Chronic neurosteroid treatment produces functional heterologous uncoupling at the γ-aminobutyric acid type A/benzodiazepine receptor complex in mammalian cortical neurons

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70 Scopus citations

Abstract

We have investigated the effects of chronic treatment with the neurosteroid 5α-pregnan-3α-ol-20-one (5α3α) on the γ-aminobutyric acid (GABA)(A) receptor complex in cultured mammalian cortical neurons. Chronic 5α3α treatment (up to 2 μM, 5 days) 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 not altered after the chronic treatment. Chronic 5α3α treatment did not alter the K(d) or B(max) values of [3H]flunitrazepam binding to intact cortical neurons. However, chronic 5α3α treatment produced uncoupling between GABA, barbiturate, and neurosteroid sites and the benzodiazepine site. The EC50 values of these ligands were not significantly altered; however, their E(max) values were decreased after chronic 5α3α treatment. The 5α3α-induced uncoupling was time and concentration dependent. The binding of [3H]GABA and t-[35S]butylbicyclophosphorothionate was also decreased after chronic 5α3α treatment. Chronic 5α3α treatment decreased the B(max) of the low affinity GABA(A) receptor sites, without affecting the high affinity sites, and decreased the B(max) of t- butylbicyclophosphorothionate binding sites. The EC50 value for GABA- induced 36Cl- influx was not altered, whereas the E(max) value was decreased after chronic 5α3α treatment. Furthermore, the 5α3α-induced uncoupling was reversed by concomitant exposure of the cortical neurons to 5α-pregnan-3β-ol-20-one or R5135, suggesting an involvement of the neurosteroid and GABA recognition sites in the observed uncoupling. Taken together, these results suggest that chronic 5α3α treatment produces heterologous uncoupling at the GABA(A) receptor complex.

Original languageEnglish (US)
Pages (from-to)603-610
Number of pages8
JournalMolecular pharmacology
Volume47
Issue number3
StatePublished - 1995

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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