Cerebral ischemia can result in varying degrees of tissue damage. Conditions of severe ischemia can produce extensive areas of irreversible injury, whereas in conditions of moderate ischemia, tissue damage may be reversible, as in the region of the ischemic penumbra. The reversibility of tissue damage in the penumbral region is of clinical interest, because the characterization of conditions underlying this reversible state may provide information needed for the development of new therapeutic approaches for treatment. Our previous studies demonstrated neurochemical alterations in the levels of dopamine (DA) within the striatum after cerebral ischemia. In the present study, we postulate that these changes may be caused, in part, by alterations in transmitter release and reuptake. To test this hypothesis, forebrain ischemia was induced in Sprague-Dawley rats (Harlan, Indianapolis, IN) by means of bilateral common carotid artery occlusion and hemorrhagic hypotension. Cerebral blood flow (CBF) in the striatum was measured by the method of hydrogen clearance, and the extracellular DA ([DA]e) levels were measured by in vivo microdialysis. Varied reductions of CBF were induced and maintained for 5 hours. Three subgroups were established retrospectively according to the degree of CBF reduction: 67.7, 35.6, and 13.2% of normal CBF in the mild, moderate, and severe ischemic groups, respectively. The induction of ischemia resulted in 1.9-, 9.3-, and 122.3-fold increases in [DA]e above baseline in the mild, moderate, and severe ischemia groups, respectively. At 3 hours after the induction of ischemia, high potassium (100 mmol/L) or Nomifensin (Sigma, St. Louis, MO) (10 mmol/L), a DA uptake blocker, was administrated via a microdialysis probe to stimulate DA release while reductions in CBF were maintained continuously. Thirteen rats were used in the study of the release of DA by potassium or Nomifensin in nonischemic conditions. The administration of high potassium or Nomifensin stimulated DA release in conditions of mild and moderate ischemia. The increase in DA release by potassium stimulation was higher in rats with mild ischemia (106.6-fold) than that in normal rats (22.3-fold). This suggests a hyperexcitability of DA terminals under mild ischemia, as compared with nonischemic conditions. On the other hand, Nomifensin increased [DA]e levels more in moderately ischemic brains than in control brains, suggesting that DA uptake is up-regulated in the former case. The increased release of DA by potassium and Nomifensin was sustained after stimulation in conditions of mild and moderate ischemia. The high level of [DA]e with severe ischemia after ischemic induction was sustained throughout the period of study and was not stimulated by potassium or Nomifensin. We conclude that under conditions of mild and moderate ischemia, DA terminals become highly excitable and reuptake mechanisms are compromised. These changes of DA metabolism during mild and moderate ischemia may explain the sustainability of neurons in the "penumbra" condition of cerebral ischemia and the transformation of the ischemic penumbra to a necrotic core.