CHRONIC ADMINISTRATION OF A GLYCINE PARTIAL AGONIST ALTERS THE EXPRESSION OF N-METHYL-D-ASPARTATE RECEPTOR SUBUNIT MESSENGER-RNAS

Both acute and chronic treatments with the glycine partial agonist 1-a minocyclopropanecarboxylic acid (ACPC) are neuroprotective in animal m odels of focal, global and spinal ischemia. After a chronic regimen of ACPC, brain and plasma levels were undetectable at the time of ischem ic insult, which suggests that the neuroprotective effects of acute an d chronic ACPC are mediated by different mechanisms. To investigate th e possibility that chronic administration of ACPC alters N-methyl-D-as partate (NMDA) receptor composition, the levels of mRNAs encoding xi a nd epsilon subunits were quantified by in situ hybridization histochem istry with S-35-labeled riboprobes. Chronic ACPC administered to mice (200 mg/kg for 14 days) increased the level of epsilon-l mRNA in the h ippocampus (particularly CA1 and CA2 regions) and cerebral cortex (fro ntal, parietal and occipital regions), without altering levels in cere bellum. In contrast, this regimen decreased epsilon-3 subunit mRNA lev els in the hippocampus (especially CAI and dentate gyrus) and frontal and occipital cortices. Decreases in epsilon-2 subunit mRNA levels in cerebral cortex (especially frontal and parietal cortices) were also o bserved without accompanying alterations in the cerebellum, hippocampu s or dentate gyrus. The levels of zeta subunit mRNA (determined with a probe that detects all splice variants) were not altered in any brain areas examined. Based an studies in recombinant receptors, these regi on-specific changes in mRNAs produced by a chronic reg imen of ACPC co uld result in NMDA receptors with reduced affinities for glycine and g lutamate. It is hypothesized that such alterations in NMDA receptor su bunit composition may explain the neuroprotective effects produced by chronic ACPC.