Chronic neurosteroid treatment decreases the efficacy of benzodiazepine ligands and neurosteroids at the gamma-aminobutyric acidA 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 [36Cl-]influx in intact cultured mammalian cortical neurons. Chronic 5 alpha 3 alpha treatment (1 microM; 5 days) decreased the efficacy of GABA, because its Emax (maximal response) value was decreased, whereas the EC50 (potency) value was not altered. Chronic 5 alpha 3 alpha treatment also decreased the Emax value of BZ agonists like diazepam to potentiate GABA-induced [36Cl-] influx, and decreased the -Emax (maximal inhibitory response) value of inverse agonists like methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3'-carboxylate to inhibit GABA-induced [36Cl-] influx, whereas not altering their EC50/IC50 values. Furthermore, chronic 5 alpha 3 alpha treatment decreased the Emax value of 5 alpha 3 alpha to potentiate GABA-induced [36Cl-] influx, without altering its EC50 value. The decreased efficacy of GABA and 5 alpha 3 alpha were reversed by concomitant exposure of the neurons to R 5135 (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 GABAA-BZ receptor complex. The decreased efficacy is heterologous in nature and involves mediation via the GABAA receptor site.
D000818:Animals; D002243:Carbolines / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011280:Pregnanolone / Q000008:administration & dosage*; D018079:Receptors, GABA / Q000502:physiology*
D002243:Carbolines; D018118:Chloride Channels; D018757:GABA Modulators; D018079:Receptors, GABA; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D011280:Pregnanolone