The gamma-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats.
The effect of systemic administration of the gamma-aminobutyric acid (GABA) uptake inhibitor, R(-)N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid, hydrochloride (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 pentylenetetrazole-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 (21 mg/kg) produced a peak value of 200% compared to the basal level. Thus, tiagabine acts as a GABA uptake inhibitor in vivo also.
Fink-Jensen
A
A
Novo Nordisk A/S, Pharmaceuticals Research, CNS, Måløv, Denmark.
Suzdak
P D
PD
Swedberg
M D
MD
Judge
M E
ME
Hansen
L
L
Nielsen
P G
PG
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D010433:Pentylenetetrazole; D000078308:Tiagabine