We have developed various animal models of fatigue. Here, two types of models using rats are introduced : one is a model of central fatigue obtained by excessive depolarizing stimuli to the central nervous system ; another is that of immunological fatigue obtained by intraperitoneal injection of polyriboinosinic : polyribocytidylic acid (poly I : C) , double- strand RNA, which mimics viral infection. In the central fatigue model, we introduced cortical spreading depression, the propagation of neuronal membrane depolarization throughout the cerebral cortex. Prostaglandins (PG) including PGD2 were produced by COX- 2 expression in neurons in the cortex following cortical spreading depression. In such a model, the amount of non- REM sleep, but not of REM sleep, increased subsequently for several hours in the animals, and the increase was completely attenuated by application of NS- 398, a COX- 2 inhibitor. Such a system is thought to relieve excessive brain activity by inducing resting behavior and non- REM sleep. In the immunological fatigue model, intraperitoneal administration of poly I : C induced transient fever and suppression of locomotor activity in rats. We have demonstrated that interleukin (IL) - 1 βexpression was up- regulated in various brain regions, and that intracerebroventricular infusion of IL- 1 receptor antagonist significantly attenuated the poly I : C- induced fatigue- like behavior. The balance of IL- 1 βand the endogenous antagonist in the brain possibly regulates immunological fatigue sensation.