Effect of acidotic challenges on local depolarizations evoked by N-methyl-D-aspartate in the rat striatum.
We have examined how various challenges to brain acid-base homeostasis, resulting in extracellular acidosis, alter N-methyl-D-aspartate (NMDA)-evoked depolarizations in vivo. Repeated stimuli were produced by perfusion of 200 microM NMDA for 2 min through a microdialysis probe implanted into the striatum of halothane anesthetized rats. Hypercapnia reduced NMDA-evoked responses in a concentration-dependent manner, with 7.5 and 15 % CO2 in the breathing mixture reducing the depolarization amplitude to 74 % and 64 % of that of the initial stimuli, respectively. Application of 50 mM NH4+ progressively reduced dialysate pH, and a further acidification was observed when NH4+ was discontinued. Perfusion of NMDA after NH4+ application evoked smaller depolarizations (56 % of the corresponding control, 5 min after NH4+ removal), and this effect persisted for over 1 h. Perfusion of acidic ACSF did not alter the amplitude of NMDA-evoked depolarization, despite changes in dialysate pH confirming that exchange/buffering of acid equivalents took place between the perfusion medium and the surrounding tissue. This negative result probably reflected the remarkable capacity of the brain to buffer H+. Together, these results demonstrate that extracellular acidosis, such as that associated with excessive neuronal activation or ischemia, inhibits NMDA-evoked responses in vivo.
Urenjak
J
J
Discovery Biology, Pfizer Central Research, Sandwich, England.
Zilkha
E
E
Gotoh
M
M
Obrenovitch
T P
TP
D000136:Acid-Base Equilibrium / Q000187:drug effects; D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001784:Blood Gas Analysis; D004594:Electrophysiology; D006935:Hypercapnia / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D016202:N-Methylaspartate / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects* / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000644:Quaternary Ammonium Compounds; D016202:N-Methylaspartate