Convulsant and Subconvulsant Doses of Norfloxacin in the Presence and Absence of Biphenylacetic Acid Alter Extracellular Hippocampal Glutamate but Not Gamma-Aminobutyric Acid Levels in Conscious Rats

Abstract

Fluoroquinolones are antibiotics with central excitatory side effects. These adverse effects presumably result from inhibition of ␥-aminobutyric acid (GABA) binding to GABA A receptors. This GABA antagonistic effect is greatly potentiated by the active metabolite of fenbufen, biphenylacetic acid (BPAA). Nevertheless, it remains questionable whether GABA receptor antagonism alone can explain the convulsant activity potentials of these antimicrobial agents. The present study was undertaken to investigate the possible effects of norfloxacin, both in the absence and in the presence of BPAA, on the extracellular hippocampal levels of GABA and glutamate, the main central inhibitory and excitatory amino acid neurotransmitters, respectively. This in vivo microdialysis approach with conscious rats allows monitoring of behavioral alterations and concomitant transmitter modulation in the hippocampus. Peroral administration of 100 mg of BPAA per kg of body weight had no effect on behavior and did not significantly alter extracellular GABA or glutamate concentrations. Intravenous perfusion of 300 mg of norfloxacin per kg did not change the rat's behavior or the concomitant neurotransmitter levels in about half of the experiments, while the remaining animals exhibited severe seizures. These norfloxacin-induced convulsions did not affect extracellular hippocampal GABA levels but were accompanied by enhanced glutamate concentrations. Half of the rats receiving both 100 mg of BPAA per kg and 50 mg of norfloxacin per kg displayed lethal seizures, while the remaining animals showed no seizure-related behavior. In the latter subgroup, again no significant alterations in extracellular GABA levels were observed, but glutamate overflow remained significantly elevated for at least 3 h. In conclusion, norfloxacin exerts convulsant activity in rats, accompanied by elevations of extracellular hippocampal glutamate levels but not GABA levels, even in the presence of BPAA.

Norfloxacin-Induced Electroencephalogram Alteration and Seizures in Rats Are Not Triggered by Enhanced Levels of Intracerebral Glutamate

“…Extracellular glutamate concentrations in the hippocampus had a tendency to fluctuate with time but no general trend could be observed, and similar fluctuations were observed in the two control rats. This observation may seem to be inconsistent with the previous report of enhancement of glutamate concentrations occurring with seizures (10). However, the present study was conducted with Sprague-Dawley rats receiving norfloxacin at 150 mg/kg of body weight compared to Wistar rats treated with 300 mg/kg of norfloxacin in the previous experiment (10), which could partially explain this apparent discrepancy.…”

“…This observation may seem to be inconsistent with the previous report of enhancement of glutamate concentrations occurring with seizures (10). However, the present study was conducted with Sprague-Dawley rats receiving norfloxacin at 150 mg/kg of body weight compared to Wistar rats treated with 300 mg/kg of norfloxacin in the previous experiment (10), which could partially explain this apparent discrepancy. The difficulty of finding doses appropriate for the inducement of reversible and therefore nonlethal seizures but sufficiently severe to have an effect on the EEG signal was previously mentioned (2,5).…”

“…It is usually asserted that these excitatory side effects result from inhibition of GABA (␥-aminobutyric acid) binding to its receptors (1,11). Using intracerebral microdialysis, however, Smolders et al have previously observed in conscious rats norfloxacin-induced convulsions accompanied not by any apparent effect on the extracellular hippocampal GABA levels but rather by enhanced intracerebral glutamate concentrations (10). Studies of the relationship between glutamate concentrations and epileptic seizures have yielded conflicting observations, as recently reviewed (12).…”

“…Studies of the relationship between glutamate concentrations and epileptic seizures have yielded conflicting observations, as recently reviewed (12). Smolders et al have hypothesized that enhanced glutamate levels might be essential for the induction of norfloxacin seizures (10), but it could also be argued that the generation, spreading, and maintenance of seizures eventually leads to glutamate release and elevation (9). Quantitative electroencephalogram (EEG) recording combined with intracerebral microdialysis offers a unique opportunity to address this question.…”

Quinolones

“…The mechanism underlying this interaction is not established but does not appear to be mediated via benzodiazepine receptor effects [361]. Studies have suggested that the mechanism may involve enhanced cerebral glutamate (an excitatory amino acid neurotransmitter) or nitric acid concentrations [369][370][371]. Using a pharmacodynamic model created using in vitro receptor occupancy data and in vivo human pharmacokinetic data, the combination of fenbufen with prulifloxacin or enoxacin were considered the most hazardous in terms of seizure risk [362].…”