QUINOLONES AND FENBUFEN INTERACT WITH GABA-A RECEPTOR IN DISSOCIATED HIPPOCAMPAL CELLS OF RAT

1. Interaction of quinolone antibiotics and the anti-inflammatory agent fenbufen with the gamma-aminobutyric acid-A (GABA(A)) receptor-chloride channel complex in pyramidal neurons freshly dissociated from the hippocampal CA1 region of the rats was investigated in whole-cell mode, using the patch-clamp technique under voltage-clamp conditions. 2. Quinolones in clinical doses had no effects on the GABA-gated Cl- current (I(Cl)) but slightly suppressed the response at concentrations > 10(-5) M. A metabolite of fenbufen, 4-biphenylacetic acid (BPA), also had little effect on the GABA response at therapeutic concentrations. 3. Coadministration of one of quinolones and BPA suppressed the GABA-gated I(Cl) with increase in each of them in a concentration-dependent manner, and there was a parallel shift of the concentration-response curve for GABA to the right but with no effect on the maximum response, thereby indicating a competitive antagonism. The inhibitory potency of antibiotics in combination with BPA was in the order of norfloxacin >> enoxacin > ciprofloxacin > pipemidic acid >> ofloxacin > cinoxacin = piromidic acid = nalidixic acid = 0. 4. Norfloxacin and BPA, administered simultaneously, also strongly suppressed pentobarbital sodium (PB)-gated I(Cl), but they did not act on benzodiazepine (BZP) receptors. 5. Both GABA- and PB-induced I(Cl)s reversed at the Cl- equilibrium potential (E(Cl)). In the presence of BPA, the quinolone-induced inhibition of GABA-gated I(Cl)s showed no voltage dependence. 6. It was concluded that, in the presence of an anti-inflammatory agent, the quinolone antibiotics decrease the affinity of GABA(A) receptors, the result being induction of epileptogenic neurotoxicities.