RT Journal Article
SR Electronic
T1 Region-Specific and Calcium-Dependent Increase in Dialysate Choline Levels by NMDA
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3597
OP 3605
DO 10.1523/JNEUROSCI.18-10-03597.1998
VO 18
IS 10
A1 Agustí Zapata
A1 Jordi L. Capdevila
A1 Ramon Trullas
YR 1998
UL http://www.jneurosci.org/content/18/10/3597.abstract
AB NMDA receptor-induced excitotoxicity has been hypothesized to mediate abnormal choline (Cho) metabolism that is involved in alterations in membrane permeability and cell death in certain neurodegenerative disorders. To determine whether NMDA receptor overactivation modulates choline metabolism in vivo, we investigated the effects of NMDA on interstitial choline concentrations using microdialysis. Perfusion of NMDA by retrodialysis increased dialysate choline (∼400%) and reduced dialysate acetylcholine (Ach) (∼40%). Choline levels remained increased for at least 2.5 hr, but acetylcholine returned to pretreatment values 75 min after NMDA perfusion. The NMDA-evoked increase in dialysate choline was calcium and concentration dependent and was prevented with 1 mmAP-5, a competitive NMDA antagonist, but was not altered by mepacrine, a phospholipase A2 inhibitor. NMDA increased extracellular choline levels four- to fivefold in prefrontal cortex and hippocampus, produced a slight increase in neostriatum, and did not modify dialysate choline in cerebellum. Perfusion with NMDA for 2 hr produced a delayed, but not acute, reduction in choline acetyltransferase activity in the area surrounding the dialysis probe. Consistent with a lack of acute cholinergic neurotoxicity evoked by this treatment, basal acetylcholine levels were unaltered by 2 hr of continuous NMDA perfusion. Prolonged NMDA perfusion produced a 34% decrease in phosphatidylcholine content in the lipid fraction of the tissue surrounding the dialysis probe. These results show that NMDA modulates choline metabolism, eliciting a receptor-mediated, calcium-dependent, and region-specific increase in extracellular choline from membrane phospholipids that is not mediated by phospholipase A2 and precedes delayed excitotoxic neuronal cell death.