Pharmacological characterization of metabotropic glutamate receptors potentiating NMDA responses in mouse cortical wedge preparations

1 Mouse cortical wedge preparations were used in order to study the effects of metabotropic glutamate receptor (mGluR) agonists and antagonists on the depolarization induced by N-methyl-D-aspartate (NMDA) or by (S)-alpha-amino-4-bromo-3-hydroxy-5-isoxazoacid (AMPA). 2 (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (30-300 mu M) significantly potentiated the depolarizations induced by NMDA, leaving unchanged those mediated by AMPA. This potentiation developed slowly and lasted for up to 60 min provided that the slices were continuously perfused with the mGluR agonist. 3 Concentration-response curves to NMDA in the absence and in the presence of 1S,3R-ACPD (100 mu M) indicated that the potentiation was due to increased affinity of the NMDA receptor complex for its agonist. The maximal responses to NMDA were not potentiated. 4 Selective agonists of group 1 mGluR such as quisqualate (Quis) (30 mu M) or (RS)-3,5-dihydroxyphenylglycine (DHPG) (300 mu M) did not potentiate NMDA responses. Similarly, selective agonists of group 2 mGluRs, such as (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (L-CCG-I) (3-30 mu M), and of group 3, such as L-2-amino-4-phosphonobutyric acid (L-AP4) (100 mu M) were inactive in our test. A number of other putative mGluR agents having partial agonist activity on mGluRs in brain slices and in expression systems, such as 1R,3S-ACPD (500 mu M), DL-2-amino-3-phosphonopropionic acid (DL-AP3) (300 mu M) and (S)-4-carboxy-3-hydroxyphenylglycine (S-4C3HPG; 500 mu M), when placed in the experimental protocol we used, did not change NMDA responses. 5 Available mGluR antagonists, such as DL-AP3 (1 mM), (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) (500 mu M), S-4-carboxyphenylglycine (4CPG; 500 mu M) and S-4-carboxy-3 -hydroxyphenylglycine (S-4C3HPG; 500 mu M), did not reduce 1S,3R-ACPD potentiation of NMDA responses. 6 It is concluded that the potentiation of NMDA currents induced by the mGluR agonist 1S,3R-ACPD, in mouse cortical wedges, has a pharmacological profile which is different from that of the three mGluR groups so far described in expression systems.