Simon Authier1, Leanne Bassett2, Mylene Pouliot3, Adeline Rachalski4, Eric Troncy5, Dominique Paquette3, Valérie Mongrain6. 1. CIToxLAB North America, 445 Armand Frappier, Laval, QC, Canada, H7V 4B3; Faculty of Veterinary Medicine, University of Montreal, P.O. box 5000, St-Hyacinthe, QC, Canada, J2S 7C6. Electronic address: authiers@ca.citoxlab.com. 2. CIToxLAB North America, 445 Armand Frappier, Laval, QC, Canada, H7V 4B3; Faculty of Veterinary Medicine, University of Montreal, P.O. box 5000, St-Hyacinthe, QC, Canada, J2S 7C6. 3. CIToxLAB North America, 445 Armand Frappier, Laval, QC, Canada, H7V 4B3. 4. Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada, H4J 1C5. 5. Faculty of Veterinary Medicine, University of Montreal, P.O. box 5000, St-Hyacinthe, QC, Canada, J2S 7C6. 6. Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada, H4J 1C5; Department of Neuroscience, Université de Montréal, Montreal, QC, Canada, H3C 3J7.
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.
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.
Authors: Jessica R Lunsford-Avery; Scott H Kollins; Sujay Kansagra; Ke Will Wang; Matthew M Engelhard Journal: J Clin Sleep Med Date: 2022-03-01 Impact factor: 4.324
Authors: Steven Cassar; Isaac Adatto; Jennifer L Freeman; Joshua T Gamse; Iñaki Iturria; Christian Lawrence; Arantza Muriana; Randall T Peterson; Steven Van Cruchten; Leonard I Zon Journal: Chem Res Toxicol Date: 2019-11-16 Impact factor: 3.739