Endogenous sulphur-containing amino acids: Potent agonists at presynaptic metabotropic glutamate autoreceptors in the rat central nervous system

Abstract

1 We have recently demonstrated that presynaptically located metabotropic glutamate (mGlu) autoreceptors regulate synoptic 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. 2 Neuronal glutamate release was monitored using electrically-evoked efflux of preloaded [3H]-D-aspartate from rat forebrain hemisections. 3 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. 4 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. 5 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. 6 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.