Modulation of 35S-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 35S-t-butylbicyclophosphorothionate (35S-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 35S-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 microM). In unwashed membranes, the GABAA receptor antagonist, bicuculline, and the inverse agonist for benzodiazepine receptors, 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid-methyl ester (DMCM) increased 35S-TBPS binding in a concentration-dependent manner in adult rats, but not in newborn rats. By contrast, in extensively washed membranes (plus 3 microM GABA) both bicuculline and DMCM were able to stimulate 35S-TBPS binding either in newborn or in adult rats. On the other hand, the inhibitory effect of diazepam on 35S-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 GABAA receptor complex. In addition, the age-dependent changes in the concentration of endogenous GABA play a critical role in the modulation of 35S-TBPS binding by GABAergic drugs.
Corda
M G
MG
Department of Toxicology, University of Cagliari, Italy.
Cancedda
E
E
Giorgi
O
O
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000031:analogs & derivatives* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D003292:Convulsants / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology; D007700:Kinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013462:Sulfur Radioisotopes; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines; D003292:Convulsants; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; C041598:t-butylbicyclophosphorothionate receptor; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; C017069:bicuculline methiodide; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate; D003975:Diazepam; D001640:Bicuculline