The antiseizure activities of glial or neuronal
GABA uptake inhibitors and
GABA agonists were compared following intracerebroventricular administration in 2 acute models of chemoconvulsion in rats. The glia-selective
GABA uptake inhibitor, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (
THPO), given at doses of 100-750 micrograms, i.c.v., protected against maximal
pentylenetetrazol (PTZ)
seizures and increased the latency to
isonicotinic acid hydrazide (INH)
seizures for at least 1 h following central administration.
THPO failed to increase PTZ seizure thresholds. In contrast, the more potent partly glia-selective
GABA uptake inhibitor, cis-4-hydroxynipecotic
acid (30-300 micrograms), which is also a substrate for neuronal and glial transport systems, protected only 33% of rats against PTZ-induced tonic extension and had no effect on INH seizure latency. The neuron-selective uptake inhibitor
L-2,4-diaminobutyric acid (
DABA) at 1500 micrograms exhibited anti-PTZ activity initially and then, after a delay, produced proconvulsant behavior and spontaneous
myoclonus in some animals. Intracerebroventricular injection of the
GABA receptor agonist,
muscimol, at toxic doses, gave rise to mixed
anticonvulsant (INH
seizures) and proconvulsant (PTZ seizure thresholds) effects. The results suggest that
THPO, of the 4 compounds tested, possesses significant
anticonvulsant activity. Its ability to suppress tonic but not generalized minor
seizures suggests that it may block seizure spread.