- The mechanism of interferon (IFN)-alpha-induced depression remains poorly understood. Recently, modulation of glucocorticoid receptor (GR) and serotonin receptor 1A (5-HTR1A) were implicated in mechanism(s) leading to depression. To gain insight into this mechanism, we assessed the effect of IFN-alpha on the modulation of GR and 5-HTR1A expression. Hepatoblastoma, myelocyte-derived and T cell leukemia-derived cell lines were treated with titrated doses of IFN-alpha for different incubation times and analyzed by Western blot, RT-PCR, and microarrays. Dose- and time-dependent decreases of proteins and mRNA levels of GR and 5-HTR1A were observed. The expression of GR and 5-HTR1A in cells treated for 6 days decreased by 74 and 72%, respectively. Recovery was observed following IFN-alpha withdrawal. Co-incubation with tricyclic antidepressants (desipramine) or serotonin reuptake inhibitors (fluoxetine) attenuated the effect of IFN-alpha on GR or 5-HTR1A. GR and 5-HTR1A were unaffected by treatment with either IFN-gamma or tauroursodeoxycholic acid (TUDCA). However, the effect of IFN-alpha on GR was abolished when used in combination with TUDCA. In conclusion, IFN-alpha downregulated GR and 5-HTR1A levels in cell lines. These levels of GR and 5-HTR1A, following IFN-alpha-induced downregulation, recovered after withdrawal of IFN-alpha or addition of desipramine or fluoxetine. These data provide insights regarding pathogenesis of IFN-alpha-induced depression.