Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys

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This funded research project, now in its 13th year, is aimed at understanding the neurobiology of cocaine abuse in a unique nonhuman primate model: intravenous cocaine self-administration (SA) in socially housed cynomolgus monkeys. The scientific premise is that different mechanisms maintain cocaine SA based on social rank and sex and thus different drug treatments will be required to produce a positive outcome in these groups. For this Administrative Supplement, we are proposing to extend the phenotypic characteristics of socially housed female and male monkeys to include measures of sleep. Cocaine-induced changes in sleep duration, architecture and quality could impact cognitive processes that would aid someone in refraining from continuing cocaine use. There is a gap in knowledge related to the relationship between cocaine-induced sleep disruptions and cognitive performance and how those affect treatment outcomes. We have a unique opportunity to study cocaine-sleep interactions because we currently have cocaine-naïve socially housed female and male cynomolgus monkeys (n=4/sex) being trained under various cognitive tasks. We propose to implant them with telemetry devices to record electroencephalographic (EEG) activity to assess sleep/wake states while cocaine-naïve and following cocaine SA. In Aim 1, we will examine the relationship between cognition and sleep/wake architecture in cocaine-naive socially housed male and female cynomolgus macaques. Each monkey is currently being trained on four cognitive tasks that assess different cognitive domains using the Cambridge Neuropsychological Test and Battery (CANTAB) apparatus. After implanting telemetry devices to record EEG from freely-moving monkeys within their home cage, we will examine each animal’s sleep-wake architecture as it relates to their social rank; these data will serve as a baseline for examining the effects of cocaine SA in Aim 2. We hypothesize sex, menstrual cycle and social rank differences in sleep architecture and that monkeys (females and males) with a less disrupted sleep cycle will have better cognitive profiles. The studies in Aim 2 will be the first to determine the effects of acquisition of cocaine SA on sleep architecture in socially housed monkeys. We hypothesize that dominant females and subordinate males will acquire at lower doses than the other monkeys and that when acquisition occurs, sleep and cognition will be disrupted. In Aim 3, we propose to examine the effects of cocaine dose (saline, 0.01-0.3 mg/kg/injection) on sleep architecture. We propose to give monkeys access to high cocaine doses daily, in order to determine if tolerance develops to the effects on sleep. Finally, we will examine the effects of cocaine abstinence on sleep/wake architecture. We hypothesize that sleep, as assessed with EEG, will be sensitive to cocaine abstinence, providing evidence of cocaine withdrawal symptoms in an animal model. Future studies will examine how drug treatments affect sleep/wake architecture and cognition, during cocaine abstinence and following re-exposure to cocaine. Expanding our research to include sleep also provides rationale for the evaluation of future drug treatments.