Animal models are used to decipher the pathophysiology of IFN-alpha-induced psychiatric complications in humans. However, the behavioral effects of IFN-alpha in rodents remain highly controversial. In contrast to homologous IFN-alpha, our recent study revealed that human IFN-alpha, which was used in many previous investigations, had no biological activity in mice. To evaluate the behavioral effects of homologous IFN-alpha in mice, adult C57BL/6J mice were treated with carrier-free murine IFN-alpha and tested on a number of behavioral paradigms. Surprisingly, contrary to previous reports, IFN-alpha treatment decreased the time spent immobile in the forced-swimming test after a single intraperitoneal injection at 2 x 10(6)IU/kg, whereas general locomotor activity was not altered. The elevated plus-maze (EPM) test showed a trend toward an increased anxiety profile in IFN-alpha-treated mice. The tail-suspension and light dark exploration test revealed no difference between IFN-alpha-treated and control animals. Interestingly, neurochemical analysis revealed significantly increased concentrations of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA)/serotonin (5-HT) ratios following IFN-alpha treatment in selected brain regions. Thus, systemic murine IFN-alpha treatment increases swimming time in mice. Increased cerebral serotonin turnover as well as increased tryptophan concentrations, induced by IFN-alpha, implicates serotonergic neurotransmission in behavioral dysfunction caused by this innate immune mediator.