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

Abstract.

Rationale: γ-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 µg (1,2,5,6,-tetrahydropyridine)-methylphosphinic acid (TPMPA), a specific antagonist of GABA_C receptors. Results: Principally at 50 µg, 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.