S. Bovetto et al., CHRONIC ADMINISTRATION OF A GLYCINE PARTIAL AGONIST ALTERS THE EXPRESSION OF N-METHYL-D-ASPARTATE RECEPTOR SUBUNIT MESSENGER-RNAS, The Journal of pharmacology and experimental therapeutics, 283(3), 1997, pp. 1503-1508
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.