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 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 Lcysteine sulphinic acid (CSA), at presynaptic group I mGlu receptors, speci®cally 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 e ux of preloaded [ 3 H]-Daspartate from rat forebrain hemisections. 3 Both CA (3 ± 100 mM) and CSA (1 ± 100 mM), in addition to the selective group I mGlu receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-DHPG), concentration-dependently enhanced electrically-stimulated e ux of [ 3 H]-D-aspartate from the rat forebrain slices. Basal e ux of label remained unchanged. 4 The inhibitory activity of the broad spectrum mGlu receptor antagonist, (+)-a-methyl-4-carboxyphenylglycine ((+)-MCPG; 200 mM), coupled with the inactivity of the selective mGlu1 receptor antagonists, (R,S)-1-aminoindan-1,5-dicarboxylic acid ((R,S)-AIDA; 100 ± 500 mM) and the more potent (+)-2-methyl-4-carboxyphenylglycine (LY367385; 10 mM) 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 mM). The observed enhancement of the responses to high concentrations of CA by the selective mGlu5 receptor desensitization inhibitor, cyclothiazide (CYZ; 10 mM), is also consistent with this concept. 5 Administration of the agonists in the presence of bovine serum albumin (BSA; 5 ± 15 mg ml 71 ) 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.

Reduction of Ethanol‐Derived Acetaldehyde Induced Motivational Properties by l‐Cysteine

“…Evidence is also accumulating to suggest that sulphur-containing amino acids are analogues of glutamate (Thompson and Kilpatrick, 1996). Interestingly, low concentrations of l-cysteic acid (1 lM), a similar concentration range to that of l-cysteine tested in our study, inhibited synaptic glutamate release by an interaction with presynaptic group mGlu autoreceptors (Croucher et al, 2001). In line with these results, Blednov and Harris (2008) have shown that group I mGluR5 antagonists decrease alcohol self-administration and suggest that the anticraving medication, acamprosate, may also act to decrease mGluR5 function.…”

“…In line with these results, Blednov and Harris (2008) have shown that group I mGluR5 antagonists decrease alcohol self-administration and suggest that the anticraving medication, acamprosate, may also act to decrease mGluR5 function. Currently, no explanation are available for these reports but it is evident the importance of mGluR5 for several actions of alcohol (Blednov and Harris, 2008;Croucher et al, 2001).…”

Methotrexate induces seizure and decreases glutamate uptake in brain slices: Prevention by ionotropic glutamate receptors antagonists and adenosine

“…Some works demonstrated the role of homocysteine metabolites, named sulfur-containing excitatory amino acids, on glutamatergic system. It was shown that these substances are excitotoxic to neurons and they stimulate pre-synaptic metabotropic glutamate receptors group I, which leads to enhancement of glutamate release to synaptic cleft (Flott-Rahmel et al, 1998;Croucher et al, 2001). Also, sulfur containing amino acids inhibit the uptake of glutamate and aspartate in both neuronal and glial plasma membranes (Vezmar et al, 2003).…”

Behavioral and biochemical evidence of the role of acetaldehyde in the motivational effects of ethanol

“…The first is consistent with the conjugation/inactivation mechanism that would take place between ACD and the first metabolite of glutathione (Kera et al, 1985). Furthermore, being L-cysteine an analogue of L-glutamate (Thompson and Kilpatrick, 1996) it is posited to interact at presynaptic group I metabotropic glutamate receptors (mGluR) of the mGluR5 subtype to exert a positive modulatory control on synaptic glutamate release (Harman et al, 1984; Croucher et al, 2001). In support of these results is the finding that L-cysteine reduces ethanol-induced stimulation of DA transmission in the nucleus accumbens shell (Sirca et al, 2011).…”