TYPE-2 METABOTROPIC GLUTAMATE (MGLU) RECEPTORS TONICALLY INHIBIT TRANSMITTER RELEASE IN RAT CAUDATE-NUCLEUS - IN-VIVO STUDIES WITH S,3'R)-2-(2'-CARBOXY-3'-PHENYLCYCLOPROPYL)GLYCINE, A NEW POTENT AND SELECTIVE ANTAGONIST

Anatomical, biochemical and electrophysiological studies have previous ly shown that cortico-striatal terminals contain abundant presynaptic group 2 metabotropic glutamate (mGlu) receptors. Using brain slices we have previously shown that these receptors inhibit depolarization-ind uced transmitter release. Using microdialysis in freely moving rats, w e now report the effects of group 2 mGlu receptor agonists and antagon ists on glutamate concentration in the caudate extracellular fluid. A mild decrease (20-30%) in glutamate concentration in caudate dialysate s was observed when 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid or (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (L-CCG-1), mGlu receptor agonists, was locally administered. On the contrary, alpha-methyl-4-ca rboxyphenylglycine, 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 i ncrease of glutamate output in striatal dialysate was also found after local administration of S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)gly cine, 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 t erminals. Since the cortico-striatal pathway profoundly affects the fu nction of a large percentage of caudate neurons, it is reasonable to p redict that the use of selective type 2 mGlu receptor agents will be h elpful for scientific and therapeutic studies on the physiopathology o f basal ganglion disorders.