Metabotropic glutamate autoreceptors of the mGlu5 subtype positively modulate neuronal glutamate release in the rat forebrain in vitro

In the present study we have examined the role of presynaptic group I metabotropic glutamate (mGlu) receptors in the control of neuronal glutamate release using rat forebrain slices pre-loaded with [H-3]D-aspartate. We have also addressed the question of which group I mGlu receptor subtype, mGlu(1) or mClu(5), mediates the facilitatory response observed by the use of a range of established and some more novel agonists and antagonists showing selectivity for these receptors. The electrically-stimulated release of pre-loaded [H-3]D-aspartate from rat forebrain slices was markedly potentiated by the potent group I mClu receptor agonist, L-quisqualic acid (L-QUIS), in a concentration-dependent manner (EC50 17.31 mu M) This response was inhibited by the mGlu receptor antagonists (S)-MCPG (100 mu M) and (RS)-MTPG (100 mu M) but not by the AMPA-type ionotropic glutamate receptor antagonist, NBQX (100 mu M) The selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine ((S)-DHPG) also enhanced electrically-stimulated efflux of label, although responses diminished with high (10-100 mu M) concentrations of the agonist. Maximum responses were fully restored when (S)-DHPG (10 mu M) was applied in the presence of the proposed mGlu, receptor desensitization inhibitor, cyclothiazide (10 mu M). The positive modulatory response to (S)-DHPG (1 mu M) was powerfully inhibited by (S)-MCPG (IC50 0.08 mu M) but was resistant to the mGlu, receptor antagonists, (RS)-AIDA (1-500 mu M), CPCCOEt (0.1-100 mu M) and (+)-2-methyl-4-carboxyphenylglycine (LY367385) (0.1-10 mu M). The recently developed, selective mClu, receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine ((RS)-CHPG) enhanced electrically-stimulated [H-3]D-aspartate efflux from rat forebrain slices with a similar concentration-response profile to that of (S)-DHPG. Responses to this receptor subtype-selective agonist were: also blocked by (S)-MCPG (IC50 1.13 mu M) but were unaffected by (RS)-AIDA (500 mu M), CPCCOEt (100 mu M) or LY367385 (10 mu M). These results indicate that the positive modulation of neuronal glutamate release seen in the rat forebrain in the presence of group I mClu receptor agonists is mediated by presynaptically located mClu, glutamate autoreceptors. The pharmacological profile of these receptors appears to be distinct from that of postsynaptic mGlu receptors. Novel antagonists acting at these presynaptic receptors may provide new drugs for the experimental therapy of a range of acute or chronic neurodegenerative disorders. (C) 2000 Elsevier Science Ltd. All rights reserved.