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 γ‐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 μ M )‐evoked responses, in the vagus nerve in vitro , were inhibited by bicuculline (0.3–10 μ M ) and picrotoxin (0.3–10 μ M ), with IC 50 values and 95% confidence intervals (CI) of 1.2 μ M (1.1–1.4) and 3.6 μ M (3.0–4.3), respectively, and were potentiated by sodium pentobarbitone (30 μ M ) and diazepam (1 μ M ) to (mean±s.e.mean) 168±18% and 117±4% of control, respectively. 5‐Hydroxytryptamine (5‐HT; 0.5 μ M )‐evoked responses were inhibited by MDL 72222 (1 μ M ) to 10±4% of control; DMPP (10 μ M )‐evoked responses were inhibited by hexamethonium (100 μ M ) to 12±5% of control, and αbMeATP (30 μ M )‐evoked responses were inhibited by PPADS (10 μ M ) to 21±5% of control. Together, these data are consistent with activation of GABA A , 5‐HT 3 , nicotinic ACh and P2 X receptors, respectively. 4 Ciprofloxacin (10–3000 μ M ) inhibited GABA A ‐mediated responses in the vagus nerve with an IC 50 (and 95% CI) of 202 μ M (148–275). BPAA (1–1000 μ 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‐HT 3 , 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 μ M ), BPAA (100 μ M ) or the combination of these drugs (both at 100 μ M ). 6 GABA (1 m M )‐evoked responses in the optic nerve were inhibited by bicuculline with an IC 50 of 3.6 μ 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 IC 50 of 334 μ M (256–437) and BPAA (100 μ 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.British Journal of Pharmacology (1997) 122 , 584–590; doi: 10.1038/sj.bjp.0701411