Disease relevance of gaboxadol

• The selective GABA(A) receptor agonist gaboxadol dose-dependently (6 and 15 mg/kg, s.c.) reversed hindpaw mechanical allodynia and hyperalgesia for at least 150 min after administration [1].

Psychiatry related information on gaboxadol

• Compared with placebo, gaboxadol did not affect endocrine activity but significantly reduced perceived sleep latency, elevated self-estimated total sleep time, and increased sleep efficiency by decreasing intermittent wakefulness and powerfully augmented low-frequency activity in the EEG within non-REM sleep [2].
• RATIONALE: Previous studies demonstrated that gaboxadol, a selective GABA(A) agonist, increases both non-REM sleep and EEG delta activity within non-REM sleep in rats and slow wave sleep (SWS) as well as low-frequency activity in the EEG within non-REM sleep in healthy humans under normal conditions [3].
• H Lundbeck A/S, in collaboration with Merck & Co Inc, is developing gaboxadol, a GABAA agonist, for the potential treatment of sleep disorders [4].

High impact information on gaboxadol

• GABAA receptor {alpha}4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol [5].
• In this double-blind, placebo-controlled study, we investigated the influence of an oral dose of 15 mg of gaboxadol on nocturnal sleep and hormone secretion (ACTH, cortisol, prolactin, growth hormone) in 10 healthy elderly subjects (6 women) [2].
• Compared with the placebo postnap night, gaboxadol tended to shorten sleep latency, significantly decreased intermittent wakefulness, increased total sleep time and SWS and enhanced delta and theta activity in the non-REM EEG [3].
• These findings indicate that gaboxadol is able to increase sleep consolidation and non-REM sleep intensity, without disrupting REM sleep, in elderly individuals and that these effects are not mediated by a modulation of hormone secretion [2].
• Evidence for inhibitory effect of the agonist gaboxadol at human alpha 1 beta 2 gamma 2S GABAA receptors [6].

Biological context of gaboxadol

• Pharmacokinetics of the gamma-aminobutyric acid agonist THIP (Gaboxadol) following intramuscular administration to man, with observations in dog [7].

Anatomical context of gaboxadol

• The sensitivity of Purkinje cells (PCs) and neurons of the cerebellar nuclei (NCNs) to iontophoretic application of gamma-aminobutyric acid (GABA), 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) and baclofen, i.e., GABAA and GABAB agonists respectively, have been studied in anesthetized rats [8].
• Importantly, the delta-containing GABAA receptor subtype activated by gaboxadol is highly expressed in the thalamus, where it might behave as a 'gain control' (independently controlling the strength of signals) in the corticothalamic pathways that govern sleep-relevant neuronal oscillations [9].

Associations of gaboxadol with other chemical compounds

• In an early phase-2 study, THIP (4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol) was investigated in a single-blind controlled trial comprising 9 outpatients suffering from epilepsy [10].

Analytical, diagnostic and therapeutic context of gaboxadol

• Gaboxadol, an investigational treatment and a selective extrasynaptic GABA(A) receptor agonist (SEGA), targets GABA(A) receptors containing a delta subunit, which are located outside the synaptic junctions of thalamic and cortical neurons thought to play an important regulatory role in the onset, maintenance, and depth of the sleep process [11].
• The selective GABA(A) receptor agonist gaboxadol has been shown to increase non-REM sleep and the duration of the non-REM episodes in rats and sleep efficiency in young subjects and to enhance low-frequency activity in the electroencephalogram (EEG) within non-REM sleep in both rats and humans [2].
• METHODS: In a randomized, placebo-controlled cross-over study using a late afternoon nap model, we assessed the effects of a single oral dose of 20 mg gaboxadol on disturbed nighttime sleep in young, healthy subjects [3].

References