Ketamine antagonizes hypoxia-induced dopamine release in rat striatum.
The purpose of this study is to investigate the hypothesis that ketamine, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, attenuates hypoxia-induced striatal dopamine release in vivo. High-speed chronoamperometric recording techniques, using Nafion-coated carbon fiber electrodes, were used to evaluate extracellular dopamine (DA) concentration in the striatum. KCl and DA were locally applied directly to the striatum of urethane-anesthetized Sprague-Dawley rats, in order to measure release and clearance, respectively, of DA. These anesthetized animals were paralyzed with D-tubocurarine and connected to a respirator to allow controlled respiration. Systemic concentrations of oxygen and carbon dioxide were altered by changing the partial pressure of O2, CO2, N2 of inspired air and the rate of the respirator. Our data indicate that lowering the respiratory rate from 90 to 20 times/min for 5 min, in room air, caused a decrease in blood O2 while increasing the CO2 concentration. These changes in blood gas concentration were reversible and reproducible. We also found that lowering the respiratory rates potentiated K(+)-induced DA release but not DA clearance in the striatum. In an attempt to induce hypercapnia, the room air was replaced with high CO2-containing air (15% CO2 + 20% O2 + 65% N2), and this change resulted in increased blood CO2 levels without lowering O2 concentration. The hypercapnia did not alter K(+)-induced DA release in the striatum. Next, we attempted to simulate anoxic hypoxia in the absence of hypercapnia. Respiration with pure N2 for 30 s resulted in lowering blood O2 without increasing CO2 levels. Both basal and K(+)-evoked DA releases were increased during N2-induced anoxic hypoxia. These data suggested that transient hypoxia facilitates DA release in the striatum. It has been suggested that NMDA is involved in many hypoxia-mediated responses. We also found that systemic application of ketamine, which itself did not affect blood O2 or CO2 levels, antagonized hypoxia-induced electrochemical responses. These data suggest that the increase in DA release in vivo during short-term hypoxia may probably be mediated through NMDA receptors.