Chronic flurazepam treatment produces decreased efficacy of the benzodiazepine ligands and pentobarbital with gamma-aminobutyric acidA receptors in cortical neurons.

The present study was designed to determine whether chronic benzodiazepine (BZ) agonist treatment alters the "set point" of the BZ pharmacological profile. This was achieved by investigating the modulation of gamma-aminobutyric acid (GABA)-mediated [36Cl-] influx by BZ ligands, as well as pentobarbital after chronic flurazepam treatment, in well characterized mammalian cortical neurons. Chronic flurazepam treatment (5 microM, 10 days) produced decreased efficacy of BZ agonists (diazepam and flunitrazepam) and inverse agonists (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3'-carboxylate and ethyl-beta-carboline-3-carboxylate), as measured by GABA-induced [36Cl-] influx. The chronic flurazepam treatment, although not altering their EC50/IC50 values, decreased the Emax/-Emax values. Furthermore, the decreased efficacy was reversed after a 72-hr withdrawal, and by concomitant exposure of the neurons to Ro15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5 alpha][1,4]- BZ-3-carboxylate), a BZ receptor antagonist, but not by R 5135 (3 alpha-hydroxy-16-imino-5 beta-17-androstan-11-one; a GABA receptor antagonist) and pircrotoxin (a channel blocker). The chronic flurazepam treatment also produced uncoupling between pentobarbital and BZ receptor sites, and decreased the efficacy of pentobarbital to enhance GABA-mediated [36Cl-] influx, events also reversed at 72-hr withdrawal and concomitant exposure to Ro15-1788. Chronic flurazepam treatment-induced uncoupling and decreased efficacy of BZ agonists was not reversed by the GABAA receptor antagonist, R 5135, or channel blocker, picrotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)