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Research ArticleNEUROPHARMACOLOGY

Binding Characteristics of the γ-Hydroxybutyric Acid Receptor Antagonist [3H](2E)-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) Ethanoic Acid in the Rat Brain

Ashok K. Mehta, Nicole M. Muschaweck, Dean Y. Maeda, Andrew Coop and Maharaj K. Ticku
Journal of Pharmacology and Experimental Therapeutics December 2001, 299 (3) 1148-1153;
Ashok K. Mehta
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Nicole M. Muschaweck
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Dean Y. Maeda
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Andrew Coop
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Maharaj K. Ticku
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Abstract

Radioligand binding studies with [3H](2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid ([3H]NCS-382), an antagonist of γ-hydroxybutyric acid (GHB) receptor, revealed specific binding sites in the rat cerebral cortex and hippocampus. However, there was very little binding in the rat cerebellum, heart, kidney, liver, and lung membranes. Binding was rapid and reached equilibrium in about 5 min. Scatchard analysis of saturation isotherms revealed two different populations of binding sites in the rat cerebral cortex (Kd1, 795 nM,Bmax1, 25.4 pmol/mg of protein;Kd2, 21 μM;Bmax2, 178 pmol/mg of protein) as well as in the rat hippocampus (Kd1, 441 nM;Bmax1, 16.2 pmol/mg of protein;Kd2, 9.8 μM;Bmax2, 255 pmol/mg of protein). (±)Baclofen (500 μM) and γ-aminobutyric acid (100 μM) inhibited the binding only partially, whereas (+)bicuculline, muscimol, picrotoxinin, and phaclofen did not modify the binding. Interestingly, potassium chloride (100–300 mM) inhibited [3H]NCS-382 binding (34–56%), and this inhibitory effect was not affected by picrotoxinin. GHB and NCS-382 completely inhibited the [3H]NCS-382 (16 nM) binding in the rat cerebrocortical and hippocampal membranes, and NCS-382 was found to be about 10 times more potent than GHB in this regard. A variety of ligands for other receptors did not modify the [3H]NCS-382 binding, thereby suggesting selectivity of this radioligand for the GHB receptor sites in the brain. Based on these observations, [3H]NCS-382 seems to be a better radioligand than [3H]GHB for investigating the role of the GHB receptors in various pharmacological actions.

Footnotes

  • Abbreviations:
    GHB
    γ-hydroxybutyric acid
    GABA
    γ-aminobutyric acid
    NCS-382
    (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid
    5-HT
    5-hydroxytryptamine
    NMDA
    N-methyl-d-aspartate
    MK-801
    (−)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
    Ro 15-1788
    8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester
    • Received July 13, 2001.
    • Accepted September 4, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 3
1 Dec 2001
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Binding Characteristics of the γ-Hydroxybutyric Acid Receptor Antagonist [3H](2E)-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) Ethanoic Acid in the Rat Brain
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Research ArticleNEUROPHARMACOLOGY

Binding Characteristics of the γ-Hydroxybutyric Acid Receptor Antagonist [3H](2E)-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) Ethanoic Acid in the Rat Brain

Ashok K. Mehta, Nicole M. Muschaweck, Dean Y. Maeda, Andrew Coop and Maharaj K. Ticku
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 1148-1153;

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Research ArticleNEUROPHARMACOLOGY

Binding Characteristics of the γ-Hydroxybutyric Acid Receptor Antagonist [3H](2E)-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) Ethanoic Acid in the Rat Brain

Ashok K. Mehta, Nicole M. Muschaweck, Dean Y. Maeda, Andrew Coop and Maharaj K. Ticku
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 1148-1153;
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