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( S )‐Carboxy‐3‐Hydroxyphenylglycine, an Antagonist of Metabotropic Glutamate Receptor (mGluR)1a and an Agonist of mGluR2, Protects Against Audiogenic Seizures in DBA/2 Mice
Author(s) -
Thomsen Christian,
Klitgaard Henrik,
Sheardown Malcolm,
Jackson Helen C.,
Eskesen Karen,
Jacobsen Palle,
Treppendahl Svend,
Suzdak Peter D.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62062492.x
Subject(s) - metabotropic glutamate receptor 2 , metabotropic glutamate receptor , metabotropic glutamate receptor 5 , chemistry , metabotropic glutamate receptor 1 , agonist , pharmacology , glutamate receptor , metabotropic receptor , medicine , receptor , biology , biochemistry
The in vivo anticonvulsant effects and in vitro metabo‐tropic glutamate receptor selectivity of ( S )‐4‐carboxy‐3‐hydroxy‐phenylglycine [(S)‐4C3HPG] were examined. Intracerebroventricular injection of (S)‐4C3HPG dose‐dependently antagonized audiogenic‐induced clonic and tonic convulsions in DBA/2 mice with ED 60 values of 76 and 110‐nmol per mouse, respectively. (S)‐4C3HPG dose‐dependently inhibited the spontaneously evoked epileptic spikes in a cingulate cortex‐corpus callosum slice preparation. (SJ‐4C3HPG displaced the binding of [ 3 H]glutamate in membranes prepared from baby hamster kidney (BHK) cells expressing the metabotropic glutamate receptor mGluR1a with an EC 50 of 5 β 1 u M. ( S )‐4C3HPG dose‐dependently antagonized glutamate‐stimulated phosphoinositide hydrolysis in BHK cells expressing mGluR 1a with an IC 50 of 15 β 3 μ M. ( S )‐4C3HPG was, however, an agonist at mGluR2 with an EC 60 of 21 β 4 μ M for inhibition of forskolin‐stimulated cyclic AMP formation in BHK cells expressing the mGluR2. ( S )‐4C3HPG had no effects at mGluR4a. These data suggest that the anticonvulsant action of ( S )‐4C3HPG is mediated by combined antagonism of mGluRIa and agonism of mGluR2. These results suggest the importance of mGluR1a and/or mGluR2 in the control of epileptic activity.