CHRONIC NEUROSTEROID TREATMENT DECREASES THE EFFICACY OF BENZODIAZEPINE LIGANDS AND NEUROSTEROIDS AT THE GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR COMPLEX IN MAMMALIAN CORTICAL-NEURONS

The effect of chronic 5 alpha-pregnane-3 alpha-ol-20-one (5 alpha 3 alpha; neurosteroid) treatment was investigated on the gamma-aminobutyric acid (GABA), 5 alpha 3 alpha, and ligands that bind to the benzodiazepine (BZ) site on GABA-induced [Cl-36(-)]influx in intact cultured mammalian cortical neurons. Chronic 5 alpha 3 alpha treatment (1 mu M; 5 days) decreased the efficacy of GABA, because its E(max) (maximal response) value was decreased, whereas the EC(50) (potency) value was not altered. Chronic 5 alpha 3 alpha treatment also decreased the E(max) value of BZ agonists like diazepam to potentiate GABA-induced [Cl-36(-)] influx, and decreased the -E(max) (maximal inhibitory response) value of inverse agonists like methyl-6,7-dimelhoxy-4-ethyl-beta-carboline-3'-carboxylate to inhibit GABA-induced [Cl-36(-)] influx, whereas not altering their EC(50)/IC50 values. Furthermore, chronic 5 alpha 3 alpha treatment decreased the E(max) value of 5 alpha 3 alpha to potentiate GABA-induced [Cl-36(-)] influx, without altering its EC(50) value. The decreased efficacy of GABA and 5 alpha 3 alpha were reversed by concomitant exposure of the neurons to R5135 (3 alpha-hydroxy-16-imino-5 beta-17-androstan-11-one; a competitive GABA antagonist). Taken together, these findings suggest that chronic 5 alpha 3 alpha treatment produces decreased efficacy of GABA, ligands that bind to the BZ site, and neurosteroids at the GABA(A)-BZ receptor complex. The decreased efficacy is heterologous in nature and involves mediation via the GABA(A) receptor site.