TIAGABINE HYDROCHLORIDE, AN INHIBITOR OF GAMMA-AMINOBUTYRIC-ACID (GABA) UPTAKE, INDUCES CORTICAL DEPOLARIZATIONS IN-VITRO

The effect of the gamma-aminobutyric acid uptake inhibitor tiagabine h ydrochloride was studied on electrical responses in cortical wedges pr epared from 20-30 day-old, audiogenic seizure-prone DBA/2 mice. Perfus ion of tiagabine (50 mu M) for 15 min, evoked large, slow depolarizati ons with a frequency of 6-8/h which persisted for 4-5 h. The GABA(A) r eceptor antagonists, bicuculline (10 mu M) and picrotoxin (100 mu M), inhibited established depolarizations. These depolarizations were also calcium-dependent and blocked by tetrodotoxin. The non-opioid antitus sive, dextromethorphan, which has been shown to inhibit glutamate rele ase, irreversibly blocked the depolarizations. Conversely, 4-aminopyri dine (50 mu M), a potassium channel antagonist, markedly potentiated t he responses. The NMDA receptor antagonist, -((R)-2-carboxypiperazin-4 -yl)-propyl-1-phosphonic acid, had no effect on the depolarizations at concentrations up to 100 mu M but the AMPA/kainate receptor antagonis t, 6,7-dinitroquinoxaline-2.3-dione at high concentrations (100 and 20 0 mu M), reversibly decreased the frequency without affecting the ampl itude. It is concluded that the tiagabine-induced depolarizations in t his in vitro preparation were initiated through GABA(A) receptors lead ing, possibly, to a release of excitatory amino acids. (C) 1997 Elsevi er Science B.V.