High extracellular glycine does not potentiate N-methyl-D-aspartate-evoked depolarization in vivo.
As N-methyl-D-aspartate receptor (NMDA) ionophore complexes have a distinct positive, allosteric regulatory site for glycine, it has been proposed that elevated extracellular glycine during or after cerebral ischaemia may induce excessive NMDA/glutamate receptor activation and, thereby, excitotoxicity. To test this hypothesis, we have perfused increasing concentrations of glycine, either alone or with co-application of NMDA, through a microdialysis probe implanted in the striatum of halothane anaesthetized rats. Changes in the extracellular field (DC) potential indicative of depolarization were recorded precisely at the site of drug application by an electrode incorporated within dialysis fibre. Microdialysis application of up to 1 mM of glycine had no effect on the basal DC potential. Above 10 mM, glycine produced concentration-dependent depolarizations, but the amplitude of these responses remained very small (e.g. 0.52 +/- 0.05 mV for 100 mM glycine, n = 10, i.e. around 30-fold smaller than that of a wave of spreading depression). Application of 200 microM NMDA via the microdialysis probe produced consistent short-lasting depolarizations (around 2.5 mV amplitude), but these were not potentiated by co-application of up to 100 mM glycine. These data do not support the view that increased extracellular concentrations of glycine, such as those observed in ischaemia, may be potentially excitotoxic. Nevertheless, as occupation of the glycine site coupled to the NMDA-receptor is required for NMDA/glutamate receptor activation, this site remains an attractive target for potential neuroprotective agents.
Obrenovitch
T P
TP
Gough-Cooper Department of Neurological Surgery, Institute of Neurology, London, UK. t.obrenovitch@ion.bpmf.ac.uk
Hardy
A M
AM
Urenjak
J
J
D000818:Animals; D004569:Electroencephalography; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D017551:Microdialysis; D016202:N-Methylaspartate / Q000494:pharmacology*; D017072:Neostriatum / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D018698:Glutamic Acid; D016202:N-Methylaspartate; D005998:Glycine