Role of sleep disruption in cognitive impairment associated with methamphetamine use

Project Abstract Methamphetamine use and abuse are on the rise. Patients seeking treatment for methamphetamine use disorder often experience cognitive deficits and an increased incidence of sleep disturbances. Of note, it is well known that sleep impairment can negatively impact cognition, suggesting that methamphetamine-induced sleep disruption may be a key factor mediating the cognitive problems observed in methamphetamine users. Because individuals experiencing cognitive or sleep problems have poorer treatment outcomes and a greater likelihood of relapse, addressing sleep and cognitive impairments associated with methamphetamine use may be a novel approach to improving treatment outcomes. Based on these observations, the working hypothesis of this application is that methamphetamine-induced cognitive deficits are mediated by the effects of methamphetamine on sleep. Our research strategy is organized around two Specific Aims. Aim 1 will evaluate the prediction that acute sleep impairment induced by methamphetamine leads to cognitive deficits in drug naïve monkeys. Male and female rhesus monkeys will be given methamphetamine alone, methamphetamine plus the sleep aid suvorexant, or suvorexant alone the day before cognitive tests (CANTAB) evaluating executive functioning (intra-extra dimensional set-shifting task) and working memory (delayed matching-to-sample task). Aim 2 will evaluate the prediction that chronic methamphetamine self-administration induces greater cognitive deficits than acute administration, which will be mediated by methamphetamine-induced sleep disruption. Monkeys will be trained to self-administer methamphetamine (i.v.), and CANTAB cognition tests will be conducted after one month of methamphetamine taking, methamphetamine taking + evening suvorexant treatments, or food taking + evening suvorexant. Throughout Aim 1 and Aim 2 studies, sleep will be evaluated using actigraphy. Results from the proposed studies will provide key information regarding the extent to which methamphetamine-induced sleep disruptions contribute to the cognitive problems experienced by methamphetamine users, and the extent to which chronic drug use is necessary for cognitive impairments to emerge. Further, positive results with suvorexant will support the notion that treating drug-induced sleep problems may be a novel therapeutic strategy to improve patient outcomes, which would be particularly relevant for behavioral therapies that rely on intact cognitive function (e.g., cognitive behavioral therapy).