Selective antagonism of the GABA(A) receptor by ciprofloxacin and biphenylacetic acid

1 Previous studies have shown that ciprofloxacin and biphenylacetic acid (BPAA) synergistically inhibit gamma-aminobutyric acid (GABA)(A) receptors. In the present study, we have investigated the actions of these two drugs on other neuronal ligand-gated ion channels. 2 Agonist-evoked depolarizations were recorded from rat vagus and optic nerves in vitro by use of an extracellular recording technique. 3 GABA (50 mu M)-evoked responses, in the vagus nerve in vitro, were inhibited by bicuculline (0.3-10 mu M) and picrotoxin (0.3-10 mu M), with IC50 values and 95% confidence intervals (CI) of 1.2 mu M (1.1-1.4) and 3.6 mu M (3.0-4.3), respectively, and were potentiated by sodium pentobarbitone (30 mu M) and diazepam (1 mu M) to (mean+/-s.e.mean) 168+/-18% and 117+/-4% of control, respectively. 5-Hydroxytryptamine (5-HT; 0.5 mu M)-evoked responses were inhibited by MDL 72222 (1 mu M) to 10+/-4% of control; DMPP (10 mu M)-evoked responses were inhibited by hexamethonium (100 mu M) to 12+/-5% of control, and alpha beta MeATP (30 mu M)-evoked responses were inhibited by PPADS (10 mu M) to 21+/-5% of control. Together, these data are consistent with activation of GABA(A), 5-HT3, nicotinic ACh and P2(X) receptors, respectively. 4 Ciprofloxacin (10-3000 mu M) inhibited GABA(A)-mediated responses in the vagus nerve with an IC50 (and 95% CI) of 202 mu M (148-275). BPAA (1-1000 mu M) had little or no effect on the GABA(A)-mediated response but concentration-dependently potentiated the effects of ciprofloxacin by up to 33,000 times. 5 Responses mediated by 5-HT3, nicotinic ACh and P2(X) receptors in the vagus nerve and strychnine-sensitive glycine receptors in the optic nerve were little or unaffected by ciprofloxacin (100 mu M), BPAA (100 mu M) or the combination of these drugs (both at 100 mu M). 6 GABA (1 mM)-evoked responses in the optic nerve were inhibited by bicuculline with an IC50 of 3.6 mu M (2.8-4.5), a value not significantly different from that determined in the vagus nerve. Ciprofloxacin also inhibited the GABA-evoked response with an IC50 of 334 mu M (256-437) and BPAA (100 mu M) potentiated these antagonist effects. However, the magnitude of the synergy was 48 times less than that seen in the vagus nerve. 7 These data indicate that ciprofloxacin and BPAA are selective antagonists of GABA(A) receptors, an action that may contribute to their excitatory effects in vivo. Additionally, our data suggest that the molecular properties of GABA(A) receptors in different regions of the CNS influence the extent to which these drugs synergistically inhibit the GABA(A) receptor.