The effect of chronic treatment with the GABA transaminase inhibitors gamma-vinyl-GABA and ethanolamine-O-sulphate on the in vivo release of GABA from rat hippocampus.
The effects of chronic treatment with the specific, mechanism-based, irreversible inhibitors of 4-aminobutyrate aminotransferase (EC 2.6.1.19; GABA transaminase), ethanolamine O-sulphate (EOS), and 4-aminohexenoate [vigabatrin; gamma-vinyl-GABA (GVG)] on the extracellular concentrations of GABA in the hippocampus have been studied using in vivo microdialysis in conscious animals. Oral dosing [3 mg/ml of drinking water, giving doses of GVG of 194 +/- 38 mg/kg/day and of EOS of 303 +/- 42 mg/kg/day (mean +/- SD)] was followed by microdialysis at 2, 8, and 21 days. The basal outflow of GABA (in the range of approximately 1-2 pmol/30 microliters/30-min sample) after 2 and 8 days of treatment was not significantly different from that in control animals, but the 21-day treatment gave significant rises in the extracellular GABA concentration (up to approximately 6-8 pmol/30 microliters/30-min sample). Both inhibitors gave similar results. Depolarisation with 100 mM K+ gave large increases in GABA release in control (approximately 20-60 pmol/30 microliters/30-min sample) and treated animals. The 8- and 21-day-treated animals showed significant increases in the stimulated release compared with control animals (approximately 80-100 pmol/30 microliters/30-min sample). Excluding Ca2+ had no significant effect on either basal or stimulated release. The significant increases in K(+)-evoked release of GABA show that the increased intracellular pool of GABA is available for release, and this may be related to the anticonvulsant action of these compounds.
Qume
M
M
Department of Neurochemistry, Institute of Neurology, London, England.
Whitton
P S
PS
Fowler
L J
LJ
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight; D002118:Calcium / Q000494:pharmacology; D004326:Drinking; D004983:Ethanolamines / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
D004983:Ethanolamines; D005680:gamma-Aminobutyric Acid; C020619:ethanolamine O-sulfate; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D011188:Potassium; D002118:Calcium