Gaboxadol - A new awakening in sleep

Merck, Sharp & Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
Current Opinion in Pharmacology (Impact Factor: 4.6). 03/2006; 6(1):30-6. DOI: 10.1016/j.coph.2005.10.004
Source: PubMed


Drugs that enhance synaptic gamma-aminobutyric acid (GABA)ergic neurotransmission are widely utilized in the clinical setting. Barbiturates and benzodiazepine receptor agonists, for example, both potentiate an inhibitory chloride conductance through GABA-gated channels, and thereby achieve their sedative-hypnotic effects. The primary locus of action of these agents, and indeed most neuroactive drugs, is the postsynaptic junction. By contrast, gaboxadol, a selective extrasynaptic GABA receptor agonist and late-stage investigational treatment for insomnia, acts on a unique delta-containing GABAA receptor subtype found exclusively outside of the synapse. Although the mechanistic details of extrasynaptic neurotransmission remain to be fully established, it is now clear that these receptors demonstrate unique pharmacological, biophysical and electrophysiological properties. 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. This unique mechanism has contributed to our increased understanding of sleep mechanisms, and targeting of this system offers potential advantages over existing insomnia treatments.

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    • "At present, the easiest way to restore ITonic(GABA) seems to be the application of gaboxadol (THIP). This compound is an already well-characterized delta-subunit-specific GABA(A) hyperagonist and has for some time been considered for treatment of insomnia (Wafford and Ebert, 2006). In view of the presently discovered HD-related deficit in ITonic(GABA), the question arises whether HD patients can benefit from this drug. "
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    ABSTRACT: The extracellular concentration of the two main neurotransmitters glutamate and GABA is low but not negligible which enables a number of tonic actions. The effects of ambient GABA vary in a region-, cell-type, and age-dependent manner and can serve as indicators of disease-related alterations. Here we explored the tonic inhibitory actions of GABA in Huntington's disease (HD). HD is a devastating neurodegenerative disorder caused by a mutation in the huntingtin gene. Whole cell patch clamp recordings from striatal output neurons (SONs) in slices from adult wild type mice and two mouse models of HD (Z_Q175_KI homozygotes or R6/2 heterozygotes) revealed an HD-related reduction of the GABA(A) receptor-mediated tonic chloride current (ITonic(GABA)) along with signs of reduced GABA(B) receptor-mediated presynaptic depression of synaptic GABA release. About half of ITonic(GABA) depended on tetrodotoxin-sensitive synaptic GABA release, but the remaining current was still lower in HD. Both in WT and HD, ITonic(GABA) was more prominent during the first 4 h after preparing the slices, when astrocytes but not neurons exhibited a transient depolarization. All further tests were performed within 1-4 h in vitro. Experiments with SNAP5114, a blocker of the astrocytic GABA transporter GAT-3, suggest that in WT but not HD GAT-3 operated in the releasing mode. Application of a transportable substrate for glutamate transporters (D-aspartate 0.1-1 mM) restored the non-synaptic GABA release in slices from HD mice. ITonic(GABA) was also rescued by applying the hyperagonist gaboxadol (0.33 μM). The results lead to the hypothesis that lesion-induced astrocyte depolarization facilitates non-synaptic release of GABA through GAT-3. However, the capacity of depolarized astrocytes to provide GABA for tonic inhibition is strongly reduced in HD.
    Frontiers in Neural Circuits 11/2013; 7:188. DOI:10.3389/fncir.2013.00188 · 3.60 Impact Factor
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    • "Drugs that directly activate δGABAA receptors, and those that act as positive allosteric modulators, are currently under investigation as potential treatments for a wide variety of disorders, including insomnia (Wafford and Ebert, 2006), pain (Bonin et al., 2011), cognitive dysfunction (Wang et al., 2007) and depression (Maguire and Mody, 2008; Christensen et al., 2012). The most widely studied of these compounds is 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a δGABAA receptor–preferring agonist (Brown et al., 2002; Meera et al., 2011). "
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    ABSTRACT: Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that contain the δ subunit (δGABAA receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABAA receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABAA receptor-preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABAA receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p.) on memory performance in wild-type (WT) and δGABAA receptor null mutant (Gabrd(-/-)) mice. Additionally, the effects of THIP on long-term potentiation (LTP), a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not Gabrd(-/-) mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not Gabrd(-/-) mice, an effect that was blocked by GABAA receptor antagonist bicuculline. Thus, acutely increasing δGABAA receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABAA receptor activity.
    Frontiers in Neural Circuits 09/2013; 7:146. DOI:10.3389/fncir.2013.00146 · 3.60 Impact Factor
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    • "For the α5 subunit-containing GABAA-Rs, there is no specific agonist available except inverse agonists that reduce receptor responses. However, THIP at low concentration is a selective agonist for the δ subunit-containing GABAA-Rs and widely used to elicit tonic inhibition both in vitro and in vivo[40-43]. Therefore, we delivered THIP (4 mg/kg) through the cannula pre-implanted in the lateral tail vein after the induction of epileptiform activity. "
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    ABSTRACT: Background GABAergic deficit is one of the major mechanisms underlying epileptic seizures. Previous studies have mainly focused on alterations of synaptic GABAergic inhibition during epileptogenesis. Recent work suggested that tonic inhibition may also play a role in regulating epileptogenesis, but the underlying mechanism is not well understood. Results We employed molecular and pharmacological tools to investigate the role of tonic inhibition during epileptogenesis both in vitro and in vivo. We overexpressed two distinct subtypes of extrasynaptic GABAA receptors, α5β3γ2 and α6β3δ receptors, in cultured hippocampal neurons. We demonstrated that overexpression of both α5β3γ2 and α6β3δ receptors enhanced tonic inhibition and reduced epileptiform activity in vitro. We then showed that injection of THIP (5 μM), a selective agonist for extrasynaptic GABAA receptors at low concentration, into rat brain also suppressed epileptiform burst activity and behavioral seizures in vivo. Mechanistically, we discovered that low concentration of THIP had no effect on GABAergic synaptic transmission and did not affect the basal level of action potentials, but significantly inhibited high frequency neuronal activity induced by epileptogenic agents. Conclusions Our studies suggest that extrasynaptic GABAA receptors play an important role in controlling hyperexcitatory activity, such as that during epileptogenesis, but a less prominent role in modulating a low level of basal activity. We propose that tonic inhibition may play a greater role under pathological conditions than in physiological conditions in terms of modulating neural network activity.
    Molecular Brain 05/2013; 6(1):21. DOI:10.1186/1756-6606-6-21 · 4.90 Impact Factor
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