Interferon-alpha (IFN-alpha) therapy is strongly associated with certain adverse effects, but the pathophysiologic mechanism is unclear. The present study was designed to investigate the influence of peripherally administered IFN- alpha on amino acid levels in the brain. IFN-alpha was administered intraperitoneally (i.p.) once daily to rats, and their brains were extracted 24 h after the last injection. The levels of glutamate, glycine, taurine, gamma-aminobutyric acid (GABA), and arginine in homogenized samples of the frontal cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, cerebellum, and brainstem were determined. One day of IFN-alpha treatment induced no significant changes in any of these amino acids. After 4 days of injections, glutamate, glycine, taurine, and gamma-aminobutyric acid levels were significantly higher than those in the control frontal cortex, striatum, hippocampus, amygdala, and thalamus. However, most of these amino acids returned to approximately basal levels, or even lower, with 14-day treatment. Our results suggest that daily peripheral administration of IFN-alpha affects the metabolism of amino acids in the brain. Further studies are necessary to determine if these effects of IFN-alpha on cerebral amino acids are involved in the pathophysiology of IFN-alpha-induced depression.