THE GABA(A) AGONIST THIP PRODUCES SLOW-WAVE SLEEP AND REDUCES SPINDLING ACTIVITY IN NREM SLEEP IN HUMANS

Recent studies in the rat demonstrated that systemic administration of muscimol and THIP, both selective GABA(A) receptor agonists, elevates slow wave activity in the EEG during non-rapid eye movement (NREM) sl eep. In this placebo-controlled study, we assessed the influence of an oral dose of 20 mg THIP on nocturnal sleep in young healthy humans. C ompared to placebo, THIP increased slow wave sleep by about 25 min. Sp ectral analysis of the EEG within NREM sleep revealed significant elev ations in the lower frequencies (< 8 Hz) and reductions in the spindle frequency range (approximate to 10-16 Hz). In accordance with previou s findings in the rat, these data imply that GABA(A) agonists promote deep NREM sleep, without suppressing REM sleep. These effects are oppo site to those induced by agonistic modulators of GABA(A) receptors suc h as benzodiazepines and are at variance with established mechanisms a ccording to which GABA(A) agonists and modulatory agonists would have similar effects. The sleep response to GABA(A) agonists is highly simi lar to that evoked by sustained wakefulness, suggesting that GABA(A) r eceptors may be implicated in the homeostatic regulation of sleep.