title: Effects of antiepileptic drugs on GABA release from rat and human neocortical synaptosomes.
abstract: In epilepsy, allegedly, a neurotransmitter imbalance between the inhibitory GABA and the excitatory glutamate prevails. Therefore, some antiepileptic drugs (AEDs) are thought to increase GABA release. Because little is known about corresponding presynaptic effects of AEDs in the human brain, this study investigated the effects of carbamazepine, lamotrigine, phenytoin, gabapentin, pregabalin, levetiracetam, and valproate on (3)H-GABA release from human neocortical synaptosomes preincubated with (3)H-GABA. To obtain information on possible species differences, rat neocortical synaptosomes were investigated concomitantly. Release was evoked by either veratridine (1, 3.2, or 10 μM), which prevents activated voltage-dependent Na(+) channels from closing, or elevation of extracellular [K(+)] from 3 to 15 mM. The exocytosis inhibitor tetanus toxin (TeT) or withdrawal of buffer Ca(2+) (Ca (e) (2+) ) reduced K(+)-evoked release in both species, while blockade of Na(+) channels with tetrodotoxin had no effect. K(+)-evoked release was characterized as predominant, Ca(2+)-dependent and Na(+)-independent, exocytosis. Carbamazepine and phenytoin in the rat and carbamazepine, phenytoin, lamotrigine, and valproate in human tissue reduced K(+)-evoked (3)H-GABA release. With respect to veratridine-evoked release, Ca (e) (2+) withdrawal did not reduce release in the rat; it even increased the release in human tissue. TeT was slightly inhibitory in the rat. Blockade of GABA transport diminished veratridine-evoked (3)H-GABA release in either species. This release was characterized as mediated mainly by transporter reversal. Carbamazepine, lamotrigine, and phenytoin in rat tissue and carbamazepine and phenytoin in human decreased veratridine-induced (3)H-GABA release. Interestingly, no AED increased (3)H-GABA release. The reduction by AEDs of veratridine-evoked release was more intense than that of K(+)-evoked release. In conclusion, reduction of GABA release by AEDs may be the actual objective in a pathologically altered neuronal network where GABA acts in a depolarizing fashion.
authors.affiliation: Section of Clinical Neuropharmacology, Department of Neurosurgery, Neurozentrum, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kammerer
authors.forename: M P
authors.initials: MP
authors.lastname: Rassner
authors.forename: T M
authors.initials: TM
authors.lastname: Freiman
authors.forename: T J
authors.initials: TJ
authors.lastname: Feuerstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000588:Amines / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000172:deficiency; D002220:Carbamazepine / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D006801:Humans; D007223:Infant; D000077213:Lamotrigine; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D010672:Phenytoin / Q000493:pharmacokinetics / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D000069583:Pregabalin; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013744:Tetanus Toxin / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D018756:GABA Antagonists; D009557:Nipecotic Acids; D010091:Oximes; D013744:Tetanus Toxin; D014227:Triazines; C078793:NNC 711; D002220:Carbamazepine; D013779:Tetrodotoxin; D000077287:Levetiracetam; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D010672:Phenytoin; D000077206:Gabapentin; D014701:Veratridine; D011188:Potassium; D002118:Calcium; D000077213:Lamotrigine; D010889:Piracetam