The γ-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats

The effect of systemic administration of the γ-aminobutyric acid (GABA) uptake inhibitor, R( − )N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid, hydrochloridc (tiagabine) (previously NO-328), on extracellular GABA levels in the globus pallidus, ventral pallidum and substantia nigra of awake Sprague-Dawley rats was investigated using in vivo microdialysis. Tiagabine was administered in doses of 11.5 or 21.0 mg/kg i.p. (ED₅₀, and ED₈₅ doses, respectively, for inhibiting pentylcnctetrazole-induced tonic seizures). Tiagabine increased the extracellular concentrations of GABA in globus pallidus with peak values 310% of basal level (after 21 mg/kg) and 240% of basal level (after 11.5 mg/kg). A significant increase in extracellular GABA levels was also found in the ventral pallidum (280% increase after 11.5 mg/kg and 350% increase after 21 mg/kg) and in the substantia nigra where the ED₈₅ dose of tiagabine 621 mg/kg) produced a peak value of 200% compared to the basal level. Thus, tiagabine acts as a GABA uptake inhibitor in vivo also.