receptor (NMDAR). Thus, tryptophan available for serotonin synthesis declines. The aim was to evaluate the effect of NMDAR antagonists on IFNa-induced depression in mice model of despair. Materials and Methods: The total immobility time in the forced swimming test (FST) was assessed as an indicator of depression in mice. Depression was induced by IFNa injection (16 × 105 IU/kg) for 6 consecutive days. The optimum dose of dextromethorphan, memantine, and dizocilpine (MK-801) was administered on the 7 th day following IFNa injection. Results: Immobility time in the FST was increased following IFNa injection (181 s ± 7 vs. control 122 s ± 10, P < 0.05) which indicated depression behavior. Dextromethorphan (15 mg/kg) and MK-801 (0.075 mg/kg) administration reduced the immobility time in IFNa-treated animals (57 s ± 14 and 46 s ± 6, respectively). Memantine (5 mg/kg) reduced the immobility time when it was administered alone but failed to decrease the immobility time induced by IFNa. The animals’ locomotor activity was normal in the experimented groups. Conclusion: Dextromethorphan and MK-801 inhibited IFNa-induced depression. Thus, at least part of IFNa depressive behavior is caused by NMDAR that is stimulated by the production of metabolites in the tryptophan-kynurenine pathway. Administrating NMDAR antagonists should be further evaluated for patients suffering from the neurologic side effects of IFNa. © 2019, Faculty of Pharmaceutical Sciences, Chulalongkorn University. All rights reserved.