Preferential stimulation of glutamate release by 4-aminopyridine in rat striatum in vivo.
The potassium channel blocker 4-aminopyridine (4-AP) is a potent convulsant drug which, in vitro, stimulates the release of neurotransmitter amino acids. We have studied the effect of 4-AP in vivo on the extracellular concentration of amino acids in rat striatum, by means of microdialysis and HPLC. Perfusion with 4-AP in the awake animal produced intense motor alterations, including barrel turning and running fits. Therefore, most microdialysis experiments were carried out in anesthetized rats. Perfusion with 20-75 mM 4-AP for 12.5 min resulted in a massive increase in extracellular glutamate (up to 20-fold), smaller increases 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 increases in glutamate and aspartate (100-300%), as well as a notable decrease in glutamine. Tetraethylammonium (TEA, 120 mM) perfusion induced taurine and glutamate elevations similar to those after high K+, but glutamine was not affected. In unanesthetized rats, perfusion with 40 mM 4-AP induced changes in extracellular amino acids similar to those 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 general depolarizing action, is an important factor in the neuronal hyperexcitability induced by 4-AP, which is consistent with the previously demonstrated inhibition of its convulsant effect by glutamate receptor antagonists.
Morales-Villagrán
A
A
División de Ciencias Biológicas, C.U.C.B.A., Universidad de Guadalajara, México.
Tapia
R
R
D015761:4-Aminopyridine / Q000494:pharmacology*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D000596:Amino Acids; D013757:Tetraethylammonium Compounds; D018698:Glutamic Acid; D011189:Potassium Chloride; D015761:4-Aminopyridine