Various NMDAR antagonists decrease interferon-alpha induced depression behavior in mice model of despair

Azadeh Mesripour, Ahmad Purhasani, valiollah Hajhashemi

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 evaluating the effect of NMDAR antagonists on IFNa induced depression in mice model of despair.  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 (16×10 5 IU/kg) for 6 consecutive days. The optimum dose of dextromethorphan, memantine, and dizocilpine (MK-801) were administered on the 7th day following IFNa injection. Results: Immobility time in the FST was increased following IFNa injection (181 sec±7 vs control 122 sec±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 sec±14, and 46 sec±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. Animals’ locomotor activity were normal in the experimented groups. Conclusion: Dextromethorphan, and MK-801 prevented 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.   


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