The effect of the γ-aminobutyric acid uptake inhibitor tiagabine hydrochloride was studied on electrical responses in cortical wedges prepared from 20–30 day-old, audiogenic seizure-prone DBA/2 mice. Perfusion of tiagabine (50 μM) for 15 min, evoked large, slow depolarizations with a frequency of 6–8/h which persisted for 4–5 h. The GABAA receptor antagonists, bicuculline (10 μM) and picrotoxin (100 μM), inhibited established depolarizations. These depolarizations were also calcium-dependent and blocked by tetrodotoxin. The non-opioid antitussive, dextromethorphan, which has been shown to inhibit glutamate release, irreversibly blocked the depolarizations. Conversely, 4-aminopyridine (50 μM), a potassium channel antagonist, markedly potentiated the responses. The NMDA receptor antagonist, 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, had no effect on the depolarizations at concentrations up to 100 μM but the AMPA/kainate receptor antagonist, 6,7-dinitroquinoxaline-2.3-dione at high concentrations (100 and 200 μM), reversibly decreased the frequency without affecting the amplitude. It is concluded that the tiagabine-induced depolarizations in this in vitro preparation were initiated through GABAA receptors leading, possibly, to a release of excitatory amino acids.
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