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Pharmacological characterization of the metabotropic glutamate receptor inhibiting D-[3H]-aspartate output in rat striatum.

Abstract：

: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-[3H]-aspartate (Asp), (ii) forskolin (30 microM)-induced adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation and (iii) phophoinositide (PI) hydrolysis. 2. K(+)-induced efflux of D-[3H]-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 microM. The maximal inhibition of D-[3H]-Asp output was 60 +/- 8%. The EC50s of mGluR agonists were: 0.5 microM for L-CCG-I, 100 microM for 1S,3R-ACPD and 100 microM 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 microM for L-CCG-I and 100 microM for 1S,3R-ACPD. The EC50s for this inhibition were: 0.9 microM for L-CCG-I and 20 microM for 1S,3R-ACPD. Quis (300 microM) 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 microM), which increased inositol phosphate formation up to 2.2 fold over control values. Its EC50 was 15 microM. L-CCG-I and 1S,3R-ACPD increased inositol phosphate formation by approximately 1.8 fold and their EC50 values were 30 and 25 microM, respectively. L-AP4 did not affect PI hydrolysis. 5. In conclusion, mGluR agonists that reduce D-[3H]-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-[3H]-Asp efflux and cyclic AMP accumulation,while Quis appears to act preferentially on the mGluR receptor linked to the metabolism of PIs.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Lombardi G,Alesiani M,Leonardi P,Cherici G,Pellicciari R,Moroni F

doi

10.1111/j.1476-5381.1993.tb13977.x

subject

Has Abstract

pub_date

1993-12-01 00:00:00

pages

1407-12

issue

eissn

0007-1188

issn

1476-5381

journal_volume

110

pub_type

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Pharmacological characterization of the metabotropic glutamate receptor inhibiting D-[3H]-aspartate output in rat striatum.