The effects of anticonvulsant compounds on 4-aminopyridine-induced de novo synthesis of neurotransmitter amino acids in rat hippocampus in vitro.
4-Aminopyridine, a voltage-dependent potassium channel blocker, causes tonic-clonic and electrographic seizures in vivo and evokes epileptiform activity and release of glutamate, aspartate and GABA in vitro. This study examined the effects of 4-aminopyridine (4AP) on de novo synthesis of neuroactive amino acids and a subsequent response to various anticonvulsant compounds (phenytoin, carbamazepine, phenobarbital, valproate, ethosuximide, diazepam, lamotrigine, felbamate, losigamone, U54494A, CPP, MK801 and CNQX) using a hippocampal slice preparation. 4-Aminopyridine had a minimal effect on total tissue concentrations of glutamate, aspartate, and GABA, but caused a significant increase in their de novo synthesis. Phenytoin, carbamazepine, lamotrigine, losigamone and U54494A were the only compounds which were effective in blocking the 4AP-induced increase in all newly synthesized amino acids. It appears that these compounds inhibit 4AP effects in this paradigm by blocking depolarization, probably at use-dependent voltage-sensitive sodium channels. Therefore, this paradigm may be useful in selectively identifying anticonvulsants which act by blocking depolarization.
Kapetanovic
I M
IM
Preclinical Pharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Yonekawa
W D
WD
Kupferberg
H J
HJ
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013779:Tetrodotoxin / Q000494:pharmacology
D000927:Anticonvulsants; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D013779:Tetrodotoxin; D015761:4-Aminopyridine; D005947:Glucose