Thip and isoguvacine are partial agonists of GABA-stimulated benzodiazepine receptor binding

Karobath, Manfred; M, Lippitsch

doi:10.1016/0014-2999(79)90321-2

Cited by 39 publications

(6 citation statements)

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“…The GABA A receptors containing the α6 subunit especially together with the δ subunit are known to be highly sensitive to GABA (Hevers and Lüddens 1998; Mody 2001). In α4β3δ receptors that are functionally closely related to α6βδ‐containing receptors, the GABA‐site agonist gaboxadol (Karobath and Lippitsch 1979; Wafford et al. 1996; Ebert et al.…”

Section: Resultsmentioning

confidence: 99%

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABA_A receptors

Saarelainen

Ranna

Rabe

et al. 2007

Journal of Neurochemistry

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The behavioral and functional significance of the extrasynaptic inhibitory GABAA receptors in the brain is still poorly known. We used a transgenic mouse line expressing the GABAA receptor α6 subunit gene in the forebrain under the Thy‐1.2 promoter (Thy1α6) mice ectopically expressing α6 subunits especially in the hippocampus to study how extrasynaptically enriched αβ(γ2)‐type receptors alter animal behavior and receptor responses. In these mice extrasynaptic α6β receptors make up about 10% of the hippocampal GABAA receptors resulting in imbalance between synaptic and extrasynaptic inhibition. The synthetic GABA‐site competitive agonist gaboxadol (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol; 3 mg/kg) induced remarkable anxiolytic‐like response in the light : dark exploration and elevated plus‐maze tests in Thy1α6 mice, while being almost inactive in wild‐type mice. The transgenic mice also lost quicker and for longer time their righting reflex after 25 mg/kg gaboxadol than wild‐type mice. In hippocampal sections of Thy1α6 mice, the α6β receptors could be visualized autoradiographically by interactions between gaboxadol and GABA via [35S]TBPS binding to the GABAA receptor ionophore. Gaboxadol inhibition of the binding could be partially prevented by GABA. Electrophysiology of recombinant GABAA receptors revealed that GABA was a partial agonist at α6β3 and α6β3δ receptors, but a full agonist at α6β3γ2 receptors when compared with gaboxadol. The results suggest strong behavioral effects via selective pharmacological activation of enriched extrasynaptic αβ GABAA receptors, and the mouse model represents an example of the functional consequences of altered balance between extrasynaptic and synaptic inhibition.

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Section: Resultsmentioning

confidence: 99%

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABA_A receptors

Saarelainen

Ranna

Rabe

et al. 2007

Journal of Neurochemistry

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“…Thus, GABA-mimetics decreased the actions of AVM in a bicuculline methiodide-sensitive mode. It was interesting that all GABA-mimetics had a similar attenuating effect on AVM stimulation of benzodiazepine receptor binding, although THIP and PSA have recently been found, unexpectedly, to antagonize the stimulatory effects of GABA on benzodiazepine receptor binding performed at 0°C (Braestrup et al, 1979;Karobath and Lippitsch, 1979). Since investigations with THIAVM suggest that GABA does not interfere with the binding of this ligand to cerebellar membranes , it appears that the interaction of GABA and GABA mimetics with GABA recognition sites can attenuate the actions of bound AVM on benzodiazepine receptor binding.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Modulation by Avermectin B₁a of the GABA/Benzodiazepine Receptor Complex of Rat Cerebellum

Supavilai

Karobath

1981

Journal of Neurochemistry

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Avermectin B1a, a macrocyclic lactone anthelmintic agent, causes a concentration-dependent increase of [3H]flunitrazepam binding to membranes from rat cerebellum by increasing the affinity and the number of binding sites. This effect appears to be independent of the concentration of chloride ions. The effects of avermectin B1a occur with high affinity (EC50 = 70 nM), and they persist after washing of the membranes with drug-free buffer. Pretreatment of the membranes with Triton X-100 completely abolishes the action of avermectin B1a. GABA and the GABA-mimetic compounds piperidine-4-sulfonic acid and THIP diminish the effects of avermectin B1a on benzodiazepine receptor binding in a bicuculline-methiodide-sensitive mode. In addition, the stimulation of [3H]flunitrazepam binding by avermectin B1a is decreased by the pyrazolopyridines etazolate and cartazolate. These observations suggest that avermectin B1a stimulates benzodiazepine receptor binding by acting on a modulatory site which is independent of the GABA recognition site and of the drug receptor for the pyrazolopyridines, but which is in functional interaction with these sites.

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“…Indeed, there was no correlation between the relative potencies of GABA mimetics as stimulants of benzodiazepine binding and as inhibitors of 3H-GABA binding (KAROBATH et aI., 1979b;MAURER, 1979a). Rigid molecules (e.g., muscimol, isoguvacine, THIP, and imidazole-acetic acid) were less potent as stimulants of benzodiazepine binding than more flexible analogues and, in part, even antagonized the effect of GAB A (KAROBATH and LIPPITSCH, 1979;BRAESTRUP et aI., 1979cBRAESTRUP et aI., , 1980KAROBATH et aI., 1980KAROBATH et aI., , 1981.…”

Section: Modulation Of Benzodiazepine Binding By Gaba-mimetic Cmentioning

confidence: 96%

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

Haefely¹,

Pieri²,

Polc³

et al. 1981

Handbook of Experimental Pharmacology

114

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Thip and isoguvacine are partial agonists of GABA-stimulated benzodiazepine receptor binding

Cited by 39 publications

References 9 publications

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABA_A receptors

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABA_A receptors

In Vitro Modulation by Avermectin B₁a of the GABA/Benzodiazepine Receptor Complex of Rat Cerebellum

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

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Thip and isoguvacine are partial agonists of GABA-stimulated benzodiazepine receptor binding

Cited by 39 publications

References 9 publications

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABAA receptors

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABAA receptors

In Vitro Modulation by Avermectin B1a of the GABA/Benzodiazepine Receptor Complex of Rat Cerebellum

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

Contact Info

Product

Resources

About

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABA_A receptors

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABA_A receptors

In Vitro Modulation by Avermectin B₁a of the GABA/Benzodiazepine Receptor Complex of Rat Cerebellum