PREFERENTIAL STIMULATION OF GLUTAMATE RELEASE BY 4-AMINOPYRIDINE IN RAT STRIATUM IN-VIVO

The potassium channel blocker 4-aminopyridine (4-AP) is a potent convu lsant drug which, in vitro, stimulates the release of neurotransmitter amino acids. We have studied the effect of 4-AP in vivo on the extrac ellular concentration of amino acids in rat striatum, by means of micr odialysis and HPLC. Perfusion with 4-AP in the awake animal produced i ntense motor alterations, including barrel turning and running fits. T herefore, most microdialysis experiments were carried out in anestheti zed rats. Perfusion with 20-75 mM 4-AP for 12.5 min resulted in a mass ive increase in extracellular glutamate (up to 20-fold), smaller incre ases in aspartate and taurine (up to 10-fold) and slight increments in glutamine, alanine, glycine and GABA. In contrast, perfusion with 100 mM K+ produced, mainly, an increment in taurine (7-fold) and modest i ncreases in glutamate and aspartate (100-300%), as well as a notable d ecrease in glutamine. Tetraethylammonium (TEA, 120 mM) perfusion induc ed taurine and glutamate elevations similar to those after high K+, bu t glutamine was not affected. In unanesthetized rats, perfusion with 4 0 mM 4-AP induced changes in extracellular amino acids similar to thos e observed under anesthesia. In these animals neither high K+ nor TEA affected significantly the motor behavior. The results suggest that an enhancement of glutamatergic synaptic transmission, rather than a gen eral depolarizing action, is an important factor in the neuronal hyper excitability induced by 4-AP, which is consistent with the previously demonstrated inhibition of its convulsant effect by glutamate receptor antagonists.