Tigabine hydrochloride, an inhibitor of gamma-aminobutyric acid (GABA) uptake, induces cortical depolarizations in vitro.
The effect of the gamma-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 microM) for 15 min, evoked large, slow depolarizations with a frequency of 6-8/h which persisted for 4-5 h. The GABA(A) receptor antagonists, bicuculline (10 microM) and picrotoxin (100 microM), 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 microM), 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 microM but the AMPA/kainate receptor antagonist, 6,7-dinitroquinoxaline-2.3-dione at high concentrations (100 and 200 microM), reversibly decreased the frequency without affecting the amplitude. It is concluded that the tiagabine-induced depolarizations in this in vitro preparation were initiated through GABA(A) receptors leading, possibly, to a release of excitatory amino acids.
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Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Davies
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JA
D000161:Acoustic Stimulation; D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA / Q000235:genetics; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000494:pharmacology*; D012640:Seizures / Q000235:genetics; D000078308:Tiagabine
D018756:GABA Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D000078308:Tiagabine