Chronic benzodiazepine agonist treatment produces functional uncoupling of the γ-aminobutyric acid-benzodiazepine receptor ionophore complex in cortical neurons

Xian Jue Hu, Maharaj K. Ticku

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

We have investigated the effect of chronic flurazepam HCl treatment on the γ-aminobutyric acid (GABA)(A) receptor complex in cultured mammalian cortical neurons. Chronic flurazepam (1-5 μM, for 1-10 days) treatment did not produce any changes in the morphological appearance or the cell protein content of cortical neurons. The basal binding of [3H]flunitrazepam, [3H]Ro15-1788, and [3H]Ro15-4513 was also not altered after the chronic treatment. However, chronic flurazepam treatment produced uncoupling between GABA and pentobarbital sites and the [3H]flunitrazepam binding site. The EC50 values of GABA and pentobarbital were not significantly altered after chronic flurazepam treatment; however, their E(max) values were decreased by ~50%. The effect of chronic flurazepam treatment on the observed uncoupling was both time and concentration dependent. Furthermore, the binding of [3H]GABA and t-butylbicyclophosphoro[35S]thionate was also not altered by chronic flurazepam treatment. The effect of GABA on 36Cl influx was not altered after chronic flurazepam treatment; however, treatment significantly attenuated the ability of diazepam to enhance GABA-induced 36Cl influx. Chronic flurazepam-induced uncoupling and decreased diazepam efficacy were reversed by the concomitant presence of the benzodiazepine antagonist Ro15- 1788, suggesting that these events are mediated via the benzodiazepine receptor site. Taken together, these results suggest that chronic benzodiazepine treatment produces uncoupling of GABA and pentobarbital sites from the benzodiazepine site and decreased coupling between the benzodiazepine site and GABA receptor gated Cl- channels. The uncoupling and decreased efficacy may be due to an alteration in the levels of various α subunits and may be responsible for the tolerance associated with chronic benzodiazepine agonist treatment.

Original languageEnglish (US)
Pages (from-to)618-625
Number of pages8
JournalMolecular pharmacology
Volume45
Issue number4
StatePublished - Apr 1994
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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