The GABA A agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans

Abstract

Recent studies in the rat demonstrated that systemic administration of muscimol and THIP, both selective GABAA receptor agonists, elevates slow wave activity in the EEG during non-rapid eye movement (NREM) sleep. In this placebo-controlled study, we assessed the influence of an oral dose of 20 mg THIP on nocturnal sleep in young healthy humans. Compared to placebo, THIP increased slow wave sleep by about 25 min. Spectral analysis of the EEG within NREM sleep revealed significant elevations in the lower frequencies (< 8 Hz) and reductions in the spindle frequency range (approximately 10-16 Hz). In accordance with previous findings in the rat, these data imply that GABAA agonists promote deep NREM sleep, without suppressing REM sleep. These effects are opposite to those induced by agonistic modulators of GABAA receptors such as benzodiazepines and are at variance with established mechanisms according to which GABAA agonists and modulatory agonists would have similar effects. The sleep response to GABAA agonists is highly similar to that evoked by sustained wakefulness, suggesting that GABAA receptors may be implicated in the homeostatic regulation of sleep.

Thalamic δ-Subunit Containing GABAAReceptors Promote Electrocortical Signatures of Deep Non-REM Sleep But Do Not Mediate the Effects of Etomidate at the ThalamusIn Vivo

“…These include an increase in 1-4 Hz EEG activity and a decrease in spindle-like oscillations, with these effects observed in wildtype but not Gabrd Ϫ/ Ϫ mice. These findings are consistent with the sedating property of THIP and its effects on electrocortical activity when administered systemically in humans and rodents (Faulhaber et al, 1997;Vyazovskiy et al, 2005;Cremers and Ebert, 2007). Importantly, we also show that etomidate at the thalamus does not recapitulate the electrocortical effects of THIP, with etomidate eliciting changes in electrocortical activity that were largely independent of ␦GABA A R expression.…”

“…Microperfusion of 50 M THIP into the ventrobasal complex increased 12-30 Hz power in Gabrd Ϫ / Ϫ mice, indicating that THIP had some non-␦GABA A R-mediated effects, potentially via effects on synaptic GABA A Rs (Brown et al, 2002;Stó rustovu and Ebert, 2003). Importantly, the effective delivered concentrations of THIP used in this study (see Materials and Methods) were selected based on previous reports showing that THIP, at those concentrations, has minimal effects on synaptic GABA A Rs (Brown et al, 2002;Stó rustovu and Ebert, 2003;Belelli et al, 2005;Jia et al, 2005) and promotes sleep and sedation in humans (Madsen et al, 1983;Faulhaber et al, 1997). Nonetheless, it is possible that THIP also had non-␦GABA A R-mediated effects that contributed to the changes identified in the wild-type mice.…”

“…Thus, the effective concentrations of THIP at the ventrobasal complex are expected to have been ϳ1-1.8 and 5-9 M, while the expected effective concentrations of etomidate at the thalamus were ϳ1-1.8 and 3-5.4 M at the probe tip. The concentrations of THIP used in this study were selected based on clinically relevant doses in humans, with serum and plasma concentrations in the same range as our effective concentrations enhancing sleep quality and sedation (Madsen et al, 1983;Faulhaber et al, 1997). Additionally, the effects of THIP at synaptic GABA A Rs are minimal at these concentrations, whereas there is modulation of extrasynaptic GABA A Rs (Brown et al, 2002;Belelli et al, 2005;Jia et al, 2005;Drasbek and Jensen, 2006).…”

GABAAReceptor-Mediated Tonic Inhibition in Thalamic Neurons

“…Therefore, endogenous agents that decrease the tonic current may promote wakefulness, and those that enhance it may promote sleep. THIP is a potent hypnotic that promotes slow-wave sleep in both humans and rats (Lancel and Faulhaber, 1996;Faulhaber et al, 1997). We suggest that part of its hypnotic action is mediated by increasing the tonic current in TC neurons, thereby shifting them into a membrane potential region in which low-threshold burst firing can occur and sleep is promoted.…”

Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep–wakefulness: Role of δ-subunit containing extrasynaptic GABAA receptors

“…Systemic administration of THIP induces sleep in rats and humans (Faulhaber et al, 1997;Lancel, 1997). However it is yet unknown where in the brain does THIP act to induce sleep.…”