The dual orexin receptor antagonist almorexant blocks the sleep-disrupting and daytime stimulant effects of methamphetamine in rhesus monkeys

Background: The present study investigated the effects of the dual orexin receptor antagonist (DORA) almorexant, a sleep-modulating drug, on the sleep-disrupting effects of methamphetamine in adult rhesus monkeys. Methods: Monkeys were fitted with primate collars to which actigraphy monitors were attached. To determine the effects of methamphetamine on daytime activity and sleep-like parameters, monkeys were given acute injections of vehicle or methamphetamine (0.03, 0.1 or 0.3 mg/kg, i.m.) in the morning (9:00 h) (n = 4 males). We then determined the ability of almorexant to alter the daytime and/or sleep-like effects of the largest (effective) dose of methamphetamine. Vehicle or almorexant (1, 3 or 10 mg/kg, i.m.) were administered in the evening (16:30 h, 1.5 h before "lights off") following morning (9:00 h) administration of methamphetamine (0.3 mg/kg, i.m.), or as a pretreatment (8:30 h) before methamphetamine injections (9:00 h) (n = 4 males). The ability of almorexant (10 mg/kg) to improve sleep-like behaviors also was assessed in a group of monkeys quantitatively identified with short-duration sleep (n = 2 males, 2 females). Results: Morning methamphetamine administration dose-dependently impaired sleep in rhesus monkeys (0.3 mg/kg significantly increased sleep latency and decreased sleep efficiency). Administration of almorexant, both as a pretreatment or as an evening treatment, improved methamphetamine-induced sleep impairment in a dose dependent manner. Morning pretreatment with almorexant also blocked the daytime stimulant effects of methamphetamine. Evening, but not morning, treatment with almorexant in a group of monkeys with baseline short-duration sleep improved sleep measures. Conclusions: Our findings indicate that orexin receptor systems are involved in methamphetamine-induced hyperarousal and sleep disruption.