Chronic neurosteroid treatment decreases the efficacy of benzodiazepine ligands and neurosteroids at the γ-aminobutyric acid(A) receptor complex in mammalian cortical neurons

The effect of chronic 5α-pregnane-3α-ol-20-one (5α3α; neurosteroid) treatment was investigated on the γ-aminobutyric acid (GABA), 5α3α, and ligands that bind to the benzodiazepine (BZ) site on GABA-induced [³⁶Cl^- ]influx in intact cultured mammalian cortical neurons. Chronic 5α3α treatment (1 μM; 5 days) decreased the efficacy of GABA, because its E(max) (maximal response) value was decreased, whereas the EC₅₀ (potency) value was not altered. Chronic 5α3α treatment also decreased the E(max) value of BZ agonists like diazepam to potentiate GABA-induced [³⁶Cl^-] influx, and decreased the -E(max) (maximal inhibitory response) value of inverse agonists like methyl-6,7-dimethoxy-4-ethyl-β-carboline-3'-carboxylate to inhibit GABA-induced [³⁶Cl^-] influx, whereas not altering their EC₅₀/IC₅₀ values. Furthermore, chronic 5α3α treatment decreased the E(max) value of 5α3α to potentiate GABA-induced [³⁶Cl^-] influx, without altering its EC₅₀ value. The decreased efficacy of GABA and 5α3α were reversed by concomitant exposure of the neurons to R 5135 (3α-hydroxy-16-imino-5β-17- androstan-11-one; a competitive GABA antagonist). Taken together, these findings suggest that chronic 5α3α 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.