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 O-2, CO2, N-2 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 O-2 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% O-2 + 65% N-2), and this change resulted in increased blood CO, levels without lowering O-2 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 N-2 for 30 s resulted in lowering blood O-2 without increasing CO2 levels. Both basal and K+-evoked DA releases were increased during N-2-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 O-2 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.