DIFFERENTIAL-EFFECTS OF NIPECOTIC ACID AND 4,5,6,7-TETRAHYDROISOXAZOLO[4,5-C]PYRIDIN-3-OL ON EXTRACELLULAR GAMMA-AMINOBUTYRATE LEVELS IN RAT THALAMUS

Using the microdialysis technique acid HPLC (high-performance liquid c hromatography) determination of amino acids, the extracellular concent rations of gamma-aminobutyrate (GABA), glutamate, aspartate and a numb er of other amino acids were determined in rat thalamus during infusio n through the microdialysis tubing of the GAB A transport inhibitors 4 ,5,6,7-tetrahydroisoxaxolo[4,5-c]pyridin-3-ol (THPO) and nipecotic aci d, Administration of 5.0 mM THPO led to a 200% increase in the extrace llular GABA concentration. Simultaneous infusion of THPO and GABA (50 mu M) increased the extracellular GABA concentration to 1200% of the b asal level whereas GABA alone was found to increase the GABA level to 500%. If nipecotic acid (0.5 mM) was administered together with GABA ( 50 mu M) the extracellular concentration of GABA was not increased fur ther. While administration of GABA alone or GABA together with nipecot ic acid had no effect on the extracellular levels of glutamate and asp artate it was found that GABA plus THPO increased the extracellular co ncentration of these amino acids. GABA administered alone or together with nipecotic acid or THPO led to relatively small but significant in creases in the extracellular concentrations of the amino acids glycine , glutamine, serine and threonine. The results demonstrate that THPO, which preferentially inhibits glial GABA uptake and which is not a sub strate for the GABA carriers, was more efficient increasing the extrac ellular concentration of GABA than nipocotic acid which is a substrate and an inhibitor of both neuronal and glial GABA uptake. This indicat es that GABA uptake inhibitors that are not substrates for the carrier and which preferentially inhibit glial GABA uptake may constitute a g roup of drugs by which the efficacy of GABAergic neurotransmission may be enhanced. (C) 1997 Elsevier Science B.V.