Effects of antiepileptic drugs on GABA release from rat and human neocortical synaptosomes

  • M. Kammerer
  • M. P. Rassner
  • T. M. Freiman
  • T. J. Feuerstein
ORIGINAL ARTICLE

DOI: 10.1007/s00210-011-0636-8

Cite this article as:
Kammerer, M., Rassner, M.P., Freiman, T.M. et al. Naunyn-Schmiedeberg's Arch Pharmacol (2011) 384: 47. doi:10.1007/s00210-011-0636-8

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 3H-GABA release from human neocortical synaptosomes preincubated with 3H-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 Ca2+ (Cae2+) reduced K+-evoked release in both species, while blockade of Na+ channels with tetrodotoxin had no effect. K+-evoked release was characterized as predominant, Ca2+-dependent and Na+-independent, exocytosis. Carbamazepine and phenytoin in the rat and carbamazepine, phenytoin, lamotrigine, and valproate in human tissue reduced K+-evoked 3H-GABA release. With respect to veratridine-evoked release, Cae2+ 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 3H-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 3H-GABA release. Interestingly, no AED increased 3H-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.

Keywords

EpilepsyAntiepileptic drugsGABANeocortical synaptosomesVeratridinePotassium

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • M. Kammerer
    • 1
  • M. P. Rassner
    • 1
  • T. M. Freiman
    • 2
  • T. J. Feuerstein
    • 1
  1. 1.Section of Clinical Neuropharmacology, Department of Neurosurgery, NeurozentrumAlbert-Ludwigs UniversityFreiburgGermany
  2. 2.Department of Neurosurgery, NeurozentrumAlbert-Ludwigs UniversityFreiburgGermany