n-(4-methylthiazol-2-yl)-2-(6-phenylpyridazin-3-ylthio)acetamide and Seizures

GABAA receptor-mediated inhibition--which is due to Cl(-) and HCO3 (-) currents controlled by KCC2 and carbonic anhydrase activity, respectively--contributes to short- and long-lasting interictal events recorded from the CA3 region of hippocampus during application of 4-aminopyridine (4AP, 50 μM). Here, we employed field potential recordings in an in vitro brain slice preparation to establish the effects induced by the KCC2 blockers VU0240551 (10 μM) or bumetanide (50 μM) and by the carbonic anhydrase inhibitor acetazolamide (10 μM) on the two types of interictal events. We found that blocking KCC2 activity decreased the amplitude of the short-lasting events. In addition, this pharmacological procedure increased the interval of occurrence of the long-lasting events and reduced their amplitude. Blocking carbonic anhydrase activity with acetazolamide reduced the interval of occurrence and the duration of the short-lasting events while increasing their amplitude; acetazolamide also reduced the duration and amplitude of the long-lasting events. Finally, blocking either KCC2 or carbonic anhydrase activity increased the interval of occurrence of pharmacologically isolated synchronous GABAergic events and decreased their duration and amplitude. These data substantiate further the role of GABAA receptor-mediated signaling in driving neuronal populations toward hypersynchronous states presumably by increasing extracellular [K(+)].

Topics: Acetazolamide; Animals; CA3 Region, Hippocampal; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; gamma-Aminobutyric Acid; Male; Membrane Potentials; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures; Solute Carrier Family 12, Member 1; Thiazoles; Thioglycolates