0093 Orexin Receptor Antagonism Improves Stress-related Insomnia, “Next Day” Hypersomnia, And Sleep Dependent Memory Consolidation In The Rat

Introduction Sleep facilitates learning and memory, and sleep loss/disruption such as experienced in insomnia may impact cognition. Of utmost importance is the development of hypnotics that improve the sleep profile of the insomniac, but minimally impair sleep dependent memory consolidation (SDMC) and “next day” cognition. Here, we evaluated if treatment in the rat with the dual orexin receptor antagonist DORA-22 (Merck & Co., Inc.) would improve insomnia-related sleep disruption, consequent hypersomnia, as well as memory impairment. Methods To evaluate improvement of insomnia-related sleep disruption, animals were first administered doses of DORA-22 (vehicle 20% TPGS or DORA-22 doses of either 10, 30, or 100 mg/kg), and then exposed to 6 hours of a dirty cage change insomnia model. Recovery period hypersomnia following model exposure was also evaluated. In a second experiment, to evaluate DORA-22 improvement of insomnia-impaired SDMC, animals were first trained to learn the location of a platform in the Morris Water Maze, and then administered DORA-22 (above doses), followed by insomnia model exposure. Animals were then evaluated for memory of the platform location. Results Select doses of DORA-22 improved insomnia-related sleep disruption, producing an overall decrease in wake and increase in sleep. Furthermore, in the recovery period following model exposure, NREM and REM sleep latencies were decreased, indicating improved “next day” hypersomnia. Several water maze measures indicated improved probe trial performance due to DORA-22 treatment (select doses), including time and distance spent in the target quadrant and platform location, as well as number of platform crossings. Conclusion Our rodent dirty cage change models successfully disrupted sleep, as well as produced hypersomnia and impaired sleep-dependent memory consolidation. DORA-22 treatment was hypnotically effective, including improvement of insomnia-related sleep disruption and attenuated measures of hypersomnia. Additionally,DORA-22 treatment improved insomnia-associated memory consolidation deficits. Support (If Any) Merck Investigator Studies Program