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γ‐Aminobutyric Acid A Receptor Function Is Desensitised in Rat Cultured Cerebellar Granule Cells Following Chronic Flunitrazepam Treatment
Author(s) -
Brown Maria J.,
Wood Martyn D.,
Coldwell Martyn C.,
Bristow David R.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71031232.x
Subject(s) - muscimol , flunitrazepam , gabaa receptor , endocrinology , receptor , extracellular , medicine , gaba receptor , chemistry , protein subunit , granule cell , gamma aminobutyric acid , cerebellum , biology , biochemistry , hippocampal formation , gene , dentate gyrus
This study examined γ‐aminobutyric acid A (GABA A ) 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 [ 3 H]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 (EC 50 ) (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 EC 50 ± SEM, n = 7). Flunitrazepam exposure also abolished the flunitrazepam potentiation of the GABA response, caused a transient reduction of the GABA A receptor α1 and β2/3 subunit proteins over the initial 2 days, but did not alter [ 3 H]muscimol binding compared with vehicle‐treated cells. The results suggest that changes in GABA A receptor subunit protein expression, rather than loss of [ 3 H]muscimol binding sites, underlie the chronic flunitrazepam‐mediated desensitisation of GABA A receptor function.