NEUROTRANSMITTER RELEASE DURING cerebral ischemia has been extensively studied and is thought to play a key role in excitotoxic neuronal death. The changes in neurotransmitter release and its metabolism may reflect changes in cellular metabolism during ischemia. The purpose of this study is to assess alterations in extracellular dopamine and serotonin and their metabolites under varied degrees of ischemia in rat striatum to elucidate the pathophysiology of cerebral ischemia. Twenty rats were used to induce varied forebrain ischemia by means of bilateral common carotid artery occlusion along with hemorrhagic hypotension. Cerebral blood flow (CBF) in the striatum was measured every 40 minutes by methods of hydrogen clearance and maintained within certain ranges for 6 hours. Dopamine, serotonin, and their metabolites were measured every 20 minutes by in vivo microdialysis. Varying degrees of ischemia were obtained, ranging from 9.4 to 81.3% of control CBF. The animals were divided into three groups according to CBF levels measured 20 minutes after the induction of ischemia. In the mild ischemia group (n = 5), CBF ranged from 65 to 88% of baseline levels and resulted in only a slight increase of dopamine. In the moderate ischemia group (n = 10), CBF ranged from 21 to 48% of baseline levels and resulted in transient increases of dopamine (24-fold) and serotonin (5-fold). In the severe ischemia group (n = 5), CBF was below 14% of baseline levels and resulted in marked increases in dopamine (462-fold) and serotonin (225-fold). These alterations remained elevated for 3 hours. An analysis for the maximum release of dopamine showed a logarithmic linear correlation with CBF (r= 0.912), whereas serotonin showed a threshold-like increase at lower values of CBF. The levels of metabolites of these neurotransmitters also decreased according to the degree of ischemia, and dopaminergic metabolite levels decreased more than serotonergic metabolite levels. Under severe ischemia, all of the metabolites decreased to levels less than 30% of the control value. These results suggest that the metabolism of dopamine and serotonin is affected not only under conditions of severe ischemia but also under moderate ischemia. However, under severe ischemia, both dopaminergic and serotonergic systems are markedly affected, whereas under moderate ischemia, the dopaminergic system appears to be more vulnerable.