Systemic administration of lipopolysaccharide (LPS), a non-specific activator of proinflammatory cytokine release from macrophages, provokes sickness characterized by anorexia, soporific effects, and disturbances of locomotor activity and exploration. In addition, endotoxin treatment may provoke an anhedonic response. Assessment of anhedonia in appetitive paradigms, however, is compromised by the anorexia provoked by the treatment. The present investigation assessed the anhedonic effects of LPS on rewarding lateral hypothalamic brain stimulation. Using a simultaneous discrimination, current titration procedure in the assessment of intracranial self-stimulation (ICSS), it was found that acute systemic administration of LPS (50 microg, 100 microg or 200 microg) reduced ICSS during the ascending sequence of current presentations, but had little effect on responding to a series of descending currents. In a parallel experiment, peripheral administration of LPS (100 microg) increased in vivo dopamine (DA) efflux from the nucleus accumbens, a region thought to be involved in goal-directed responding to positively reinforcing stimuli. It is suggested that LPS alters ICSS in a manner different than that observed following stressor exposure or peripheral IL-2 treatment. Furthermore, LPS may engender an anhedonic effect (possibly secondary to sickness), and the decline of responding reflects the relation between the cost of responding given in the face of sickness and the reward received for responding.