The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model.Sleep 2019S
Insomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally impacting mnemonic function, yet many hypnotic drugs (e.g., benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine if the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze, then administered DORA-22 (10, 30, or 100mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a six-hour time period (at timepoints 0 and 3 hours), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption - wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared to vehicle treatment for one dose (30mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg); and time spent in platform location and number of platform crossings (10mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits.