INFLUENCE OF INHIBITORS OF THE HIGH-AFFINITY GABA UPTAKE ON SEIZURE THRESHOLDS IN MICE

The inhibitors of the high affinity GABA uptake, nipecotic acid, guvacine and cis-4-hydroxynipecotic acid were administered to mice in the form of their methyl and ethyl esters in order to enable the drugs to penetrate into the brain. The effect of these drugs on thresholds for electro-and penetetrazole-convulsions was studied 30 min after intraperitoneal injection at a dose of 0.22 mmol/kg. The resulting elevations of the convulsant thresholds correlated well with the in vtitro potency of the inhibitors, ( -)-nipecotic acid ethyl ester having the most pronounced effect. The effect on the convulsant threshold was not paralleled by alterations in GABA levels in the brain or the activities of glutamate decarboxylase (GAD) or GABA-α-oxoglutarate amino transferase (GABA-T). The esters had a cholinergic action of their own which could be blocked by atropine, and this is considered to be the consequence of peripheral stimulation of muscarinic receptors. The GABA agonist, muscimol (5.5 μmol/kg i.p.) also elevated both convulsant thresholds; this effect was accompanied by a lowered GABA level in brain and a reduced activity of GAD. The results make a role of GABA in the regulation of seizure susceptibility and in the pathogenesis of epileptic disorders likely. © 1979.