Activation of the immune system produces psychological and physiological effects, which resemble the characteristics of depression. The present study was designed to investigate further, in rats, the similarity between the behavioral effects of immune activation and a model of depression in animals. Reduction in the preference for and consumption of saccharin solutions and suppression of sexual behavior were used as models of one essential feature of depression, the inability to experience pleasure (anhedonia). Other measures testing this model were the reduction in food consumption, body weight, locomotor activity, and social interaction. It was found that systemic injection of lipopolysaccharide (endotoxin), which is a potent activator of the immune system, significantly decreased saccharin preference in fluid-deprived rats. Lipopolysaccharide (LPS) also decreased free consumption of saccharin, but not water, in non-deprived rats. Several indices of male sexual behavior were significantly suppressed following LPS administration. Chronic, but not acute, treatment with the tricyclic antidepressant imipramine abolished the suppressive effect of LPS on saccharin preference. Moreover, chronic, but not acute, treatment with imipramine also reduced and facilitated the recovery from the suppressive effects of LPS on food consumption, body weight, social interaction and activity in the open-field test. The results suggest that activation of the immune system in rats produces anhedonia and other depressive-like symptoms, which can be attenuated or completely blocked by chronic treatment with an antidepressant drug.