The ammonium-induced increase in rat brain lactate concentration is rapid and reversible and is compatible with trafficking and signaling roles for ammonium.
The glutamate-glutamine shuttle requires a flux of fixed N from neurons to astrocytes. The suggestion that some or all of this N is ammonium has received support from reports that ammonium (as NH(4)(+)) rapidly enters astrocytes. Ammonium might also help control astrocyte energy metabolism by increasing lactate production. If ammonium has these functions, then its effect on brain metabolism must be rapid and reversible. To make a minimal test of this requirement, we have followed the time courses of the changes induced by a 4 min venous infusion of 1 mol/L NH(4)Cl, 2.5 mmol/kg body weight, in rat. Extracellular [NH(4)(+)] in cortex, monitored with ion-selective microelectrodes, reached a peak of approximately 0.7 mmol/L 1.65 mins after the end of the infusion, then recovered. Brain metabolites were monitored non-invasively every 4 mins by (1)H magnetic resonance spectroscopy. Lactate peak area during the 3.2 min acquisition starting at the end of the infusion was 1.84+/-0.24 times baseline (+/-s.e.m., P=0.009, n=9). Lactate increased until 13.2+/-2.1 mins after the end of the infusion and recovered halfway to baseline by 31.2 mins. Glutamate decreased by at least 7.1% (P=0.0026). Infusion of NaCl caused no change in lactate signal. Cerebral blood flow, measured by arterial magnetization labeling, more than doubled, suggesting that the lactate increase was not caused by hypoxia. At least three consecutive ammonium-induced increases in lactate signal could be evoked. The results are compatible with an intercellular trafficking/signaling function for ammonium.
Provent
Peggy
P
INSERM, UMR-S 836, Grenoble Institut des Neurosciences, Grenoble, France.
Kickler
Nils
N
Barbier
Emmanuel L
EL
Bergerot
Astrid
A
Farion
Régine
R
Goury
Sarah
S
Marcaggi
Païkan
P
Segebarth
Christoph
C
Coles
Jonathan A
JA
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000502:physiology; D003627:Data Interpretation, Statistical; D004567:Electrodes, Implanted; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000302:isolation & purification / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D019344:Lactic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009474:Neurons / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012965:Sodium Chloride / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D000644:Quaternary Ammonium Compounds; D000643:Ammonium Chloride; D019344:Lactic Acid; D018698:Glutamic Acid; D012965:Sodium Chloride; D011188:Potassium