Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant

RATIONALE: Orexins play a key role in the maintenance of alertness and are implicated in the modulation of diverse physiological processes, including cognitive function. Almorexant, a dual orexin receptor antagonist, transiently and reversibly blocks the action of orexin peptides at both OX(1) and OX(2) receptors and increases time spent in rapid eye movement (REM) and non-REM sleep. OBJECTIVES: We explored the direct effects on learning and memory of single and repeated administration of almorexant in rats. METHODS: Following administration of high doses of almorexant (300 mg/kg, p.o.), scopolamine (0.8 mg/kg, i.p.), combination almorexant-scopolamine, or vehicle alone, rats were trained on a Morris water maze spatial navigation task, or on a passive avoidance task. RESULTS: Rats treated with almorexant learned the spatial navigation task with similar efficacy as vehicle-treated animals. After 4 days, almorexant—but not vehicle-treated rats had established spatial memory; after 8 days, spatial memory had been established in both vehicle—and almorexant-treated rats. Scopolamine-treated rats failed to learn the spatial task. Both vehicle—and almorexant—but not scopolamine-treated rats demonstrated passive avoidance learning. Almorexant did not ameliorate scopolamine-induced impairment of learning in either task. CONCLUSIONS: Rats treated with almorexant are fully capable of spatial and avoidance learning.