The influence of increased endogenous gamma-aminobutyric acid (GABA) concentrations on benzodiazepine receptor (BZR) function was studied in the living baboon brain. By using positron emission tomography and the radiotracer [11C] flumazenil combined with electroencephalography, the anticonvulsant/proconvulsant activity and the potency of the BZR agonist diazepam and the inverse agonist methyl-beta-carboline-3-carboxylate (beta-CCM), a beta-carboline, were determined in baboons pretreated or not with 500mg/kg of vigabatrin (irreversible inhibitor of the GABA-aminotransferase which increases GABA concentrations in vivo). Pretreatment with vigabatrin increased the threshold of paroxysmal pentylenetetrazol-induced seizure. In both vigabatrin-treated and -untreated animals, the threshold dose of pentylenetetrazol increased with increasing doses of diazepam; it decreased with increasing doses of beta-CCM. The proconvulsant activity of beta-CCM was at all doses reduced in vigabatrin-treated animals compared to untreated animals, whereas, surprisingly, the anticonvulsant activity of high doses of diazepam was reduced after vigabatrin. The potency of diazepam in displacing [11C] flumazenil was enhanced in vigabatrin-pretreated animals, contrasting with the reduced anticonvulsant effects of diazepam in those animals. We determined the linear relationship between the fractional receptor occupancy and the anticonvulsant/proconvulsant effect. The slope, an estimate of the intrinsic efficacy of a BZR ligand, was reduced markedly for diazepam after vigabatrin pretreatment, whereas that for beta-CCM was unmodified. This indicates that increasing GABA levels in vivo reduce the anticonvulsant activity of the BZR agonist diazepam by decreasing its intrinsic efficacy, whereas the intrinsic efficacy of the inverse agonist beta-CCM remains essentially unaltered.