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Research ArticleNeuropharmacology

Antiseizure Activity of Midazolam in Mice Lacking δ-Subunit Extrasynaptic GABAA Receptors

Sandesh D. Reddy, Iyan Younus, Bryan L. Clossen and Doodipala Samba Reddy
Journal of Pharmacology and Experimental Therapeutics June 2015, 353 (3) 517-528; DOI: https://doi.org/10.1124/jpet.114.222075
Sandesh D. Reddy
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
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Iyan Younus
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
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Bryan L. Clossen
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
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Doodipala Samba Reddy
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
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Abstract

Midazolam is a benzodiazepine anticonvulsant with rapid onset and short duration of action. Midazolam is the current drug of choice for acute seizures and status epilepticus, including those caused by organophosphate nerve agents. The antiseizure activity of midazolam is thought to result from its allosteric potentiation of synaptic GABAA receptors in the brain. However, there are indications that benzodiazepines promote neurosteroid synthesis via the 18-kDa cholesterol transporter protein (TSPO). Therefore, we investigated the role of neurosteroids and their extrasynaptic GABAA receptor targets in the antiseizure activity of midazolam. Here, we used δ-subunit knockout (DKO) mice bearing a targeted deletion of the extrasynaptic receptors to investigate the contribution of the extrasynaptic receptors to the antiseizure activity of midazolam using the 6-Hz and hippocampus kindling seizure models. In both models, midazolam produced rapid and dose-dependent protection against seizures (ED50, 0.4 mg/kg). Moreover, the antiseizure potency of midazolam was undiminished in DKO mice compared with control mice. Pretreatment with PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide], a TSPO blocker, or finasteride, a 5α-reductase neurosteroid inhibitor, did not affect the antiseizure effect of midazolam. The antiseizure activity of midazolam was significantly reversed by pretreatment with flumazenil, a benzodiazepine antagonist. Plasma and brain levels of the neurosteroid allopregnanolone were not significantly greater in midazolam-treated animals. These studies therefore provide strong evidence that neurosteroids and extrasynaptic GABAA receptors are not involved in the antiseizure activity of midazolam, which mainly occurs through synaptic GABAA receptors via direct binding to benzodiazepine sites. This study reaffirms midazolam’s use for controlling acute seizures and status epilepticus.

Footnotes

    • Received December 14, 2014.
    • Accepted March 16, 2015.
  • This work supported in part by the CounterACT Program, National Institutes of Health, Office of the Director and the National Institute of Neurologic Disorders and Stroke [Grant U01-NS083460]. The authors have no competing financial interests. The views expressed in this article are those of the authors and do not reflect the official policy of the National Institutes of Health or the U.S. Government.

  • dx.doi.org/10.1124/jpet.114.222075.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 3
1 Jun 2015
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Research ArticleNeuropharmacology

Mechanisms of Antiseizure Action of Midazolam

Sandesh D. Reddy, Iyan Younus, Bryan L. Clossen and Doodipala Samba Reddy
Journal of Pharmacology and Experimental Therapeutics June 1, 2015, 353 (3) 517-528; DOI: https://doi.org/10.1124/jpet.114.222075

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Research ArticleNeuropharmacology

Mechanisms of Antiseizure Action of Midazolam

Sandesh D. Reddy, Iyan Younus, Bryan L. Clossen and Doodipala Samba Reddy
Journal of Pharmacology and Experimental Therapeutics June 1, 2015, 353 (3) 517-528; DOI: https://doi.org/10.1124/jpet.114.222075
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