Gaboxadol

BACKGROUND: Neuronal hyperactivity related to β-amyloid (Aβ) is considered an early warning sign of Alzheimer disease (AD). Although increasing evidence supports this opinion, the underlying mechanisms are still unknown. METHODS: Here, we recorded whole-cell synaptic currents and membrane potentials using patch clamping of acute hippocampal slices from human amyloid precursor protein (APP)/presenilin-1 transgenic (5XFAD) mice and their wild-type littermates. Biochemical methods, electron microscopic imaging, behavioral tests, and intraventricular drug delivery applied with osmotic pumps were used in this study...

Sleep is a conserved and essential behavior, but its mechanistic and functional underpinnings remain poorly defined. Through unbiased genetic screening in Drosophila , we discovered a novel short-sleep mutant we named argus . Positional cloning and subsequent complementation, CRISPR/Cas9 knock-out, and RNAi studies identified Argus as a transmembrane protein that acts in adult peptidergic neurons to regulate sleep. argus mutants accumulate undigested Atg8a(+) autophagosomes, and genetic manipulations impeding autophagosome formation suppress argus sleep phenotypes, indicating that autophagosome accumulation drives argus short-sleep...

BACKGROUND: Bipolar disorder type I is a severe psychiatric condition that leads to significant morbidity and mortality and whose treatment remains suboptimal. Its pathophysiology involves disturbance in the control of ionic fluxes so that when patients are either manic or depressed, the resting membrane potential of neurons is more depolarized than normal. Available mood stabilizers have a shared mechanism of normalizing ion flux by compensating for ionic abnormalities, and normalizing membrane potential...

OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit-containing extrasynaptic γ-aminobutyric acid type A (GABAA ) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose...

BACKGROUND: The Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales are widely accepted tools that measure overall disease severity and change, synthesizing the clinician's impression of the global state of an individual. Frequently employed in clinical trials for neuropsychiatric disorders, the CGI scales are typically used in conjunction with disease-specific rating scales. When no disease-specific rating scale is available, the CGI scales can be adapted to reflect the specific symptom domains that are relevant to the disorder...

In the spinal cord, γ-aminobutyric acid (GABA) interneurons play an essential role in antinociception. However, not all actions of GABA favor antinociception at the supraspinal level. We previously reported that gabaculine, which increases endogenous GABA in the synaptic clefts, induces loss of the righting reflex (LORR) that is one indicator of hypnosis, but not immobility in response to noxious stimulus. A slow pain is transmitted to the spinal cord via C fibers and evokes substance P (SP) release from their terminals...

Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors such as frequent laughter and is caused by dysfunctional maternal UBE3A gene (maternal 15q11-13 deletions, maternal specific UBE3A mutation, uniparental disomy, and imprinting defect). Intractable epileptic seizures since early childhood with characteristic EEG abnormalities are present in 80-90% patients with AS. Underlying pathophysiology may involve neocortical and thalamocortical hyperexcitability secondary to severe reduction of GABAergic input, as well as dysfunctional synaptic plasticity, deficient synaptogenesis, and neuronal morphological immaturity...

The proton-coupled amino acid transporter, PAT1, is known to be responsible for intestinal absorption drug substances such as gaboxadol and vigabatrin. The aim of the present study was to investigate, if 17-α-ethinyl-estradiol (E-E2) and 17-β-estradiol (E) inhibit PAT1-mediated intestinal absorption of proline and taurine in vitro in Caco-2 cells and in vivo using Sprague-Dawley rats to assess the potential for taurine-drug interactions. E and E-E2 inhibited the PAT1-mediated uptake of proline and taurine in Caco-2 cells with IC50 values of 10...

Phosphodiesterase type 4 (PDE4) inhibitors prevent hydrolysis of cyclic adenosine monophosphate and increase protein kinase A (PKA)-mediated phosphorylation. PDE4 inhibitors also regulate responses to ethanol and GABAergic drugs. We investigated mechanisms by which the PDE4 inhibitor, apremilast, regulates acute effects of ethanol and GABAergic drugs in male and female mice. Apremilast prolonged the sedative-hypnotic effects of gaboxadol, zolpidem, and propofol but did not alter etomidate effects, and unexpectedly shortened the sedative-hypnotic effects of diazepam...

STUDY OBJECTIVES: To compare delta spectral power (delta) and odds ratio product (ORP) as measures of sleep depth during sleep restriction with placebo or a drug that increases delta. METHODS: This is a secondary analysis of data from a study of 41 healthy participants randomized to receive placebo or gaboxadol 15 mg during sleep restriction. Participants underwent in-laboratory sleep studies on two baseline, four sleep restriction (5-h), and two recovery nights...

Pharmacological studies implicate toll-like receptor 3 (TLR3) signaling in alcohol drinking. We examined the role of TLR3 in behavioral responses to alcohol and GABAergic drugs by studying Tlr3 -/- mice. Because of opposing signaling between TLR3 and MyD88 pathways, we also evaluated Myd88 -/- mice. Ethanol consumption and preference decreased in male but not in female Tlr3 -/- mice during two-bottle choice every-other-day (2BC-EOD) drinking. There were no genotype differences in either sex during continuous or limited-access drinking...

Chronic sleep disturbance is associated with numerous health consequences, including neurodegenerative disease and cognitive decline [1]. Neurite damage due to apoptosis, trauma, or genetic factors is a common feature of aging, and clearance of damaged neurons is essential for maintenance of brain function. In the central nervous system, damaged neurites are cleared by Wallerian degeneration, in which activated microglia and macrophages engulf damaged neurons [2]. The fruit fly Drosophila melanogaster provides a powerful model for investigating the relationship between sleep and Wallerian degeneration [3]...

Sleep plays an important role in regulating plasticity. In Drosophila , the relationship between sleep and learning and memory has primarily focused on mushroom body dependent operant-learning assays such as aversive phototaxic suppression and courtship conditioning. In this study, sleep was increased in the classic mutant rutabaga ( rut2080 ) and dunce ( dnc1 ) by feeding them the GABA-A agonist gaboxadol (Gab). Performance was evaluated in each mutant in response to social enrichment and place learning, tasks that do not require the mushroom body...

OBJECTIVE: The determinants of sleep quality (sQUAL) are poorly understood. We evaluated how well a large number of objective polysomnography (PSG) parameters can predict sQUAL in insomnia patients participating in trials of sleep medications or placebo. METHODS: PSG recordings over multiple nights from two clinical drug development programs involving 1158 insomnia patients treated with suvorexant or placebo and 903 insomnia patients treated with gaboxadol or placebo were used post-hoc to analyze univariate and multivariate associations between sQUAL and 98 PSG sleep parameters plus patient's age and gender...

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism. FXS is also accompanied by attention problems, hyperactivity, anxiety, aggression, poor sleep, repetitive behaviors, and self-injury. Recent work supports the role of γ-aminobutyric-acid (GABA), the primary inhibitory neurotransmitter in the brain, in mediating symptoms of FXS. Deficits in GABA machinery have been observed in a mouse model of FXS, including a loss of tonic inhibition in the amygdala, which is mediated by extrasynaptic GABAA receptors...

THIP (gaboxadol), a superagonist of the δ subunit-containing extrasynaptic GABAA receptors, produces persistent neuroplasticity in dopamine (DA) neurons of the ventral tegmental area (VTA), similarly to rewarding drugs of abuse. However, unlike them THIP lacks abuse potential and induces conditioned place aversion in mice. The mechanism underlying the aversive effects of THIP remains elusive. Here, we show that mild aversive effects of THIP were detected 2 h after administration likely reflecting an anxiety-like state with increased corticosterone release and with central recruitment of corticotropin-releasing factor corticotropin-releasing factor receptor 1 (CRF1 ) receptors...

The voltage-gated sodium channel subunit β4 (SCN4B) regulates neuronal activity by modulating channel gating and has been implicated in ethanol consumption in rodent models and human alcoholics. However, the functional role for Scn4b in ethanol-mediated behaviors is unknown. We determined if genetic global knockout or targeted knockdown of Scn4b in the central nucleus of the amygdala (CeA) altered ethanol drinking or related behaviors. We used four different ethanol consumption procedures (continuous and intermittent two-bottle choice, drinking-in-the dark, and chronic intermittent ethanol vapor) and found that male and female Scn4b knockout mice did not differ from their wild-type littermates in ethanol consumption in any of the tests...

Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA-approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well-replicated autism-relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model...

Synaptic pruning during adolescence is critical for optimal cognition. The CA3 hippocampus contains unique spine types and plays a pivotal role in pattern separation and seizure generation, where sex differences exist, but adolescent pruning has only been studied in the male. Thus, for the present study we assessed pruning of specific spine types in the CA3 hippocampus during adolescence and investigated a possible mechanism in the female mouse. To this end, we used Golgi-impregnated brains from pubertal (∼PND 35, assessed by vaginal opening) and post-pubertal (PND 56) mice...

Background: Metabolic imaging has revealed excessive cerebellar activity in essential tremor patients. Golgi cells control cerebellar activity by releasing gamma-aminobutyric acid (GABA) onto synaptic and extrasynaptic receptors on cerebellar granule cells. We postulated that the extrasynaptic GABAA receptor-specific agonist THIP (gaboxadol; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) would suppress tremor in the harmaline model of essential tremor and, since cerebellar extrasynaptic receptors contain α 6 and δ subunits, would fail to do so in mice lacking either subunit...