Uncoupling of GABA-benzodiazepine receptors in chick cerebral cortical neurons requires co-activation of both receptor sites.
Primary cultures of chick cerebral cortical neurons were exposed to 1 microM flurazepam in vitro, and the effect of flurazepam on GABA-activated membrane current (IGABA) was examined using whole-cell voltage-clamp recording. Exposure of chick cerebral cortical neurons to flurazepam alone for 3-10 days resulted in a significant decrease in the degree of potentiation of IGABA elicited by 0.5 microM flurazepam. When GABA or nipecotic acid (a GABA uptake blocker) were added with flurazepam during chronic drug exposure, neuronal responses to GABA were significantly less sensitive to modulation by 0.5 microM flurazepam compared to flurazepam treatment alone. Furthermore, this effect was significantly reduced by co-administration of the GABAA receptor antagonist bicuculline. These results suggest that tolerance to benzodiazepines in vitro requires activation of both the GABA and the benzodiazepine binding sites on the GABAA receptor-channel complex.
Prasad
A
A
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
Reynolds
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JN
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D002642:Chick Embryo; D005479:Flurazepam / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009557:Nipecotic Acids / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives*; D011963:Receptors, GABA-A / Q000187:drug effects*; D014475:Uncoupling Agents / Q000494:pharmacology*
D009557:Nipecotic Acids; D011963:Receptors, GABA-A; D014475:Uncoupling Agents; C030278:nipecotic acid; D011392:Proline; C010983:homoproline; D005479:Flurazepam