Short Sleep Duration as a Predictor of Methamphetamine Intake: Role of Orexin Mechanisms

Project Summary_________________________________________________________________________ Insufficient sleep predicts substance use and associated psychosocial problems, and puts individuals at a higher risk for substance use disorders. In fact, our preliminary data suggest that the quality of overall baseline sleep may influence methamphetamine intake in rhesus monkeys. These findings raise the important possibility that short sleep increases the probability of enhanced methamphetamine use and/or use disorder. We recently dis- covered that short sleep is a strikingly prevalent phenotype among adult female rhesus monkeys, with a preva- lence of nearly 40%. While the biological factors contributing to this particular phenotype remain unknown, al- tered circadian rhythm of orexin (hypocretin) regulation has been proposed as a key mediator of short sleep (insomnia) in humans, and our studies suggest that the orexin system is involved in the short sleep phenotype in female monkeys. Moreover, our recent research also has implicated the orexin system as a potential modu- lator of both the sleep impairing and reinforcing effects of methamphetamine, suggesting an important mecha- nistic link between sleep regulation and methamphetamine pharmacology. Based on these observations, the working hypothesis of this application is that dysregulation of orexin processes and specific orexin receptor subtypes play a key role in phenotypic short sleep in female monkeys that, in turn, increases vulnerability to the addictive properties of methamphetamine. Our Research Strategy is organized around three Specific Aims, and all experiments will be conducted in female short sleepers and female normal sleepers. Aim 1 will evaluate the hypothesis that dysregulation of orexin processes underlies the short sleep phenotype in female monkeys via OX2 receptors. We will investigate the effects of novel orexin receptor ligands on electro- encephalography-based telemetric recordings of sleep-wake cycles, and will evaluate diurnal rhythms of circu- lating orexin levels in blood. Aim 2 will evaluate the hypothesis that phenotypic short sleep increases vulnerability to the addictive properties of methamphetamine in female rhesus monkeys. Acquisition of methamphetamine self-administration will be evaluated across phenotypes, and we will use behavioral economics to investigate the reinforcing effectiveness of methamphetamine. Aim 3 will evaluate the hypothesis that the reinforcing effects of methamphetamine in short sleepers are modulated uniquely by the OX2 receptor system. We will investigate the effects of daytime and nighttime treatments with orexin receptor agonists and antagonists on methampheta- mine intake in short vs normal sleepers. The research in this application addresses a key topic for public health by proposing to investigate the effects of short sleep on methamphetamine intake and the orexin mechanisms involved in this phenomenon.