Modulation of γ‐Aminobutyric AcidA Receptor‐Operated Chloride Channels by Benzodiazepine Inverse Agonists Is Related to Genetic Differences in Ethanol Withdrawal Seizure Severity

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

Research output: Contribution to journalArticle

20 Scopus citations

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. Musci‐mol‐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‐dime‐ thoxy‐4‐ethyl‐β‐carboIine‐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
DOIs
StatePublished - Dec 1991

Keywords

  • Buck K. J. et al. Modulation of γ‐aminobutyric acid receptor‐operated chloride channels by benzodiazepine inverse agonists is related to genetic differences in ethanol withdrawal seizure severity
  • GABA—Ethanol—Benzodiazepines—Genetics—Alcohol dependence—Seizures

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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