CHRONIC ADMINISTRATION OF BETA-CARBOLINE-3-CARBOXYLIC ACID METHYLAMIDE BY CONTINUOUS INTRAVENTRICULAR INFUSION INCREASES GABAERGIC FUNCTION

The repeated, intraperitoneal administration of the benzodiazepine receptor inverse agonist, FG 7142 (beta-carboline-3-carboxylic acid methylamide), leads to pharmacological kindling and an associated decrease in GABA-stimulated influx of Cl-36- into cortical membrane preparations. The chronic administration of benzodiazepine agonists results in the development of tolerance and also results in a decrease in GABA-stimulated uptake of Cl-36-. The present study was designed to evaluate further the paradoxical reports that both chronic treatment with benzodiazepine receptor agonists and inverse agonists results in a decreased ability of GABA to stimulate uptake of Cl-36- into cortical membrane preparations. The effects of continuous administration of FG 7142 on GABA-stimulated uptake of Cl-36-, the threshold for bicuculline-induced seizures and the proconvulsant actions of acute administration FG 7142 were evaluated. The continuous administration of FG 7142 resulted in an increased capacity of GABA to stimulate the uptake of Cl-36- into cortical membrane preparations and a significant increase in the seizure threshold for bicuculline following the acute administration of FG 7142. These data, therefore, indicate that changes in GABAergic function following chronic administration of FG 7142 are dependent on the regimen of administration of drug. The results also suggest that the GABA receptor homeostatically responds to continuous occupation by inverse agonists by an upregulation of its functional response to GABA.