Clarithromycin increases neuronal excitability in CA3 pyramidal neurons through a reduction in GABA-ergic signaling.

Antibiotics are used in the treatment and prevention of bacterial infections, but effects on neuron excitability have been documented. A recent study demonstrated that clarithromycin alleviates daytime sleepiness in hypersomnia patients (Trotti et al. 2014). To explore the potential application of clarithromycin as a stimulant, we performed whole cell patch clamp recordings in rat pyramidal cells from the CA3 region of hippocampus. In the presence of the antibiotic, rheobase current was reduced by 50%, F-I relationship (number of action potentials as a function of injected current) was shifted to the left, and the resting membrane potential was more depolarized. Clarithromycin-induced hyperexcitability was dose-dependent; doses of 30 and 300 µM clarithromycin significantly increased the firing frequency and membrane potential as compared to controls (p=0.003, p<0.0001). We hypothesized that clarithromycin enhanced excitability by reducing GABAA receptor activation. 30 µM clarithromycin significantly reduced (p=0.001) the amplitude of spontaneous miniature inhibitory GABA-ergic currents (GABA-mPSCs) and at 300 µM had a minor effect on action potential width. Additionally, we tested the effect of clarithromycin in an ex vivo seizure model by evaluating its effect on spontaneous local field potentials. Bath application of 300 µM clarithromycin enhanced burst frequency 2 fold compared to controls (p=0.0006). Taken together, these results suggest that blocking GABA-ergic signaling by clarithromycin increases cellular excitability and potentially serve as a stimulant, facilitating emergence from anesthesia or normalizing vigilance in hypersomnia and narcolepsy. However, the administration of clarithromycin should be carefully considered in patients with seizure disorders.

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