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Research ArticleArticle

Antagonist-Induced Reversal of Functional and Structural Measures of Hippocampal Benzodiazepine Tolerance

Elizabeth I. Tietz, Xu J. Zeng, Shanyi Chen, Scott M. Lilly, Howard C. Rosenberg and Peter Kometiani
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 932-942;
Elizabeth I. Tietz
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Xu J. Zeng
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Shanyi Chen
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Scott M. Lilly
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Howard C. Rosenberg
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Peter Kometiani
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Abstract

One week oral flurazepam (FZP) administration in rats results in anticonvulsant tolerance in vivo, tolerance measured in vitro in hippocampal CA1 pyramidal cells, and regulation of hippocampal γ-aminobutyric acidA-receptor subunit protein expression. A single injection (4 or 20 mg/kg i.p) of the benzodiazepine antagonist flumazenil (FLM) was given 1 day after FZP treatment, and tolerance and subunit protein expression were evaluated 1 day later. In vivo tolerance was measured by a reduced ability of the α1-subunit-selective agonist zolpidem to suppress pentylenetetrazole-induced seizures. This tolerance was reversed by 20 but not 4 mg/kg FLM. In in vitro hippocampal slices, there was tolerance to the effect of zolpidem to prolong the decay of pyramidal cell miniature inhibitory postsynaptic currents, which was reversed by FLM (4 mg/kg) pretreatment. A reduction in miniature inhibitory postsynaptic current amplitude (∼50%) was also restored by FLM injection. [3H]Zolpidem binding measured 0, 2, and 7 days after FZP treatment was significantly decreased in the hippocampus and cortex at 0 days but not thereafter. Changes in α1- and β3-subunit protein expression were examined via quantitative immunohistochemical techniques. α1-Subunit protein levels were down-regulated in the CA1 stratum oriens and β subunit levels were up-regulated in the stratum oriens and stratum radiatum of the CA3 region. Chronic FZP effects on α1- and β3-subunit protein levels were also reversed by prior FLM injection. FLM's effect on both functional and structural correlates of benzodiazepine tolerance suggests that each of these measures plays an interdependent role in mediating benzodiazepine tolerance.

Footnotes

  • Send reprint requests to: Elizabeth I. Tietz, Ph.D., Department of Pharmacology, Medical College of Ohio, Block Health Science Building, 3035 Arlington Ave., Toledo, OH 43614-5804. E-mail:etietz{at}mco.edu

  • ↵1 This work was supported by National Institutes of Health Grants R01-DA04075 and K02-DA00180 to E.I.T. and predoctoral fellowships to S.M.L. and P.K. from the Medical College of Ohio. Portions of this work have appeared in abstract form: Chen S, Cox A and Tietz EI (1996) Soc Neurosci Abstr 21:1590; Zeng XJ and Tietz EI (1998) Soc Neurosci Abstr24:1012; Lilly SM, Chen S and Tietz EI (1998) Soc Neurosci Abstr24:1012.

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    GABAR
    GABAA receptor
    IPSC
    inhibitory postsynaptic current
    PTZ
    pentylenetetrazole
    FZP
    flurazepam
    FLM
    flumazenil
    • Received May 25, 1999.
    • Accepted July 20, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Antagonist-Induced Reversal of Functional and Structural Measures of Hippocampal Benzodiazepine Tolerance

Elizabeth I. Tietz, Xu J. Zeng, Shanyi Chen, Scott M. Lilly, Howard C. Rosenberg and Peter Kometiani
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 932-942;

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Research ArticleArticle

Antagonist-Induced Reversal of Functional and Structural Measures of Hippocampal Benzodiazepine Tolerance

Elizabeth I. Tietz, Xu J. Zeng, Shanyi Chen, Scott M. Lilly, Howard C. Rosenberg and Peter Kometiani
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 932-942;
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