Pharmacological characterization of the metabotropic glutamate receptor inhibiting<scp>d</scp>‐[³H]‐aspartate output in rat striatum

Abstract

The effects of several agonists of the metabotropic glutamate receptor (mGluR) were studied in adult rat striatal slices by measuring (i) KCl (30 m m )‐induced output of previously taken up d ‐[ 3 H]‐aspartate (Asp), (ii) forskolin (30 μ m )‐induced adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) accumulation and (iii) phophoinositide (PI) hydrolysis. K + ‐induced efflux of d ‐[ 3 H]‐Asp was inhibited by the following mGluR agonists: (1S,3S,4S)‐(carboxycyclopropyl)glycine ( l ‐CCG‐I), (1S,3 R )‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (1S,3 R ‐ACPD) and quisqualic acid (Quis). 2‐Amino‐4‐phosphonobutyrate ( l ‐AP4) was inactive up to 300 μ m . The maximal inhibition of d ‐[ 3 H]‐Asp output was 60 ± 8%. The EC 50 s of mGluR agonists were: 0.5 μ m for l ‐CCG‐I, 100 μ m for 1S,3 R ‐ACPD and 100 μ m for Quis. 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 μ m for l ‐CCG‐I and 100 μ m for 1S,3 R ‐ACPD. The EC 50 s for this inhibition were: 0.9 μ m for l ‐CCG‐I and 20 μ m for 1S,3 R ‐ACPD. Quis (300 μ m ) inhibited cyclic AMP accumulation by approximately 20%. l ‐AP4 slightly potentiated cyclic AMP accumulation. PI hydrolysis was stimulated by mGluR agonists. The most potent compound was Quis (100 μ m ), which increased inositol phosphate formation up to 2.2 fold over control values. Its EC 50 was 15 μ m.l ‐CCG‐I and 1S,3 R ‐ACPD increased inositol phosphate formation by approximately 1.8 fold and their EC 50 values were 30 and 25 μ m , respectively. l ‐AP4 did not affect PI hydrolysis. In conclusion, mGluR agonists that reduce d ‐[ 3 H]‐Asp output have a pharmacological profile similar to that of mGluR agonists inhibiting cyclic AMP accumulation. l ‐CCG‐I appears to be a relatively selective agonist for the mGluR receptor which inhibits d ‐[ 3 H]‐Asp efflux and cyclic AMP accumulation, while Quis appears to act preferentially on the mGluR receptor linked to the metabolism of PIs.