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γ-Aminobutyric AcidA Receptor Function Is Desensitised in Rat Cultured Cerebellar Granule Cells Following Chronic Flunitrazepam Treatment
Authors:Maria J. Brown  Martyn D. Wood  Martyn C. Coldwell   David R. Bristow
Affiliation:Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester;and; SmithKline Beecham Pharmaceuticals, Neurosciences Research, Harlow, Essex, England
Abstract:Abstract: This study examined γ-aminobutyric acidA (GABAA) receptor function in cultured rat cerebellar granule cells by using microphysiometry following chronic flunitrazepam exposure, and correlated the findings with the α1 and β2/3 subunit protein expression and [3H]muscimol binding after the same treatment paradigm. Flunitrazepam treatment reduced ( p < 0.05) the maximal GABA-stimulated increase in extracellular acidification rate ( E max) (16.5 ± 1.2% and 11.3 ± 1.0%, 2-day control and treated cells, respectively; 17.4 ± 1.0% and 9.9 ± 0.7%, 7-day control and treated cells, respectively; best-fit E max± SEM, n = 7), without affecting the GABA concentration required to elicit 50% of maximal response (EC50) (1.2 ± 1.7 and 2.3 ± 1.8 µ M , 2-day control and treated cells, respectively; 1.7 ± 1.5 and 1.5 ± 1.5 µ M , 7-day control and treated cells, respectively; best-fit EC50± SEM, n = 7). Flunitrazepam exposure also abolished the flunitrazepam potentiation of the GABA response, caused a transient reduction of the GABAA receptor α1 and β2/3 subunit proteins over the initial 2 days, but did not alter [3H]muscimol binding compared with vehicle-treated cells. The results suggest that changes in GABAA receptor subunit protein expression, rather than loss of [3H]muscimol binding sites, underlie the chronic flunitrazepam-mediated desensitisation of GABAA receptor function.
Keywords:Benzodiazepine    Microphysiometry    GABAA receptor    Subunit protein expression
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