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 delta-subunit containing extrasynaptic GABAA receptors.

Gaboxadol or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP) is a selective agonist for the delta-subunit containing extrasynaptic GABA(A) receptors that will soon enter the U.S. market as a sleep aid [Winsky-Sommerer R, Vyazovskiy VV, Homanics GE, Tobler I (2007) The EEG effects of THIP (gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors. Eur J Neurosci 25:1893-1899]. Numerous studies have shown that systemic administration of THIP reduces wakefulness and increases sleep both in humans and rats [Lancel M, Langebartels A (2000) Gamma-aminobutyric acid(A) (GABA(A)) agonist 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. J Pharmacol Exp Ther 293:1084-1090; Walsh JK, Deacon S, Dijk DJ, Lundahl J (2007) The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia. Sleep 30:593-602]. However, it is yet unclear where in the brain THIP acts to promote sleep. Since the perifornical lateral hypothalamus (PFH) contains orexin neurons and orexin neurons are critical for maintenance of arousal [McCarley RW (2007) Neurobiology of rapid eye movement (REM) and NREM sleep. Sleep Med 8:302-330], we hypothesized that THIP may act on PFH neurons to promote sleep. To test our hypothesis, we used reverse microdialysis to perfuse THIP unilaterally into the PFH and studied its effects on sleep-wakefulness during the light period in freely behaving rats. Microdialysis perfusion of THIP (100 microM) into the PFH produced a significant reduction in wakefulness with a concomitant increase in non-rapid eye movement or slow wave sleep as compared with artificial cerebrospinal fluid perfusion. REM sleep was unaffected. This is the first study implicating the delta-subunit containing extrasynaptic GABA(A) receptors in PFH in control of sleep-wakefulness in freely behaving rats.