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Keywords:

  • Sulphur-containing amino acids;
  • L-cysteic acid;
  • L-cysteine sulphinic acid;
  • mGlu receptors;
  • [3H]-D-aspartate;
  • glutamate release;
  • presynaptic;
  • autoreceptors
  • We have recently demonstrated that presynaptically located metabotropic glutamate (mGlu) autoreceptors regulate synaptic glutamate release both in vitro and in vivo. We now report a positive modulatory action of the sulphur-containing amino acids (SCAAs), L-cysteic acid (CA) and L-cysteine sulphinic acid (CSA), at presynaptic group I mGlu receptors, specifically of the mGlu5 subtype, acting to enhance synaptic glutamate release from the rat forebrain in vitro.

  • Neuronal glutamate release was monitored using electrically-evoked efflux of preloaded [3H]-D-aspartate from rat forebrain hemisections.

  • Both CA (3 – 100 μM) and CSA (1 – 100 μM), in addition to the selective group I mGlu receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-DHPG), concentration-dependently enhanced electrically-stimulated efflux of [3H]-D-aspartate from the rat forebrain slices. Basal efflux of label remained unchanged.

  • The inhibitory activity of the broad spectrum mGlu receptor antagonist, (±)-α-methyl-4-carboxyphenylglycine ((±)-MCPG; 200 μM), coupled with the inactivity of the selective mGlu1 receptor antagonists, (R,S)-1-aminoindan-1,5-dicarboxylic acid ((R,S)-AIDA; 100 – 500 μM) and the more potent (+)-2-methyl-4-carboxyphenylglycine (LY367385; 10 μM) against these responses, indicates an action of the SCAAs at the mGlu5 receptor subtype. This proposal is supported by the potent inhibition of these responses by the selective, non-competitive mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP; 10 μM). The observed enhancement of the responses to high concentrations of CA by the selective mGlu5 receptor desensitization inhibitor, cyclothiazide (CYZ; 10 μM), is also consistent with this concept.

  • Administration of the agonists in the presence of bovine serum albumin (BSA; 5 – 15 mg ml−1) markedly attenuated the positive modulatory responses observed, strongly supporting a role for arachidonic acid in the expression of these mGlu5 receptor-mediated responses.

  • The regulatory actions of SCAAs on synaptic glutamate release demonstrated in the present study may provide a physiological function for these putative neurotransmitter amino acids in the mammalian brain. These central actions of the SCAAs may have wide-ranging implications for a range of neurological and neuropsychiatric disease states and their treatment.

British Journal of Pharmacology (2001) 133, 815–824; doi:10.1038/sj.bjp.0704138