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 ef fects of metabotropic glutamate receptor (mGluR) agonists and antagoni sts 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-a minocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (30-300 mu M) sign ificantly potentiated the depolarizations induced by NMDA, leaving unc hanged those mediated by AMPA. This potentiation developed slowly and lasted for up to 60 min provided that the slices were continuously per fused 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 recept or complex for its agonist. The maximal responses to NMDA were not pot entiated. 4 Selective agonists of group 1 mGluR such as quisqualate (Q uis) (30 mu M) or (RS)-3,5-dihydroxyphenylglycine (DHPG) (300 mu M) di d not potentiate NMDA responses. Similarly, selective agonists of grou p 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 p utative mGluR agents having partial agonist activity on mGluRs in brai n 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-carbox y-3-hydroxyphenylglycine (S-4C3HPG; 500 mu M), when placed in the expe rimental protocol we used, did not change NMDA responses. 5 Available mGluR antagonists, such as DL-AP3 (1 mM), (+)-alpha-methyl-4-carboxyph enylglycine (MCPG) (500 mu M), S-4-carboxyphenylglycine (4CPG; 500 mu M) and S-4-carboxy-3 -hydroxyphenylglycine (S-4C3HPG; 500 mu M), did n ot reduce 1S,3R-ACPD potentiation of NMDA responses. 6 It is concluded that the potentiation of NMDA currents induced by the mGluR agonist 1 S,3R-ACPD, in mouse cortical wedges, has a pharmacological profile whi ch is different from that of the three mGluR groups so far described i n expression systems.