QUANTITATION OF GABA(A) RECEPTOR INHIBITION REQUIRED FOR QUINOLONE-INDUCED CONVULSIONS IN MICE

We quantified the amount of inhibition of gamma-aminobutyric acid (GAB A)(A) rending required for the onset of convulsions induced by ciprofl oxacin in combination with biphenylacetic acid (BPAA) in mice. In fast ing mice iv ciprofloxacin given 30 min after oral BPAA (50 mg/kg) indu ced convulsions at does of 40 mg/kg or above. In contrast, ofloxacin c aused no convulsions even at 100 mg/kg, the highest dose tested. When mice received 40 mg/kg of ciprofloxacin or ofloxacin, maximal brain co ncentrations of each quinolone at 30 min were 0.37 or 1.97 mu g/g, res pectively. These brain concentrations of ciprofloxacin and ofloxacin w ere not affected by combination with BPAA. In the presence of ciproflo xacin and BPAA (at brain tissue concentrations which induced convulsio ns), the binding of H-3-muscimol to GABA(A)or sites was inhibited by a pproximately 30%. Using results from a similar binding study, an impra cticable iv dose of ofloxacin (500 mg/kg) was estimated to be required to inhibit GABA(A) rinding by 30%, and therefore to induce similar co nvulsions to those seen with ciprofloxacin at a dose of 40 mg/kg. Thes e results may indicate that epileptic convulsions occur when ciproflox acin and BPAA interact with each other to antagonize at least 30% of G ABA(A) rinding in mice, and provide evidence for a significant role of GABA(A) rhibition in the occurrence of quinolone-induced convulsions.