Anticonvulsant and glutamate release-inhibiting properties of the highly potent metabotropic glutamate receptor agonist (2S,2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV)

Brain Res. 1998 Sep 14;805(1-2):138-43. doi: 10.1016/s0006-8993(98)00698-2.

Abstract

The anticonvulsant effects of intracerebral administration of the highly potent group II metabotropic glutamate receptor agonist, DCG-IV, were tested in fully kindled rats following daily electrical stimulation of the basolateral amygdala. The agonist caused a dose-dependent increase in the generalized seizure threshold (GST) of these seizure susceptible animals within the dose range tested (0. 01-1.0 nmol). The estimated GST100 value (dose causing a 100% increase in GST) for this effect was 0.22 nmol. The anti-seizure activity of DCG-IV was fully inhibited in the presence of the group II metabotropic glutamate receptor antagonist (2S,1'S, 2'S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG; 40 nmol), while MCCG alone showed no significant inhibitory effect on seizure activity. DCG-IV also powerfully inhibited depolarization-induced release of [3H]D-aspartate from rat cerebrocortical synaptosomes, with an IC50 value of 0.39 microM. In this respect, DCG-IV was approximately 70-fold more potent than the clinically effective anticonvulsant drug lamotrigine (IC50=27.7 microM), a proposed neurotransmitter release inhibitor known to inhibit glutamate release, also tested in this assay. These findings demonstrate the high potency of DCG-IV as an anticonvulsant agent and confirm a key role for group II metabotropic glutamate receptors in the control of seizure activity via their modulatory action on neuronal glutamate release.

MeSH terms

  • Amygdala / physiology
  • Animals
  • Anticonvulsants / pharmacology*
  • Aspartic Acid / metabolism
  • Cerebral Cortex / metabolism
  • Cyclopropanes / pharmacology*
  • Glutamic Acid / metabolism*
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Kindling, Neurologic / physiology
  • Lamotrigine
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / agonists*
  • Seizures / physiopathology
  • Synaptosomes / metabolism
  • Triazines / pharmacology

Substances

  • Anticonvulsants
  • Cyclopropanes
  • Receptors, Metabotropic Glutamate
  • Triazines
  • 2-(2,3-dicarboxycyclopropyl)glycine
  • Aspartic Acid
  • Glutamic Acid
  • Glycine
  • Lamotrigine