MODULATION OF S-35 TBPS BINDING BY GABAERGIC DRUGS IN THE CEREBRAL-CORTEX OF NEWBORN AND ADULT-RATS

The present study was designed to compare the allosteric modulatory effects of GABAergic drugs on S-35-t-butylbicyclophosphorothionate (S-35-TBPS) binding in the cerebral cortex of newborn (5-day-old) and adult (90-day-old) rats. To examine the influence of GABA on the modulation of S-35-TBPS binding, the assays were performed in unwashed membranes (in which the concentration of GABA was dependent on the content of this neurotransmitter in vivo), and in extensively washed membranes in the presence of defined concentrations of exogenous GABA (3 muM). In unwashed membranes, the GABA(A) receptor antagonist, bicuculline, and the inverse agonist for benzodiazepine receptors, 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid-methyl ester (DMCM) increased S-35-TBPS binding in a concentration-dependent manner in adult rats, but not in newborn rats. By contrast, in extensively washed membranes (plus 3 muM GABA) both bicuculline and DMCM were able to stimulate S-35-TBPS binding either in newborn or in adult rats. On the other hand, the inhibitory effect of diazepam on S-35-TBPS binding was observed in both unwashed and extensively washed membranes from newborn and adult rats. These results reflect the early development of the allosteric interaction between the different components of the GABA(A) receptor complex. In addition, the age-dependent changes in the concentration of endogenous GABA play a critical role in the modulation of S-35-TBPS binding by GABAergic drugs.