Metabotropic
glutamate (mGlu) receptors have multiple actions on neuronal excitability through
G-protein-linked modifications of
enzymes and
ion channels. They act presynaptically to modify glutamatergic and
gamma-aminobutyric acid (
GABA)-ergic transmission and can contribute to long-term changes in synaptic function. The recent identification of subtype-selective agonists and antagonists has permitted evaluation of mGlu receptors as potential targets in the treatment of
epilepsy. Agonists acting on group I mGlu receptors (mGlu1 and mGlu5) are
convulsant. Antagonists acting on mGlu1 or mGlu5 receptors are
anticonvulsant against
3,5-dihydroxyphenylglycine (
DHPG)-induced
seizures and in mouse models of generalized
motor seizures and absence
seizures. The competitive, phenylglycine mGlu1/5 receptor antagonists generally require intracerebroventricular administration for potent
anticonvulsant efficacy but noncompetitive antagonists, e.g., (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydrocyclopenta[c]
furan-1-on (BAY36-7620),
2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) block
generalized seizures with systemic administration. Agonists acting on group II mGlu receptors (mGlu2, mGlu3) to reduce
glutamate release are
anticonvulsant, e.g., 2R,4R-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC], (+)-2-aminobicyclo[3.1.0]
hexane-2,6-dicarboxylic
acid (
LY354740), and (-)-2-oxa-4-aminobicyclo[3.1.0]
hexane-4,6-dicarboxylate (
LY379268). The classical agonists acting on group III mGlu receptors such as L-(+)-2-amino-4-phosphonobutyric
acid, and
L-serine-O-
phosphate are acutely proconvulsant with some
anticonvulsant activity. The more recently identified agonists
(R,S)-4-phosphonophenylglycine [(R,S)-PPG] and (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] and
(1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid [ACPT-1] are all
anticonvulsant without proconvulsant effects. Studies in animal models of kindling reveal some efficacy of mGlu receptor
ligands against fully kindled limbic
seizures. In genetic mouse models, mGlu1/5 antagonists and mGlu2/3 agonists are effective against absence
seizures. Thus, antagonists at group I mGlu receptors and agonists at groups II and III mGlu receptors are potential
antiepileptic agents, but their clinical usefulness will depend on their acute and chronic side effects. Potential also exists for combining mGlu receptor
ligands with other glutamatergic and non-
glutamatergic agents to produce an enhanced
anticonvulsant effect. This review also discusses what is known about mGlu receptor expression and function in rodent
epilepsy models and human epileptic conditions.