0151 The Dual Orexin Receptor Antagonist Almorexant Blocks the Sleep-Disrupting Effects of Methamphetamine in Male Rhesus Monkeys

Abstract

Abstract Introduction Individuals with stimulant use disorder show a high prevalence of sleep problems. In the laboratory, stimulant drugs have been shown to affect sleep parameters in human and nonhuman primates, even when administered many hours before bedtime. Although the mechanisms underlying the relationship between stimulant use/abuse and sleep impairment remain unclear, recent research has implicated the orexin (also called “hypocretin”) system as a critical regulator of sleep-wake states. The aim of the present study was to investigate the effects of the dual orexin receptor antagonist (DORA) almorexant on the sleep-disrupting effects of methamphetamine in rhesus monkeys. Methods Male adult rhesus monkeys (Macaca mulatta, n=4) were fitted with primate collars to which Actiwatch monitors were attached. Actigraphy recording was conducted during baseline conditions and on the night after acute morning (9h) administration of vehicle or methamphetamine (0.03, 0.1 or 0.3 mg/kg, i.m.). During a second set of treatments, vehicle or almorexant (1, 3 or 10 mg/kg, i.m.) were administered in the evening (16:30h, 1.5h before “lights off”) following morning (9h) administration of methamphetamine (0.3 mg/kg, i.m.). Results Morning methamphetamine administration dose-dependently impaired sleep in rhesus monkeys, with the dose of 0.3 mg/kg significantly increasing sleep latency and decreasing sleep efficiency. Evening administration of almorexant improved both actigraphy-based sleep measures after morning administration of methamphetamine in a dose dependent manner. Conclusion Our findings indicate that orexin receptor systems are involved in methamphetamine-induced sleep disruption. The exact role of the two orexin receptors in this effect, alone or together, remains to be determined. This study suggests that DORAs can be effective in treating sleep impairment in individuals with methamphetamine use disorder or under stimulant prescription for other sleep and psychiatric disorders. Support Supported by UMMC Research Enhancement Funds.