Effects of amphetamine, diazepam and caffeine on polysomnography (EEG, EMG, EOG)-derived variables measured using telemetry in Cynomolgus monkeys

Abstract

Introduction: Medication-induced sleep disturbances are a major concern in drug development as a multitude of prescription drugs alter sleep patterns, often negatively. Polysomnography is used in clinical diagnostics but is also applicable to animal models. Rodent sleep architecture (nocturnal) differs from larger diurnal mammals, including humans, increasing the translational potential of non-rodent species to the clinic. This study aimed to characterize the response to pharmacological agents known to affect sleep structure and EEG activity in a non-human primate (Macaca fascicularis) using telemetry-based polysomnography. Methods: Animals were instrumented with telemetry transmitters for continuous electroencephalogram (EEG), electro-oculogram (EOG) and electromyogram (EMG) monitoring combined with video. EEG, EMG and EOG were monitored for 12 to 24h to establish baseline values, followed by administration of pharmacological agents (saline, d-amphetamine, diazepam or caffeine). Results: Amphetamine (0.3 and 1mg/kg, by oral administration (PO)) significantly reduced total sleep time, including the duration of both non-rapid eye movement [NREM] sleep and REM sleep. It also decreased EEG activity in low frequencies (i.e., 4–6Hz) during wakefulness. Diazepam (2mg/kg, PO) did not significantly alter sleep duration, but importantly reduced EEG activity in low frequencies (approximately 2–12Hz) during wakefulness, NREM and REM sleep. Finally, caffeine (10 and 30mg/kg, PO) decreased both NREM and REM sleep duration. In addition, spectral analysis revealed important decreases in low frequency activity (i.e., 1–8Hz) during wakefulness with a parallel increase in high frequency activity (i.e., 20–50Hz) during NREM sleep. Discussion: As these observations are similar to previously reported pharmacological effects in humans, results support that EEG, EOG and EMG monitoring by telemetry in Cynomolgus monkeys represents a useful non-clinical model to investigate and quantify drug-induced sleep disturbances.