Modulation of γ-aminobutyric acidA receptor-operated chloride channels by benzodiazepine inverse agonists is related to genetic differences in ethanol withdrawal seizure severity

Kari Buck, Susan J. McQuilkin, R. Adron Harris

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20 Citations (Scopus)

Abstract

To determine whether genetic differences in development of ethanol dependence are related to changes in γ-aminobutyric acidA (GABAA) receptor function, we measured 36Cl- uptake by brain cortical membrane vesicles from withdrawal seizure prone and withdrawal seizure resistant (WSP/WSR) mice treated chronically with ethanol. Muscimol-stimulated chloride flux was not different between WSP and WSR mice before or after ethanol treatment. Also, augmentation of muscimol action by flunitrazepam or inhibition of muscimol action by the inverse agonists Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a]-[1,4]benzodiazepine- 3-carboxylate) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) was not different for ethanol-naive WSP and WSR mice. However, chronic ethanol administration enhanced the inhibitory actions of DMCM and Ro 15-4513 on membranes from WSP but not WSR mice. Conversely, chronic ethanol treatment attenuated the action of flunitrazepam on membranes from WSR but not WSP mice, suggesting that the actions of benzodiazepine agonists and inverse agonists are under separate genetic control. These genetic differences in actions of DMCM and Ro 15-4513 indicate that sensitization to benzodiazepine inverse agonists produced by chronic ethanol treatment may be related to development of withdrawal seizures and suggest that differences in the GABA/benzodiazepine receptor complex represent alleles that have segregated during the selection of the WSP/WSR mice.

Original languageEnglish (US)
Pages (from-to)2100-2105
Number of pages6
JournalJournal of Neurochemistry
Volume57
Issue number6
StatePublished - Dec 1991
Externally publishedYes

Fingerprint

Chloride Channels
Benzodiazepines
Seizures
Ethanol
Modulation
Muscimol
Flunitrazepam
GABA-A Receptors
Membranes
Carbolines
Chlorides
Brain
Alleles
Fluxes
methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate
Ro 15-4513

Keywords

  • Alcohol dependence
  • Benzodiazepines
  • Ethanol
  • GABA
  • Genetics
  • Seizures

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

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title = "Modulation of γ-aminobutyric acidA receptor-operated chloride channels by benzodiazepine inverse agonists is related to genetic differences in ethanol withdrawal seizure severity",
abstract = "To determine whether genetic differences in development of ethanol dependence are related to changes in γ-aminobutyric acidA (GABAA) receptor function, we measured 36Cl- uptake by brain cortical membrane vesicles from withdrawal seizure prone and withdrawal seizure resistant (WSP/WSR) mice treated chronically with ethanol. Muscimol-stimulated chloride flux was not different between WSP and WSR mice before or after ethanol treatment. Also, augmentation of muscimol action by flunitrazepam or inhibition of muscimol action by the inverse agonists Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a]-[1,4]benzodiazepine- 3-carboxylate) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) was not different for ethanol-naive WSP and WSR mice. However, chronic ethanol administration enhanced the inhibitory actions of DMCM and Ro 15-4513 on membranes from WSP but not WSR mice. Conversely, chronic ethanol treatment attenuated the action of flunitrazepam on membranes from WSR but not WSP mice, suggesting that the actions of benzodiazepine agonists and inverse agonists are under separate genetic control. These genetic differences in actions of DMCM and Ro 15-4513 indicate that sensitization to benzodiazepine inverse agonists produced by chronic ethanol treatment may be related to development of withdrawal seizures and suggest that differences in the GABA/benzodiazepine receptor complex represent alleles that have segregated during the selection of the WSP/WSR mice.",
keywords = "Alcohol dependence, Benzodiazepines, Ethanol, GABA, Genetics, Seizures",
author = "Kari Buck and McQuilkin, {Susan J.} and Harris, {R. Adron}",
year = "1991",
month = "12",
language = "English (US)",
volume = "57",
pages = "2100--2105",
journal = "Journal of Neurochemistry",
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T1 - Modulation of γ-aminobutyric acidA receptor-operated chloride channels by benzodiazepine inverse agonists is related to genetic differences in ethanol withdrawal seizure severity

AU - Buck, Kari

AU - McQuilkin, Susan J.

AU - Harris, R. Adron

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N2 - To determine whether genetic differences in development of ethanol dependence are related to changes in γ-aminobutyric acidA (GABAA) receptor function, we measured 36Cl- uptake by brain cortical membrane vesicles from withdrawal seizure prone and withdrawal seizure resistant (WSP/WSR) mice treated chronically with ethanol. Muscimol-stimulated chloride flux was not different between WSP and WSR mice before or after ethanol treatment. Also, augmentation of muscimol action by flunitrazepam or inhibition of muscimol action by the inverse agonists Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a]-[1,4]benzodiazepine- 3-carboxylate) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) was not different for ethanol-naive WSP and WSR mice. However, chronic ethanol administration enhanced the inhibitory actions of DMCM and Ro 15-4513 on membranes from WSP but not WSR mice. Conversely, chronic ethanol treatment attenuated the action of flunitrazepam on membranes from WSR but not WSP mice, suggesting that the actions of benzodiazepine agonists and inverse agonists are under separate genetic control. These genetic differences in actions of DMCM and Ro 15-4513 indicate that sensitization to benzodiazepine inverse agonists produced by chronic ethanol treatment may be related to development of withdrawal seizures and suggest that differences in the GABA/benzodiazepine receptor complex represent alleles that have segregated during the selection of the WSP/WSR mice.

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