Seizures and neurodegeneration induced by 4-aminopyridine in rat hippocampus in vivo: Role of glutamate- and GABA-mediated neurotransmission and of ion channels

Infusion of the K+ channel blocker 4-aminopyridine in the hippocampus induc es the release of glutamate, as well as seizures and neurodegeneration. Sin ce an imbalance between excitation and inhibition, as well as alterations o f ion channels, may be involved in these effects of 4-aminopyridine, we hav e studied whether they are modified by drugs that block glutamatergic trans mission or ion channels, or drugs that potentiate GABA-mediated transmissio n. The drugs were administered to anesthetized rats subjected to intrahippo campal infusion of 4-aminopyridine through microdialysis probes, with simul taneous collection of dialysis perfusates and recording of the electroencep halogram, and subsequent histological analysis. Ionotropic glutamate recept or antagonists clearly diminished the intensity of seizures and prevented t he neuronal damage, but did not alter substantially the enhancement of extr acellular glutamate induced by 4-aminopyridine. None of the drugs facilitat ing GABA-mediated transmission, including uptake blockers, GABA-transaminas e inhibitors and agonists of the A-type receptor, was able to reduce the gl utamate release, seizures or neuronal damage produced by 4-aminopyridine. I n contrast, nipecotate, which notably increased extracellular levels of the amino acid, potentiated the intensity of seizures and the neurodegeneratio n. GABA(A) receptor antagonists partially reduced the extracellular accumul ation of glutamate induced by 4-aminopyridine, but did not exert any protec tive action. Tetrodotoxin largely prevented the increase of extracellular g lutamate, the electroencephalographic epileptic discharges and the neuronal death in the CA1 and CA3 hippocampal regions. Valproate and carbamazepine, also Na+ channel blockers that possess general anticonvulsant action, fail ed to modify the three effects of 4-aminopyridine studied. The N-type Ca2channel blocker omega -conotoxin, the K+ channel opener diazoxide, and the non-specific ion channel blocker riluzole diminished the enhancement of ext racellular glutamate and slightly protected against the neurodegeneration. However, the two former compounds did not antagonize the 4-aminopyridine-in duced epileptiform discharges, and riluzole instead markedly increased the intensity and duration of the discharges. Moreover, at the highest dose tes ted (8 mg/kg, i.p.), riluzole caused a 75% mortality of the rats. We conclude that 4-aminopyridine stimulates the release of glutamate from n erve endings and that the resultant augmented extracellular glutamate is di rectly related to the neurodegeneration and is involved in the generation o f epileptiform discharges through the concomitant overactivation of glutama te receptors. Under these conditions, a facilitated GABA-mediated transmiss ion may paradoxically boost neuronal hyperexcitation. Riluzole, a drug used to treat amyotrophic lateral sclerosis, seems to be toxic when combined wi th neuronal hyperexcitation. (C) 2000 IBRO. Published by Elsevier Science L td. All rights reserved.