Study of a GABAc receptor antagonist on sleep-waking behavior in rats

Rationale: gamma -Aminobutyric acid (GABA) is the main inhibitory transmitter of the brain. The involvement of GABA(A) and GABA(B) receptors in sleep-waking processes is well established. Objectives: This research studied the influence of GABA(C) receptors. Methods: The rats were randomly infused in the fourth ventricle with vehicle and 25, 50, and 100 mug (1,2,5,6,-tetrahydropyridine)-methylphosphinic acid (TPMPA), a specific antagonist of GABA, receptors. Results: Principally at 50 mug, the molecule induced an increase of waking from 44.7% to 61.7% (P<0.003), which was the consequence of enhancement of both active and quiet wakefulness. Total slow wave sleep was decreased, particularly the slow-wave stage from 39% to 27.7% (P<0.02). Paradoxical sleep was also decreased from 14.5% to 9.1% (P<0.01). Conclusions: GABA(C) receptors are also involved in sleep-waking regulation. Since the sensitivity of GABA(C) receptors to GABA is much higher than that of GABA(A) and GABA(B) receptors, GABA(C) receptor modulators could be potential medications acting at low doses with fewer side effects.