Gaboxadol - A new awakening in sleep
ABSTRACT 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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- "For example, direct enhancement of d-GABA A Rs with gaboxadol (4,5,6,7- tetrahydroisoxazolo(5,4-c)pyridin-3-ol, or THIP) has been shown to lessen negative symptoms in a mouse model of postpartum depression (Maguire & Mody, 2008). At 500 nM, THIP acts as a d-GABA A R-selective agonist (Brown et al., 2002) and was previously proposed as a sleep-promoting drug (Wafford & Ebert, 2006), only to fail phase III clinical trials because of its side effects (Brickley & Mody, 2012). Safer d-GABA A R-specific agonists are currently under investigation (Wafford et al., 2009). "
ABSTRACT: Epilepsies consist of a spectrum of neurologic disorders typically characterized by unpredictable and dysfunctional network behaviors in the central nervous system (CNS), which lead to discrete episodes of large bouts of uncontrolled neuronal synchrony that interfere with the normal functioning of the brain. Temporal lobe epilepsy (TLE) is accompanied by changes in interneuronal innervation and modifications in different γ-aminobutyric acid (GABA)A receptor subunits. Hormones play an important role in modulating the overall excitability of neurons, and at the same time hormonal pathways are frequently modified during epilepsy. This review focuses on TLE-correlated modifications of GABAergic transmission, and in particular on the implications of some of our own findings related to GABAARs containing the δ subunits (δ-GABAARs). These are extra- or perisynaptic GABAARs that mediate tonic inhibition, a major component of the inhibitory mechanism in the brain. The most potent endogenous modulators of δ-GABAARs are neurosteroids, which act as positive allosteric modulators. Plasticity of δ-GABAARs during TLE consists of down-regulation of the subunit in the dentate gyrus granule cells (DGGCs), while being up-regulated in interneurons. Surprisingly, the level of tonic inhibition in DGGCs remains unchanged, consistent with the idea that it becomes mediated by GABAARs containing other subunits. In parallel, tonic inhibition in a TLE model ceases to be sensitive to neurosteroid potentiation. In contrast, as predicted by the anatomic plasticity, interneuronal tonic current is increased, and remains sensitive to neurosteroids. These findings have important pharmacologic implications. Where neurosteroids normally have sedative and anticonvulsant effects, bimodal and cell-type specific modulations in their natural targets might weaken the inhibitory control on the dentate gate, under circumstances of altered neurosteroids levels (stress, ovarian cycle, or the postpartum period).Epilepsia 12/2012; 53(s9). DOI:10.1111/epi.12038 · 4.58 Impact Factor
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- "Accordingly, d-subunit containing receptors have recently attracted much attention as drug targets for the possible treatment of insomnia, anxiety and depression (Wafford and Ebert, 2006). The d-selective GABA A agonist THIP (or gaboxadol) has been in clinical trials for insomnia, and is at the same time a valuable selective tool to activate d-containing extrasynaptic receptors and experimentally induce tonic inhibition (Drasbek and Jensen, 2006). "
ABSTRACT: δ-subunit containing extrasynaptic GABA(A) receptors are potential targets for modifying neuronal activity in a range of brain disorders. With the aim of gaining more insight in synaptic and extrasynaptic inhibition, we used a new positive modulator, AA29504, of δ-subunit containing GABA(A) receptors in mouse neurons in vitro and in vivo. Whole-cell patch-clamp recordings were carried out in the dentate gyrus in mouse brain slices. In granule cells, AA29504 (1 μM) caused a 4.2-fold potentiation of a tonic current induced by THIP (1 μM), while interneurons showed a potentiation of 2.6-fold. Moreover, AA29504 (1 μM) increased the amplitude and prolonged the decay of miniature inhibitory postsynaptic currents (mIPSCs) in granule cells, and this effect was abolished by Zn²⁺ (15 μM). AA29504 (1 μM) also induced a small tonic current (12.7 ± 3.2 pA) per se, and when evaluated in a nominally GABA-free environment using Ca²⁺ imaging in cultured neurons, AA29504 showed GABA(A) receptor agonism in the absence of agonist. Finally, AA29504 exerted dose-dependent stress-reducing and anxiolytic effects in mice in vivo. We propose that AA29504 potentiates δ-containing GABA(A) receptors to enhance tonic inhibition, and possibly recruits perisynaptic δ-containing receptors to participate in synaptic phasic inhibition in dentate gyrus.Neuropharmacology 04/2012; 63(3):469-79. DOI:10.1016/j.neuropharm.2012.04.023 · 4.82 Impact Factor
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- "GABA A Rs play a pivotal role in the control of our sleep rhythms, and for many decades benzodiazepines and zolpidem, known for their ability to potentiate GABA A R currents, have remained the most widely prescribed treatment for insomnia, in spite of producing tolerance, addiction and withdrawal problems. In a search for more refined drug interventions, it has become clear that the hypnotic actions of the sleep promoting drug gaboxadol (Wafford and Ebert, 2006) (4,5,6,7-tetrahydroisothiazolo-[5,4- c]pyridin-3-ol; THIP) can be attributed to this drug's selective action on δ-GABA A Rs (Brown et al., 2002). At concentrations of around 500 nM, this drug activates δ-GABA A Rs with little action on synaptic GABA A R types. "
ABSTRACT: Over the past two decades, research has identified extrasynaptic GABA(A) receptor populations that enable neurons to sense the low ambient GABA concentrations present in the extracellular space in order to generate a form of tonic inhibition not previously considered in studies of neuronal excitability. The importance of this tonic inhibition in regulating states of consciousness is highlighted by the fact that extrasynaptic GABA(A) receptors (GABA(A)Rs) are believed to be key targets for anesthetics, sleep-promoting drugs, neurosteroids, and alcohol. The neurosteroid sensitivity of these extrasynaptic GABA(A)Rs may explain their importance in stress-, ovarian cycle-, and pregnancy-related mood disorders. Moreover, disruptions in network dynamics associated with schizophrenia, epilepsy, and Parkinson's disease may well involve alterations in the tonic GABA(A)R-mediated conductance. Extrasynaptic GABA(A)Rs may therefore present a therapeutic target for treatment of these diseases, with the potential to enhance cognition and aid poststroke functional recovery.Neuron 01/2012; 73(1):23-34. DOI:10.1016/j.neuron.2011.12.012 · 15.98 Impact Factor