1. ¹School of Molecular and Microbial Biosciences, The University of Sydney, Sydney, New South Wales, Australia
2. ²Prince of Wales Medical Research Institute, Barker St Randwick, Randwick, New South Wales, Australia
3. ³Brain Sciences, The University of New South Wales, Sydney, New South Wales, Australia
4. ⁴Institute for Biomedical Research and School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia
5. ⁵Department of Biochemistry, The University of Cambridge, Tennis Court Road, Cambridge, UK
6. ⁶Department of Pathology, The University of Sydney, Sydney, New South Wales, Australia

Correspondence: Dr C Rae, Prince of Wales Medical Research Institute, The University of New South Wales, Barker Street, Randwick, New South Wales, NSW 2031, Australia. E-mail: c.rae@unsw.edu.au

Received 1 July 2005; Revised 2 November 2005; Accepted 4 November 2005; Published online 14 December 2005.

Abstract

A range of behaviours are elucidated via ionotropic glutamate receptors (iGluR). In this work, we examined the acute activation of iGluRs by a range of receptor ligands and effectors to see whether distinguishable metabolic sequelae were elucidated by the activity. We used a guinea-pig brain cortical tissue slice model using targeted receptor ligands ((RS)-(tetrazol-5-yl)glycine (TZG), (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801, dizocilpine), cis-4-[phosphomethyl]-piperidine-2-carboxylic acid (CGS 19755), (RS)--amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, (2S, 3S, 4S)-2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid (kainate) and D-serine (D-Ser), as well as compounds (quinolinic acid and kynurenic acid (KynA)) involved in some neuroinflammatory responses. The data were derived using ¹³C and ¹H NMR spectroscopy, and analysed by metabolomic approaches and multivariate statistics. The metabolic effects of agonists at the three major classes of iGluR were easily separated from each other using this method. The classical N-methyl-D-aspartate receptor agonist TZG and the antagonist CGS 19755 produced excitatory and inhibitory metabolic responses, respectively, while the blocker MK-801 resulted in a significant decrease in net metabolism and produced the largest decrease in all metabolite pool sizes seen by any glutamatergic ligand we have studied. Quinolinic acid and KynA produced similar acute metabolic responses, which were unlike those to TZG or CGS 19755, but similar to that of D-Ser. D-Ser was highly stimulatory of net flux into the Krebs cycle. These data show that the metabolic response to iGluR perturbation in vitro is a sensitive discriminator of function.