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)

The anticonvulsant effects of intracerebral administration of the high ly potent group II metabotropic glutamate receptor agonist, DCG-IV, we re tested in fully kindled rats following daily electrical stimulation of the basolateral amygdala. The agonist caused a dose-dependent incr ease in the generalized seizure threshold (GST) of these seizure susce ptible animals within the dose range tested (0.01-1.0 nmol). The estim ated GST(100) value (dose causing a 100% increase in GST) for this eff ect was 0.22 nmol. The anti-seizure activity of DCG-IV was fully inhib ited in the presence of the group II metabotropic glutamate receptor a ntagonist (2S,1'S,2'S)-2-methyl-2(carboxycyclopropyl)glycine (MCCG; 40 nmol), while MCCG alone showed no significant inhibitory effect on se izure activity. DCG-IV also powerfully inhibited depolarization-induce d release of [H-3]D-aspartate from rat cerebrocortical synaptosomes, w ith an IC50 value of 0.39 mu M In this respect, DCG-IV was approximate ly 70-fold more potent than the clinically effective anticonvulsant dr ug lamotrigine (IC50 = 27.7 mu M), a proposed neurotransmitter release inhibitor known to inhibit glutamate release, also tested in this ass ay. These findings demonstrate the high potency of DCG-IV as an antico nvulsant agent and confirm a key role for group II metabotropic glutam ate receptors in the control of seizure activity via their modulatory action on neuronal glutamate release. (C) 1998 Elsevier Science B.V. A ll rights reserved.