We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Characterisation of the actions of group I metabotropic glutamate receptor subtype selective ligands on excitatory amino acid release and sodium-dependent re-uptake in rat cerebrocortical minislices.
- Authors
Fazal, Abidali; Parker, Fred; Palmer, Alan M.; Croucher, Martin J.
- Abstract
Abstract In this study we have tested the effects of a wide range of metabotropic glutamate receptor ligands on (i) depolarisation-evoked efflux of pre-accumulated d-[[sup 3] H]aspartic acid (d-[[sup 3] H]asp) from rapidly superfused rat cerebrocortical minislices, and (ii) Na[sup +] -dependent uptake of d-[[sup 3] H]asp into cerebrocortical tissue. Transient elevations in extracellular K[sup +] produced concentration-dependent increases in d-[[sup 3] H]asp efflux. A submaximally effective concentration (50 mm) was used in all subsequent experiments. The broad-spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD; EC[sub 50] 17.8 μm], the group I mGlu-selective agonist (S)-3,5-dihydroxyphenylglycine [(S)-3,5-DHPG; EC[sub 50] 0.5 μm] and the mGlu5 receptor subtype-selective agonist (RS)-2-chloro-5-hydroxyphenylglycine [(RS)-CHPG; EC[sub 50] 7.3 μm] all concentration-dependently potentiated high K[sup +] -evoked d-[[sup 3] H]asp efflux in the absence of effects on basal outflow of radiolabel. At concentrations selective for mGlu1 receptors, the antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid [(RS)-AIDA; 10–300 μm]; (+)-2-methyl-4-carboxyphenylglycine [LY367385; 1–100 μm] and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylate ethyl ester [CPCCOEt, 1–30 μm] all failed to inhibit responses to (S)-3,5-DHPG. However, the broad-spectrum mGlu receptor antagonist (S)-α-methyl-4-carboxyphenylglycine [(S)-MCPG; IC[sub 50] 88.5 μm] together with the recently described mGlu5-selective antagonists, 2-methyl-6-(phenylethynyl)-pyridine (MPEP; IC[sub 50] 0.6 μm), 6-methyl-2-(phenyl-azo)-3-pyridinol (SIB-1757; IC[sub 50] 4.4 μm) and (E )-2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893; IC[sub 50] 3.1 μm), at mGlu5-selective concentrations, all powerfully and concentration-dependently inhibited (S)-3,5-DHPG-evoked responses. Two selective excitatory amino acid (EAA) uptake inhibitors, l-trans -2,4-pyrrolidine dicarboxylate (l-trans -2,4-PDC; IC[sub 50] 229 μm) and dl-threo -β-benzyloxyaspartate (dl-TBOA; IC[sub 50] 665 μm) both inhibited the Na[sup +] -dependent uptake of d-[[sup 3] H]asp into cerebrocortical minislices. Importantly, none of the mGlu ligands utilized in the present study significantly inhibited d-[[sup 3] H]asp uptake at concentrations shown to potentiate K[sup +] -evoked efflux. These data demonstrate for the first time that mGlu5 ligands modulate extracellular EAA concentrations by a direct effect on mGlu5-type autoreceptors on EAA nerve terminals as they evoke clear changes in EAA release in the absence of any effects on EAA uptake. Selective mGlu5 receptor antagonists that show high potency and good central bioavailability may provide novel classes of neuroprotective agents for the treatment of brain disorders associated with abnormal EAAergic neurotransmission.
- Subjects
GLUTAMIC acid; RECEPTOR-ligand complexes; CEREBRAL cortex; AMINO acids
- Publication
Journal of Neurochemistry, 2003, Vol 86, Issue 6, p1346
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1046/j.1471-4159.2003.01932.x