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Research ArticleArticle

Acute Pentylenetetrazol Injection Reduces Rat GABAAReceptor mRNA Levels and GABA Stimulation of Benzodiazepine Binding with No Effect on Benzodiazepine Binding Site Density

Laura A. Walsh, Ming Li, Tai-Jun Zhao, Ted H. Chiu and Howard C. Rosenberg
Journal of Pharmacology and Experimental Therapeutics June 1999, 289 (3) 1626-1633;
Laura A. Walsh
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Ming Li
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Tai-Jun Zhao
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Ted H. Chiu
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Howard C. Rosenberg
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Abstract

The effects of a single convulsive dose of pentylenetetrazol (PTZ, 45 mg/kg i.p.) on rat brain γ-aminobutyric acid type A (GABAA) receptors were studied. Selected GABAAreceptor subunit mRNAs were measured by Northern blot analysis (with β-actin mRNA as a standard). Four hours after PTZ, the GABAA receptor γ2-mRNA was decreased in hippocampus, cerebral cortex, and cerebellum; α1-mRNA was decreased in cerebellum; and β2 subunit mRNA was decreased in cortex and cerebellum. The α5 subunit mRNA level was not altered. Those mRNAs that had been reduced were increased in some brain regions at the 24-h time point, and these changes reverted to control levels by 48 h. PTZ effect on GABAA receptors was also studied by autoradiographic binding assay with the benzodiazepine agonist [3H]flunitrazepam (FNP), the GABAA agonist [3H]muscimol, and the benzodiazepine antagonist [3H]flumazenil. There was an overall decrease in [3H]FNP binding 12 but not 24 h after PTZ treatment. In contrast, [3H]muscimol binding was minimally affected, and [3H]flumazenil binding was unchanged after PTZ treatment. Additional binding studies were performed with well-washed cerebral cortical homogenates to minimize the amount of endogenous GABA. There was no PTZ effect on specific [3H]FNP binding. However, there was a significant reduction in the stimulation of [3H]FNP binding by GABA. The results showed that an acute injection of PTZ caused transient changes in GABAAreceptor mRNA levels without altering receptor number but affected the coupling mechanism between the GABA and benzodiazepine sites of the GABAA receptor.

Footnotes

  • Send reprint requests to: Howard C. Rosenberg, MD, PhD, Department of Pharmacology and Therapeutics, Medical College of Ohio, Block Health Sciences Building, 3035 Arlington Avenue, Toledo, OH 43614-5804. E-mail hrosenberg{at}mco.edu

  • ↵1 This work constitutes a portion of the masters thesis work of L.A.W. and was supported by Department of Health and Human Services Grant RO1 DA02194 (H.C.R.) and fellowships from the Medical College of Ohio (L.A.W. and T.-J. Z.). Preliminary data were presented at the 28th Annual Meeting of the Society for Neuroscience, November 7–12, 1998, Los Angeles, CA.

  • ↵2 Present address: School of Dentistry, University of Michigan, Ann Arbor, MI 48109.

  • ↵3 Present address: Department of Pharmacology, Tzu Chi College of Medicine, 701, Section 3, Chung Yang Road, Hualien 970, Taiwan.

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    PTZ
    pentylenetetrazol
    FNP
    flunitrazepam
    TBPS
    t-butylbicyclophosphorothionate
    • Received December 14, 1998.
    • Accepted March 2, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 3
1 Jun 1999
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Research ArticleArticle

Acute Pentylenetetrazol Injection Reduces Rat GABAAReceptor mRNA Levels and GABA Stimulation of Benzodiazepine Binding with No Effect on Benzodiazepine Binding Site Density

Laura A. Walsh, Ming Li, Tai-Jun Zhao, Ted H. Chiu and Howard C. Rosenberg
Journal of Pharmacology and Experimental Therapeutics June 1, 1999, 289 (3) 1626-1633;

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Research ArticleArticle

Acute Pentylenetetrazol Injection Reduces Rat GABAAReceptor mRNA Levels and GABA Stimulation of Benzodiazepine Binding with No Effect on Benzodiazepine Binding Site Density

Laura A. Walsh, Ming Li, Tai-Jun Zhao, Ted H. Chiu and Howard C. Rosenberg
Journal of Pharmacology and Experimental Therapeutics June 1, 1999, 289 (3) 1626-1633;
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