Disease relevance of gaboxadol

• Microinjection of THIP (1.95 microgram) into nucleus ambiguus reversed bradycardia evoked by microinjection of bicuculline methiodide (160 ng) into this nucleus [1].
• Methylphenidate, apomorphine, THIP, and diazepam in monkeys: dopamine-GABA behavior related to psychoses and tardive dyskinesia [2].
• Toxic signs after THIP, 8 mg/kg, included focal or generalised myoclonus [3].
• In contrast to the hyperalgesia produced by THIP, microinjection of the GABAA receptor antagonist bicuculline methiodide (0.04 or 0.1 microgram) produced a small, but significant increase in TFL [4].
• Effects of the bicyclic GABA agonist, THIP, on myoclonic and seizure responses in mice and baboons with reflex epilepsy [3].

Psychiatry related information on gaboxadol

• THIP treatment of Huntington's disease [5].
• Compared to placebo, THIP increased slow wave sleep by about 25 min [6].
• THIP inhibits feeding behavior in fasted rats [7].
• The GABAA agonist THIP impaired motor coordination and reduced receptivity and exploratory behaviors at a dose of 10 mg/kg [8].
• The effects of THIP, a GABA agonist, were examined in patients with anxiety disorders [9].

High impact information on gaboxadol

• THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex [10].
• Since its cellular actions in the neocortex are uncertain, we studied the effects of THIP on neurons in slices of frontoparietal neocortex of 13- to 19-day-old (P13-19) mice [10].
• Binding was displaced in a dose-related manner by the GABA agonists muscimol (KI = 1 X 10(-8) M), isoguvacine (KI = 6 X 10(-7) M), THIP (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol); KI = 5 X 10(-6) M), and the antagonist (+)bicuculline (KI = 5 X 10(-5) M) but not its inactive stereoisomer (-)bicuculline (KI greater than 10(-3) M) [11].
• THIP treatment of 7-day-old cultures led to a statistically significant increase in the cytoplasmic density of rough endoplasmic reticulum, Golgi apparatus, vesicles, and coated vesicles, whereas no significant increase in the cytoplasmic density of these organelles was observed in 14-day-old cultures exposed to THIP for 6 h [12].
• The decrease in GLDH specific activity observed in THIP-treated rats during their late postnatal development possibly indicates a repression of glutamatergic neurons [13].

Chemical compound and disease context of gaboxadol

• Both the GABAA receptor agonist THIP and the GABAB receptor agonist baclofen inhibited lordosis behavior at doses from 20 and 5 mg/kg, respectively [14].
• Muscimol (0.01-10 micrograms/kg), THIP (0.01-100 micrograms/kg), kojic amine (0.1-100 micrograms/kg) and isoguvacine (0.1-100 micrograms/kg) produced dose-dependent hypotension and bradycardia [15].
• Previous results with the GABA agonists muscimol and THIP in tardive dyskinesia have not been encouraging [16].
• The anticonvulsant efficacy of the GABAmimetic drugs cetyl GABA, progabide and THIP (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol) was studied against minor (myoclonic) and major (generalized tonic-clonic) seizures in gerbils as well as against maximal electroshock and s.c. pentylenetetrazol-induced seizures in mice [17].

Biological context of gaboxadol

• The cultured cerebellar granule neurons exhibited specific binding sites for [125I]CTX, the number of which was independent of exposure of the cells to THIP during the culture period [18].
• These results provide further evidence that THIP can penetrate the "blood-brain barrier", and that central GABA-ergic systems are involved in controlling food intake [7].
• Recent studies in the rat demonstrated that systemic administration of muscimol and THIP, both selective GABAA receptor agonists, elevates slow wave activity in the EEG during non-rapid eye movement (NREM) sleep [6].
• In a first experiment, a unilateral microinjection of bicuculline, a GABAa antagonist, into the IC of normal rats increased the amplitude of the collicular auditory evoked potential, while the microinjection of THIP, a GABAa agonist, decreased this response [19].
• In chloralose-anesthetized cats, injection of THIP (30-1000 microgram) into the fourth ventricle produced dose-dependent decreases in blood pressure and heart rate [1].

Anatomical context of gaboxadol

• Our studies suggest that THIP activates an extrasynaptic GABA(A) receptor-mediated conductance in the neocortex, which may alter the cortical network activity [10].
• The binding of radioactive THIP to thoroughly washed, frozen, and thawed membranes isolated from rat brains has been studied at 2 degrees C under sodium ion-free conditions and compared with the binding of [3H]GABA and [3H]piperidine-4-sulphonic acid ([3H]P4S) [20].
• Depolarization-induced release of [3H]gamma-aminobutyric acid ([3H]-GABA) from preloaded slices of rat cerebral cortex was inhibited by muscimol and THIP in a dose-dependent fashion [21].
• A series of compounds structurally related to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), which previously were shown to antagonize glycine responses in cat spinal cord, inhibited [3H]strychnine binding in micromolar concentrations [22].
• Examination by light microscopy demonstrated that the major effect of THIP was to increase alpha6 subunit clustering on granule cell bodies as well as neurites, 15-fold and sixfold, respectively [23].

Associations of gaboxadol with other chemical compounds

• 5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAA agonist [24].
• The data provide evidence for a functional supersensitivity of GABA-sensitive nondopaminergic projections from the substantia nigra in response to chronic neuroleptic treatment and reveal differences between the precise sites or modes of action of baclofen, muscimol, and THIP within this structure [25].
• However, in the presence and absence of bicuculline, THIP reduced the total number of benzodiazepine binding sites, probably in a bicuculline insensitive manner [26].
• Naloxone, 4,5,6,7-tetrahydroisoxazolo(S,4-C)pyridin-3-ol (THIP) hydrate and haloperidol inhibited binding poorly (Ki greater than 1 microM), suggesting that these compounds do not interact significantly with the high affinity PCP receptor in vivo [27].
• GABA (10 micrograms) and two other GABA agonists [4,5,6,7-tetrahydroisoxazolo[5, 40c]pyridin-3-ol (THIP), 300 ng and chlordiazepoxide, 10-30 micrograms], microinjected into the inferior colliculus, also reduced audiogenic seizure susceptibility [28].

Gene context of gaboxadol

• Paradoxical blockade of a muscimol response by THIP, a GABA agonist and also by GABA-transaminase inhibitors [29].
• THIP has been reported to increase EEG slow-wave activity (SWA; EEG power in the 0.75-4 Hz band) in non-REM (NREM) sleep in both rats and humans [30].
• Although THP withdrawal in delta knockout mice also increased the alpha4 GABAR subunit, the anxiogenic effects of THP and the anxiolytic effects of THIP were not observed, implicating alpha4betadelta GABAR in these effects [31].
• Hence, the ability of THIP to induce low-affinity GABAA receptors was prevented by the simultaneous depletion of the cellular content of putrescine and spermidine, whereas inhibition of ornithine decarboxylase and of putrescine formation was not sufficient to prevent THIP-induced receptor formation [32].
• THIP is thus not effective against reflex epilepsy [3].

Analytical, diagnostic and therapeutic context of gaboxadol

• The effect of 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol (THIP) on the ultrastructural composition of cultured cerebellar granule cells was investigated during development by quantitative electron microscopy (morphometric analysis) [12].
• The closely related 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 3), although biologically less active than muscimol, was selected for clinical trials [33].
• The two higher doses of THIP induced an abnormal EEG pattern both in waking and NREM sleep [30].
• THIP induced analgesia as well as sedation and loss of righting reflex [34].
• Using in situ hybridization, a small THIP-induced increase in alpha6 mRNA was detected at 4 DIV; however, no effect was apparent at 8 DIV [23].

References