EFFECTS OF CHRONIC TIAGABINE TREATMENT ON [H-3] GABA(A), [H-3] GABA(B) AND [H-3] TIAGABINE BINDING TO SECTIONS FROM MICE BRAIN

4,4-Bis(3-methyl-2-thienyl)but-3-en-1-yl)nipecotic acid (tiagabine) is a potent inhibitor of gamma-aminobutyric acid (GABA) uptake, which ma intains its initial anticonvulsant effects when administered to mice f or a prolonged period (21 days). In the present study, mice received c hronic (21 days) p.o. administration of tiagabine (15 mg/kg, twice dai ly) or vehicle alone and the densities of GABA(A) and GABA(B) receptor s and of [H-3]tiagabine recognition sites were measured in several bra in regions. The following changes were observed following chronic admi nistration of tiagabine as compared to vehicle: significant reduction (18-37%) in [H-3]tiagabine binding in the temporal and entorhinal cort ex and in the molecular and granular layer of the cerebellar cortex; i ncreases in the number of GABA(A) sites (22-44%) in various regions of the frontal cortex, in caudate putamen and in the lateral septum; dec reases in the numbers of GABA(B) sites (18-42%) in the motor cortex, t he more dorsal parts of cortex, the anteroventral thalamic nucleus, me dial geniculate, superior colliculus and the molecular layer of the ce rebellar cortex. Such data suggest that the GABAergic system is differ entially modulated in a regional specific manner in response to chroni c elevation of the extracellular levels of GABA. The significance of t hese findings in relation to the reported lack of development of toler ance to the anticonvulsant effects of tiagabine is discussed.