ACTIONS OF 2 NEW ANTAGONISTS SHOWING SELECTIVITY FOR DIFFERENT SUBTYPES OF METABOTROPIC GLUTAMATE-RECEPTOR IN THE NEONATAL RAT SPINAL-CORD

1 The presynaptic depressant action of L-2-amino-4-phosphonobutyrate ( L-AP4) on the monosynaptic excitation of neonatal rat motoneurones has been differentiated from the similar effects produced by (1S,3R)-1-am inocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD), (1S,3S)-ACPD and (2S ,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I), and from the post synaptic motoneuronal depolarization produced by (1S,3R)-ACPD, by the actions of two new antagonists, alpha-methyl-L-AP4 (MAP4) and alpha-me thyl-L-CCG-I (MCCG). Such selectivity was not seen with a previously r eported antagonist, (+)-alpha-methyl-4- carboxyphenylglycine (MCPG). 2 MAP4 selectively and competitively antagonized the depression of mono synaptic excitation produced by L-AP4 (K-D 22 mu M). At ten fold highe r concentrations, MAP4 also antagonized synaptic depression produced b y L-CCG-I but in an apparently non-competitive manner. MAP4 was virtua lly without effect on depression produced by (1S,3R)- or (1S,3S)-ACPD. 3 MCCG differentially antagonized the presynaptic depression produced by the range of agonists used. This antagonist had minimal effect on L-AP4-induced depression. The antagonism of the synaptic depression ef fected by (1S,3S)-ACPD and L-CCG-I was apparently competitive in each case but of varying effectiveness, with apparent K-D values for the in teraction between MCCG and the receptors activated by the two depressa nts calculated as 103 and 259 mu M, respectively. MCCG also antagonize d the presynaptic depression produced by (1S,3R)-ACPD. 4 Neither MAP4 nor MCCG (200-500 mu M) significantly affected motoneuronal depolariza tions produced by (1S,3R)-ACPD. At the same concentrations the two ant agonists produced only very weak and variable effects (slight antagoni sm or potentiation) on depolarizations produced by lpha-amino-3-hydrox y-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate ( NMDA). 5 It is concluded that MAP4 is a potent and selective antagonis t for those excitatory amino acid (EAA) receptors on neonatal rat prim ary afferent terminals that are preferentially activated by L-AP4, and that MCCG is a relatively selective antagonist for different presynap tic EAA receptors that are preferentially activated by (1S,3S)-ACPD an d (perhaps less selectively) by L-CCG-I. These receptors probably comp rise two sub-types of metabotropic glutamate receptors negatively link ed to adenylyl cyclase activity.