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

• Published in: Brain research 1998-09, Vol.805 (1), p.138-143
• Main Authors: Attwell, P.J.E., Singh Kent, N., Jane, D.E., Croucher, M.J., Bradford, H.F.
• Format: Article
• Language: English
• Subjects: Amygdala - physiology; Animals; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Aspartic Acid - metabolism; Biological and medical sciences; Cerebral Cortex - metabolism; Cyclopropanes - pharmacology; DCG-IV; Epileptogenesis; Glutamate release; Glutamic Acid - metabolism; Glycine - analogs & derivatives; Glycine - pharmacology; Group II metabotropic glutamate receptor; Kindling; Kindling, Neurologic - physiology; Lamotrigine; Male; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Presynaptic glutamate receptor; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - agonists; Seizure; Seizures - physiopathology; Synaptosomes - metabolism; Triazines - pharmacology
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(98)00698-2

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 GST 100 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 (2 S,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 [ 3 H ] d-aspartate from rat cerebrocortical synaptosomes, with an IC 50 value of 0.39 μM. In this respect, DCG-IV was approximately 70-fold more potent than the clinically effective anticonvulsant drug lamotrigine (IC 50=27.7 μM), 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.