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PMID: 8306080 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

British journal of pharmacology ·Vol. 110 ·No. 4 ·1993-12-00 ·Pages 1407-12

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

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.

MeSH Terms
Amino Acids, Dicarboxylic/pharmacology Animals Aspartic Acid/metabolism Colforsin/pharmacology Corpus Striatum/metabolism Cyclic AMP/metabolism Cycloleucine/analogs & derivatives,pharmacology In Vitro Techniques Male Phosphatidylinositols/metabolism Quisqualic Acid/pharmacology Rats Rats, Wistar Receptors, Glutamate/drug effects
Chemicals
Amino Acids, Dicarboxylic Phosphatidylinositols Receptors, Glutamate Cycloleucine 1-amino-1,3-dicarboxycyclopentane Colforsin (alpha-carboxycyclopropyl)glycine Aspartic Acid Quisqualic Acid Cyclic AMP
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Lombardi G
Dipartimento di Farmacologia Preclinica e Clinica Mario Aiazzi Mancini, Università di Firenze, Italy.
Alesiani M
Leonardi P
Cherici G
Pellicciari R
Moroni F
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1111/j.1476-5381.1993.tb13977.x
Published
1993-12-00
Pages
1407-12
Language
English
Region
England
NLM ID
7502536
PMCID
PMC2175867
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1476-5381.1993.tb13977.x PMC Full Text View journal details
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