Abstract Mkid 121

The hypocretin/orexin (Hcrt/OX) receptor-ligand system is involved in the pathophysiology of narcolepsy/cataplexy and may play a role in the physiologic regulation of sleep and waking. Most Hcrt/OX neurons are located in the perifornicular region (PeF) of the posterior hypothalamus. In this study, we explored the possibility that some pharmacological effects on sleep may also be mediated by this system, by microinjecting the clinically used benzodiazepine hypnotic triazolam (TR) into the PeF of rats. Fourteen rats received bilateral microinjections of vehicle and TR (0.25ug and 0.50 ug) into the PeF, in randomized order, followed by 4 hours of sleep/wake recordings. Data were analyzed by repeated measures analysis of variance for dose (vehicle, TR 0.25ug and 0.50ug) and time (hours 1-4) factors. In five additional rats, TR (0.50 ug) was administered in combination with the Type A ϒ-aminobutyric acid-benzodiazepine receptor (GABAA-BZD) antagonist, flumazenil (0.95 ug). TR (0.25 and 0.50ug) significantly decreased wake and intermittent wake time and increased non-rapid eye movement (NREM) and total sleep times in the two hours following injections. TR (0.25 and 0.50ug) decreased NREM sleep latency and TR (0.25ug) decreased rapid-eye movement latency. The effects of TR (0.50 ug) were blocked by flumazenil (0.95 ug). TR significantly enhanced sleep when microinjected into the PeF region. These data provide a basis for the hypothesis that the function of the Hcrt/OX system may be altered by exogenously administered benzodiazepines, and potentially by endogenous ligands of the GABAA-BZD receptor.