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Research ArticleArticle

Decreased Benzodiazepine Binding with Little Effect on γ-Aminobutyric Acid Binding in Rat Brain After Treatment with Antisense Oligodeoxynucleotide to the γ-Aminobutyric AcidA Receptor Gamma-2 Subunit ,

Tai-Jun Zhao, Ming Li, Ted H. Chiu and Howard C. Rosenberg
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 752-759;
Tai-Jun Zhao
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Ming Li
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Ted H. Chiu
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Howard C. Rosenberg
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Abstract

Benzodiazepine potentiation of γ-aminobutyric acid (GABA) neurotransmission is associated with the presence of agamma-2 subunit in the GABAA receptor. A method was developed to modify the gamma-2 subunit expression in adult rat brain. Unilateral intracerebroventricular (i.c.v.) infusion of a 17-base phosphorothioate-modified antisense oligodeoxynucleotide (ASO) was performed every 12 hr for 3 days. Controls were treated with a sense oligodeoxynucleotide. Parasagittal brain sections were used for quantitative autoradiographic analysis of radioligand binding. ASO treatment caused a 15% to 25% decrease of specific [3H]flunitrazepam binding in most brain areas, with statistically significant decreases in frontal cortex, cerebellar molecular layer, zona reticulata of substantia nigra and CA3 of hippocampus. In contrast, [3H]muscimol binding was not changed. [3H]GABA binding was also unchanged, except for a 10% decrease in cerebellar granule cell layer. The effect on the chloride channel of the GABAA receptor complex was examined by 4′-ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate binding; most brain areas showed small decreases in 4′-ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate binding. However, hippocampal regions showed much larger decreases. Binding of the adenosine A1 receptor antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine was used to examine possible secondary effects of the ASO. There was a decrease in [3H]8-cyclopentyl-1,3-dipropylxanthine binding, but this was much smaller than the change in [3H]flunitrazepam binding, and no area showed a significant effect. Quantitative immunoblotting with a monoclonal antibody that recognizes GABAA receptor beta-2 andbeta-3 subunits showed no change in immunoreactivity in cerebellar tissue after ASO treatment. The results indicate a selective effect on benzodiazepine binding to GABAA receptors and a possible change in receptor subunit composition.

Footnotes

  • Send reprint requests to: Howard C. Rosenberg, M.D., Ph.D., Department of Pharmacology and Therapeutics, Block Health Science Building, 3035 Arlington Avenue, Medical College of Ohio, Toledo, OH 43614-5804.

  • ↵1 This work constitutes a portion of the doctoral dissertation work of T.-J. Z. and was supported by National Institutes of Health Grant DA02194 to H.C.R. and a predoctoral fellowship to T.-J. Z. from the Medical College of Ohio.

  • ↵2 Preliminary data were reported at the 26th meeting of the Society for Neuroscience, November 16–21, Washington, DC.

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

  • Abbreviations:
    ASO
    antisense oligodeoxynucleotide
    β-CCM
    methyl-β-carboline-3-carboxylate
    DPCPX
    8-cyclopentyl-1,3-dipropylxanthine
    GABA
    γ-aminobutyric acid
    [3H]EBOB
    4′-ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate
    TBOB
    t-butylbicycloorthobenzoate
    TBPS
    t-buytlbicyclophosphorothionate
    i.c.v.
    intracerebroventricular
    • Received April 6, 1998.
    • Accepted June 17, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Decreased Benzodiazepine Binding with Little Effect on γ-Aminobutyric Acid Binding in Rat Brain After Treatment with Antisense Oligodeoxynucleotide to the γ-Aminobutyric AcidA Receptor Gamma-2 Subunit ,

Tai-Jun Zhao, Ming Li, Ted H. Chiu and Howard C. Rosenberg
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 752-759;

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Research ArticleArticle

Decreased Benzodiazepine Binding with Little Effect on γ-Aminobutyric Acid Binding in Rat Brain After Treatment with Antisense Oligodeoxynucleotide to the γ-Aminobutyric AcidA Receptor Gamma-2 Subunit ,

Tai-Jun Zhao, Ming Li, Ted H. Chiu and Howard C. Rosenberg
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 752-759;
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