CART (Cocaine and Amphetamine-Regulated Transcript) peptides appear to mediate behaviors associated with psychostimulant drugs including: hypothalamically mediated suppression of food intake, activation of the HPA axis, locomotion, and reward/motivation. We hypothesized that CART-containing neurons have additional anatomical/behavioral relationships (indirect or direct) with mesolimbic dopaminergic pathways and other nuclei involved in mediating wakefulness; i.e.,a behavioral 'state' also associated with psychostimulants. Our preliminary studies are supportive in demonstrating that: 1) CART exhibits a diurnal rhythm in non-human primate spinal fluid that peaks in the early morning; 2) intracerebroventricular delivery in rats during their major sleep period produces profound, dose-dependent, increases in wake; 3) interference with endogenous CART signaling increases rapid-eye-movement sleep in the initial major active period of rats; and 4)and CART is depressed in non-human primates and humans afflicted with parkinsonism and other conditions characterized by impairments in wakefulness. We propose to further characterize the wake promoting effects of CART peptides, and explore the underlying substrates and their potential clinical significance. S.A. #1 proposes to differentiate between CART'S role as a homeostatic vs. circadian wake promoting signal by examining its daily oscillations, responsiveness to sleep deprivation, and relationship to prior sleep-wake in the diurnal (wake-active) non-human primate (rhesus). S.A. #2 proposes to demonostrate that endogenous CART is necessary for normal wakefulness by central delivery of CART antibodies to rats and characterizing sleep/wake state in Cart +/- and Cart -/- mice. S.A. #3 proposes anatomical (rat,non-human primate, and human) and behavioral (rat)determination of the regional, cellular, and pharmacologic bases of CART'S wake promoting actions. Finally, S.A. #4 proposes to examine spinal fluid CART in human conditions characterized by impairments in maintaining wakefulness (e.g., narcolepsy, parkinsonism, idiopathic hypersomnia, and myotonic dystrophy). Taken together, these findings will provide new insights into the mechanisms governing wakefulness in the context of a growing recognition that the key cellular mechanisms also involve integration of additional, seemingly disparate adaptive behaviors such as energy homeostatis, feeding, reward and motivation.