PHARMACOLOGICAL CHARACTERIZATION OF THE METABOTROPIC GLUTAMATE-RECEPTOR INHIBITING D-[(3)H]-ASPARTATE OUTPUT IN RAT STRIATUM

1 The effects of several agonists of the metabotropic glutamate recept or (mGluR) were studied in adult rat striatal slices by measuring (i) KCl (30 mm)-induced output of previously taken Up D-[H-3]-aspartate (A sp), (ii) forskolin (30 mum)-induced adenosine 3': 5'-cyclic monophosp hate (cyclic AMP) accumulation and (iii) phophoinositide (PI) hydrolys is. 2 K+-induced efflUX Of D-[H-3]-Asp was inhibited by the following mGluR agonists: (1S,3S,4S)-(carboxycyclopropyl)glycine (L-CCG-I), (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and quisqua lic acid (Quis). 2-Amino-4-phosphonobutyrate (L-AP4) was inactive up t o 300 mum. The maximal inhibition of D-[H-3]-Asp output was 60 +/- 8%. The EC50s of mGluR agonists were: 0.5 mum for L-CCG-1, 100 mum for 1S ,3R-ACPD and 100 mum for Quis. 3 Forskolin-induced cyclic AMP accumula tion was also inhibited by mGluR agonists. The maximal inhibition was 50 +/- 4% and was obtained at a concentration of 10 mum for L-CCG-1 an d 100 mum for IS,3R-ACPD. The EC50s for this inhibition were: 0.9 mum for L-CCG-1 and 20 mum for IS,3R-ACPD. Quis (300 mum) inhibited cyclic AMP accumulation by approximately 20%. L-AP4 slightly potentiated cyc lic AMP accumulation. 4 PI hydrolysis was stimulated by mGluR agonists . The most potent compound was Quis (100 mum), which increased inosito l phosphate formation up to 2.2 fold over control values. Its EC50 was 15 muM. L-CCG-1 and IS,3R-ACPD increased inositol phosphate formation by approximately 1.8 fold and their EC50 values were 30 and 25 mum, r espectively. L-AP4 did not affect PI hydrolysis. 5 In conclusion, mGlu R agonists that reduce D-[H-3]-Asp output have a pharmacological profi le similar to that of mGluR agonists inhibiting cyclic AMP accumulatio n. L-CCG-1 appears to be a relatively selective agonist for the mGluR receptor which inhibits D-[H-3]-Asp efflux and cyclic AMP accumulation , while Quis appears to act preferentially on the mGluR receptor linke d to the metabolism of PIs.