REGION-SPECIFIC AND CALCIUM-DEPENDENT INCREASE IN DIALYSATE CHOLINE LEVELS BY NMDA

Citation
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
Citations number
38
Categorie Soggetti
Neurosciences
Journal title
ISSN journal
02706474
Volume
18
Issue
10
Year of publication
1998
Pages
3597 - 3605
Database
ISI
SICI code
0270-6474(1998)18:10<3597:RACIID>2.0.ZU;2-Z
Abstract
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.