A. Zapata et al., REGION-SPECIFIC AND CALCIUM-DEPENDENT INCREASE IN DIALYSATE CHOLINE LEVELS BY NMDA, The Journal of neuroscience, 18(10), 1998, pp. 3597-3605
NMDA receptor-induced excitotoxicity has been hypothesized to mediate
abnormal choline (Cho) metabolism that is involved in alterations in m
embrane permeability and cell death in certain neurodegenerative disor
ders. To determine whether NMDA receptor overactivation modulates chol
ine metabolism in vivo, we investigated the effects of NMDA on interst
itial choline concentrations using microdialysis, Perfusion of NMDA by
retrodialysis increased dialysate choline (similar to 400%) and reduc
ed dialysate acetylcholine (Ach) (similar to 40%). Choline levels rema
ined increased for at least 2.5 hr, but acetylcholine returned to pret
reatment values 75 min after NMDA perfusion. The NMDA-evoked increase
in dialysate choline was calcium and concentration dependent and was p
revented with 1 mM AP-5, a competitive NMDA antagonist, but was not al
tered by mepacrine, a phospholipase A(2) inhibitor. NMDA increased ext
racellular choline levels four-to fivefold in prefrontal cortex and hi
ppocampus, produced a slight increase in neostriatum, and did not modi
fy dialysate choline in cerebellum. Perfusion with NMDA for 2 hr produ
ced a delayed, but not acute, reduction in choline acetyltransferase a
ctivity in the area surrounding the dialysis probe. Consistent with a
lack of acute cholinergic neurotoxicity evoked by this treatment, basa
l acetylcholine levels were unaltered by 2 hr of continuous NMDA perfu
sion. Prolonged NMDA perfusion produced a 34% decrease in phosphatidyl
choline content in the lipid fraction of the tissue surrounding the di
alysis probe. These results show that NMDA modulates choline metabolis
m, eliciting a receptor-mediated, calcium-dependent, and region-specif
ic increase in extracellular choline from membrane phospholipids that
is not mediated by phospholipase A(2) and precedes delayed excitotoxic
neuronal cell death.