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 receptor (mGluR) were studied in adult rat striatal slices by measuring (i) KCl (30 mm)-induced output of previously taken Up D-[H-3]-aspartate (Asp), (ii) forskolin (30 mum)-induced adenosine 3': 5'-cyclic monophosphate (cyclic AMP) accumulation and (iii) phophoinositide (PI) hydrolysis. 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 quisqualic acid (Quis). 2-Amino-4-phosphonobutyrate (L-AP4) was inactive up to 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 accumulation 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 and 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 cyclic AMP accumulation. 4 PI hydrolysis was stimulated by mGluR agonists. The most potent compound was Quis (100 mum), which increased inositol 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, respectively. L-AP4 did not affect PI hydrolysis. 5 In conclusion, mGluR agonists that reduce D-[H-3]-Asp output have a pharmacological profile similar to that of mGluR agonists inhibiting cyclic AMP accumulation. 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 linked to the metabolism of PIs.