Role of GABAA Receptors in Sleep Regulation Differential Effects of Muscimol and Midazolam on Sleep in Rats

Abstract

To assess the influence of the gamma-aminobutyric acid (GABA)A receptor on sleep and sleep EEG, rats were injected intraperitoneally with vehicle, two doses of muscimol (0.2 and 0.4 mg/kg), a selective GABAA agonist, and midazolam (3 mg/kg), a benzodiazepine-GABAA agonist. EEG and EMG recordings were made for 6 or 8 hours. Muscimol dose-dependently increased the amount of nonrapid eye movement sleep (nonREMS) and REMS. The higher dose of muscimol enhanced EEG activity over almost the entire frequency range (0.5-25 Hz), including delta (0.5-4 Hz) and sigma (11-16 Hz) activity, within nonREMS and in the frequencies over 10 Hz within REMS. Midazolam also increased the amount of nonREMS. However, most of the other effects of midazolam contrasted the effects of muscimol: midazolam decreased REMS, reduced low frequency (< or = 11 Hz) EEG activity within nonREMS, and enhanced the activity in higher frequencies during both nonREMS and REMS. These data demonstrate the involvement of GABAA receptors in the regulation of sleep-wake behavior as well as in the generation of spindles and delta waves during nonREMS. The effects of these two GABAA agonists indicate that activation of different binding sites on the GABAA receptor complex differentially affect sleep states and sleep EEG.

Diazepam-induced changes in sleep: Role of the α1 GABAAreceptor subtype

“…As in mice, power in the waking spectrum was enhanced in frequencies above 10 Hz (14). This increase is consistent with the induction of high-frequency power in waking in rats after tiagabine, a centrally active selective GABA-reuptake inhibitor (38,39).…”

“…15) and the rat (14,28). This effect occurred in mice of both genotypes and therefore does not seem to be mediated by the ␣1 GABA A receptor subtype.…”

“…BZ hypnotics have distinct effects both on sleep and the sleep electroencephalogram (EEG). They induce dose-dependent increases of non-rapid eye movement (NREM) sleep, a reduction of REM sleep in humans and a typical BZ ''fingerprint,'' consisting of a reduction in delta activity in humans and rats, an increase of sigma activity in humans, and high-frequency activity in rats (8)(9)(10)(11)(12)(13)(14)(15). These effects are common for agonists acting at the BZ site, irrespective of whether they are BZ or non-BZ compounds such as zolpidem and zopiclone (15)(16)(17).…”

The Influence of Subchronic Administration of the Neurosteroid Allopregnanolone on Sleep in the Rat

“…In rats, benzodiazepines reduce sleep latency, promote non-REMS (in particular its substate pre-REMS) and transiently suppress REMS (reviewed in Lancel 1999). Furthermore, such compounds depress slow frequency components and augment spindling in the EEG within non-REMS, while enhancing high-frequency activity in all vigilance states (Hashimoto et al 1992;Lancel et al 1996;Mandema et al 1991). However, various agonistic modulators of GABA A receptors, including short-acting benzodiazepines, have been shown to rapidly lose their soporific action upon repeated dosing.…”

“…Under halothane anaesthesia, 16 male Wistar rats (Charles River Laboratories, Sulzfeld, Germany), weighing between 290 and 370 g, were implanted with EEG and EMG electrodes as described in detail elsewhere (Lancel et al 1996). Additionally, an epidural thermistor (Betatherm Ireland Ltd.; type 10K3MCD1) was implanted (position: 1 posterior, 3.5 lateral relative to the bregma) to record brain temperature (Tbr).…”