Prolongation of gamma-aminobutyric acid-mediated inhibitory postsynaptic potentials by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO).

The effects of 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO), an inhibitor of gamma-aminobutyric acid (GABA) uptake, were examined in the rat hippocampal slice and compared to the actions of the potent GABA uptake inhibitor, cis-4-OH-nipecotic acid. THPO reversibly prolonged GABA-mediated inhibitory postsynaptic potentials (IPSPs) but did not prolong conductance changes evoked by iontophoresed GABA. In contrast, cis-4-OH-nipecotic acid prolonged responses to iontophoresed GABA but had little effect on IPSPs. THPO reduced the intensity of spontaneous epileptiform bursts observed in elevated (8.5 mM) potassium; this effect was absent after addition of 100 microM bicuculline. These results suggest that drugs similar to THPO may be useful for enhancing GABA-mediated inhibition, but that THPO acts by a mechanism distinct from that of the GABA uptake inhibitor, cis-4-OH-nipecotic acid.