Ghrelin plays a central role in physiologic orexigenic mechanisms and stimulates motor activity. It has been postulated that increased behavioral activity and feeding in the beginning of the dark period are due to the activation of ghrelin circuits in the brain of nocturnal rodents. C75 is known to inhibit ghrelin secretion in mice thus it seemed possible that suppressed ghrelin secretion may account for both the anorectic and motor activity-suppressing effects of C75. In this case, intact ghrelin receptor-mediated signaling would be required for the manifestations of these actions, i.e., C75 would not affect eating and activity in animals that lack ghrelin receptors. The finding that C75-induced anorexia and motoric inhibition are not attenuated in ghrelin receptor KO mice indicates that these effects of C75 are unrelated to the function of ghrelin receptors. We found significant correlation between the anorectic and motor activity effects of C75. An overall decrease in motor activity may, in theory, lead to decreased feeding. Although causality cannot be determined with certainty in the present study, it seems unlikely that the anorectic effects are exclusively due to the general CHIR-99021 suppression of motor activity. First, while the overall time-courses correlate significantly, there is a meaningful dissociation between the motor activity- and feeding-suppressive effects of C75. For example, in the ghrelin receptor KO mice, motor activity was unchanged in the first 4 h after C75 Evofosfamide treatment but feeding was already suppressed to,20% of the baseline. Second, if it is the decreased motor activity that interferes with normal feeding behavior after C75 injection then one would expect that the drive for food, i.e., hunger, progressively increases during the dark. Hunger induced by food restriction is accompanied by characteristic changes in sleep-wake activity and c-Fos activation pattern in the brain. Overnight food deprivation results in a,24% increase in waking time during the dark in mice. This arousal response was not observed after C75 injection supporting the notion that the animals were not hungry, in spite of the fact that they ate less than 18% of their normal food amount during the dark period. Also, food deprivation stimulates c-Fos expression in orexigenic brain structures such as the paraventricular nucleus, ARC and LH, but systemic C75 treatment fails to elicit similar activation pattern. A possible explanation for the decreased feeding after C75 injection is that C75 elicits a satiety-like state. The sleep findings, however, do not support this notion. Both naturally occurring satiety that follows feeding as well as injection of satietyinducing hormones such as cholecystokinin lead to increases in sleep. In our study, however, C75 induced dosedependent and long-lasting suppression of REMS. Thus the sleep phenotype after C75 treatment does not match fasting or satiated conditions but shows close similarity to the sleep pattern described in visceral pain models. Visceral illness elicited by LiCl injections is accompanied by transient increase in wakefulness followed by long-lasting suppression of REMS. An ip bolus injection of LiCl causes significant increase in the latency and a significant reduction in the occurrence of REM sleep in the immediate hours following the injection. In contrast, NREM sleep occurrence is only slightly affected by lithium administration. LiCl treatment significantly reduces the relative delta power of the EEG after LiCl treatment. We also observed the suppression of EEG SWA, i.e. delta waves, after C75 administration. Furthermore, LiCl treatment leads to behavioral inactivity and causes rats to lie quietly on the floor of the cage and elicits diarrhea.