Journal zyxwvutsrqpon of Neurochemistry zyxwvutsrqponm Raven Press, Ltd., New zyxwvutsrqp York zyxwvutsrqpon 0 1988 International Society for Neurochemistry zyxwvutsrqpo Effect of Ischemia on the In Vivo Release of Striatal Dopamine, Glutamate, and y-Aminobutyric Acid Studied by Intracerebral Microdialysis Mordecai Y.-T. Globus, Raul Busto, W. Dalton Dietrich, Elena Martinez, Isabel Valdes, and Myron D. Ginsberg Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami School of Medicine, Miami, Florida, U.S.A. Abstract: We have previously described a marked attenuation of postischemic striatal neuronal death by prior substantia nigra (SN) lesioning. The present study was carried out to evaluate whether the protective effect of the lesion involves changes in the degree of local cerebral blood flow (ICBF) reduction, energy metabolite depletion, or alterations in the extracellular release of striatal dopamine (DA), glutamate (Glu), or y-aminobutyric acid (GABA). Control and SN-le- sioned rats were subjected to 20 min of forebrain ischemia by four-vessel occlusion combined with systemic hypotension. Levels of lCBF, as measured by the autoradiographic method, and energy metabolites were uniformly reduced in both the ipsi- and contralateral striata at the end of the ischemic period, a finding implying that the lesion did not affect the severity of the ischemic insult itself. Extracellular neurotransmitter levels were measured by microdialysis; the perfusate was col- lected before, during, and after ischemia. An -500-fold in- crease in DA content, a 7-fold increase in Glu content, and a 5-fold increase in GABA content were observed during ischemia in nonlesioned animals. These levels gradually re- turned to baseline by 30 min of reperfusion. In SN-lesioned rats, the release of DA was completely prevented, the release of GABA was not affected, and the release of Glu was partially attenuated. However, excessive extracellular Glu concentra- tions were still attained, which are potentially toxic. This, taken together with the previous neuropathological findings, suggests that excessive release of DA is important for the development of ischemic cell damage in the striatum. Key Words: Dopamine-Glutamate-Striatum-Cerebral isch- emia-Microdialysis. Globus M. Y.-T. zyx et al. Effect of isch- emia on the in vivo release of striatal dopamine, glutamate, and y-aminobutyric acid studied by intracerebral microdi- alysis. J. Neurochem. 51, 1455-1464 (1988). Neuropathologistshave long noted that certain brain regions and specific neuronal types are especially vul- nerable to ischemic insults (Brierley, 1976). Among the neurons that are particularly susceptible to transient ischemia are the CA 1 pyramidal cells of the hippocam- pus and the small to medium-sized neurons of the dor- solateral striatum (Pulsinelli et al., 1982; Ginsberg et al., 1985). Although the selective vulnerability of these neurons is well established morphologically, its patho- genesis remains obscure. Recent studies have described elevations of the extracellular concentration of gluta- mate (Glu) and 7-aminobutyric acid (GABA) in the hippocampus following transient ischemia (Benveniste et al., 1984; Hagberg et al., 1985), and others have demonstrated that ischemia-induced cell death in the hippocampus is dependent on the integrity of its glu- tamatergic input (Wieloch et al., 1985~; Johansen et al., 1986; Onodera et al., 1986). These results suggest that the release of excitatory neurotransmitters is in- volved in the development of ischemic cell damage in the hippocampus. The striatum, a region highly vulnerable to ischemia, is richly innervated both by the corticostriatal gluta- matergic pathway and by nigrostriatal dopaminergic projections, which have been shown to interact with each other (Cheramy et al., 1986; Chiodo and Berger, Received March zyxwvutsrqpo 11, 1988; revised manuscript received May 9, 1988; accepted May 12, 1988. Address correspondence and reprint requests to Dr. M. Y.-T. Glo- bus at Cerebral Vascular Disease Research Center, Department of Neurology ( D 4 - 9 , University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101, U.S.A. Abbreviations used: DA, doparnine; DOPAC, 3,4-dihydroxyphe- nylacetic acid; GABA, y-arninobutyric acid; Glu, glutamate; HVA, homovanillic acid;lCBF, local cerebral blood flow; NMDA, N-methyl- D-aspartate; PCA, perchloric acid; PCr, phosphocreatine; SN, sub- stantia nigra. zyxwv 1455