Benzodiazepines (BZs) and related GABAA modulators are safe and effective anxiolytics, but also have shown dramatic increases in abuse in recent years. A major medical use of BZ-type drugs is treatment of sleep disor- ders, and at present, we have very little information on the mechanisms underlying these effects. Nonhuman primates, in particular, rhesus macaques (Macaca mulatta) are an excellent model organism for studying sleep due to the similarity in sleep architecture with human primates. The ?gold standard? for studying sleep is the use of polysomnography based on telemetric recording of electroencephalogram/electromyogram/electrooculogram (EEG/EMG/EOG; hereafter referred to as ?EEG telemetry? for brevity). In addition to the study of sleep, EEG telemetry may be used to understand the relationships of frequency band changes to behavioral effects of BZs during the wake cycle (e.g., sedation). The purpose of this Exploratory/Developmental proposal is to expand EEG telemetry technology in our program that uses rhesus macaque models and first-in-kind compounds to understand BZ/GABAA pharmacology of sleep and sedation. The premise of this strategy is that different GABAA receptor subtypes mediate changes in sleep architecture, EEG bandwidth, and sedation during sleep/wake cy- cles?all of which can be delineated using novel telemetry approaches.
Specific Aim 1 will determine systemat- ically the changes in EEG bandwidth, sleep architecture and daytime sedation induced by the non-selective BZ sleep aid temazepam and the commonly-used ?1GABAA-selective sleep aid zolpidem. Our approach will be to assess drug effects using EEG telemetry during the sleep cycle and novel observation techniques coupled with EEG telemetry during the wake cycles of female and male rhesus monkeys.
Specific Aim 2 will determine the extent to which BZ-induced modulation of sleep architecture, EEG bandwidth, and sedation are mediated by ?2 subunit-containing GABAA receptors and Specific Aim 3 will investigate the role of ?3 subunit and ?5 subunit- containing GABAA receptors in the characteristic changes in sleep architecture, EEG bandwidth, and sedative effects induced by BZ-type sleep aids. Pharmaco-EEG will greatly enhance our ability to do innovative transla- tional research that also should shed light on novel mechanisms associated with the pharmacology of abused drugs in primates.
Approximately 1 in 3 people will experience insomnia sometime in their lifetimes. Our Exploratory/Developmental (R21) application will establish EEG telemetry technology in our laboratories that will allow us to precisely study sleep patterns in rhesus macaques, a species with sleep patterns very similar to humans. We will preliminarily explore fundamental mechanisms of action underlying ?benzodiazepine? type drugs to alter sleep, with the hope of discovering novel medications for treating insomnia not involving widespread abuse potential.
