Type 2 Metabotropic Glutamate (mGlu) Receptors Tonically Inhibit Transmitter Release in rat caudate Nucleus: In Vivo studies with (2S,1’S,2’S,3’R)-phenylcarboxycyclopropylglycine, a New Potent and Selective Antagonist

contain abundant presynaptic group 2 metabotropic glutamate (mGlu) receptors. Using brain slices we have previously shown that these receptors inhibit depolarization-induced transmitter release. Using microdialysis in freely moving rats, we now report the effects of group 2 mGlu receptor agonists and antagonists on glutamate concentration in the caudate extracellular fluid. A mild decrease (20-30%) in glutamate concentration in caudate dialysates was observed when 1 S,3R-1 -aminocyclopentane-l,3-dicarboxylic acid or (2S,3S,4S)-acarboxycyclopropyl- glycine (L-CCG-1), mGlu receptor agonists, was locally administered. On the contrary, amethyl- 4-carboxyphenylglycine, an antagonist of type 1 and type 2 mGlu receptors, increased the glutamate concentration in dialysates by up to 3.5-fold, and its effects were prevented by the simultaneous administration of L-CCG-1 , a preferential type 2 mGlu receptor agonist. A significant increase of glutamate output in striatal dialysate was also found after local administration of (2S,1 'S,2'S,3'R)-2-(2'-carboxy-3'- phenylcyclopropyl)glycine, another structurally unrelated, relatively selective and potent type 2 mGlu receptor antagonist. The results suggest that type 2 mGlu receptors tonically inhibit transmitter release from corticostriatal terminals. Since the cortico-striatal pathway profoundly affects the function of a large percentage of caudate neurons, it is reasonable to predict that the use of selective type 2 mGlu receptor agents will be helpful for scientific and therapeutic studies on the physiopathology of basal ganglion disorders.