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 (NMD A)-evoked depolarizations in vivo. Repeated stimuli were produced by p erfusion of 200 mu M NMDA for 2 min through a microdialysis probe impl anted into the striatum of halothane anesthetized rats. Hypercapnia re duced NMDA-evoked responses in a concentration-dependent manner, with 7.5 and 15% CO2 in the breathing mixture reducing the depolarization a mplitude to 74% and 64% of that of the initial stimuli, respectively. Application of 50 mM NH4+ progressively reduced dialysate pH, and a fu rther acidification was observed when NH,+ 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 I h. Perfusion of acidic ACSF did not alter the am plitude of NMDA-evoked depolarization, despite changes in dialysate pH confirming that exchange/buffering of acid equivalents task place bet ween the perfusion medium and the surrounding tissue. This negative re sult 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.