Pharmacological response sensitization in nerve cell networks exposed to the antibiotic gentamicin

Abstract

Gentamicin is an aminoglycoside antibiotic that is used in clinical, organismic, and agricultural applications to combat gram-negative, aerobic bacteria. The clinical use of gentamicin is widely linked to various toxicities, but there is a void in our knowledge about the neuromodulatory or neurotoxicity effects of gentamicin. This investigation explored the electrophysiologic effects of gentamicin on GABAergic pharmacological profiles in spontaneously active neuronal networks in vitro derived from auditory cortices of E16 mouse embryos and grown on microelectrode arrays.Using the GABAA agonist muscimol as the test substance, responses from networks to dose titrations of muscimol were compared in the presence and absence of 100µM gentamicin (the recommended concentration for cell culture conditions). Spike-rate based EC50 values were generated using sigmoidal fit concentration response curves (CRCs). Exposure to 100µM gentamicin exhibited a muscimol EC50±S.E.M. of 80±6nM (n=10). The EC50 value obtained in the absence of gentamicin was 124±11nM (n=10). The 35% increase in potency suggests network sensitization to muscimol in the presence of gentamicin. Action potential (AP) waveform analyses of neurons exposed to gentamicin demonstrated a concentration-dependent decrease in AP amplitudes (extracellular recordings), possibly reflecting gentamicin effects on voltage-gated ion channels. These in vitro results reveal alteration of pharmacological responses by antibiotics that could have significant influence on the behavior and performance of animals.