Journal zyxwvutsrqpo of zyxwvutsrqponmlkji Neurochemistry Raven Press, Ltd., New York zyxwvutsrqp 0 199 1 International Society for Neurochemistry Effects of Hypoxia on the Activity of the Dopaminergic Neuron System in the Rat Striaturn as Studied by In Vivo Brain Microdialysis Yoshinori Akiyama, "Kunio Koshimura, "Tetsuya Ohue, *Ken Lee, *Soichi Miwa, Sen Yamagata, and Haruhiko Kikuchi zyx Departments of Neurosurgery and *Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan zyx ~ ~ zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Abstract: The purpose of the present study is to clarify the effects of hypoxia on the activity of the dopaminergic neurons in the brain and its mechanism of action. For this purpose, the effects of hypoxia on the extracellular levels of 3,4-dihy- droxyphenylethylamine (dopamine) were examined in the rat striatum using in vivo brain microdialysis in the presence or absence of pretreatment with either tetrodotoxin (a blocker of voltage-dependent sodium channels) or nomifensine (a blocker of dopamine reuptake). Exposure to various degrees of hypoxia (1 5, 10, and 8% O2 in N2) increased dopamine levels in striatal dialysates to 200, 400, and 1,100%, respec- tively, of the control value. On reoxygenation, dopamine lev- els in the dialysates rapidly returned to the control level. Reexposure to hypoxia increased the dopamine levels to the ~ ~ ~~ same extent as during the first exposure. After addition of tetrodotoxin (40 pM) to the perfusion fluid or pretreatment with nomifensine (100 mg/kg, i.p.), exposure to hypoxia no longer increased the dopamine levels. These results suggest that although hypoxia induces an increase in the extracellular dopamine levels (hence, an apparent increase in the activity of the dopaminergic neurons), this increase is not the result of an increase in dopamine release itself, but rather the result of inhibition of the dopamine reuptake mechanism. Key Words: zyxwv Hypoxia-Dopamine-Release-Reuptake-Stria- tum-In vivo brain microdialysis. Akiyama Y. et al. Effects of hypoxia on the activity of the dopaminergic neuron system in the rat striatum as studied by in vivo brain microdialysis. J. Neurochem. zyxwv 57, 997- 1002 (1 99 1). The susceptibility of the brain to hypoxia is greater than that of other organs, as it has a high oxygen de- mand and little energy is produced anaerobically (Smith and Sokoloff, 1981). Although there is no ap- parent alteration in energy metabolism of the brain in environmental oxygen concentrations of 27% (Mac- Millan and Siesjo, 1971; Duffy et al., 1972; Bachelard et al., 1974; Norberg and Siesjo, 1975), exposure to this degree of hypoxia produces behavioral disturbances such as blockade of the conditioned avoidance response and of amphetamine-induced stimulation of locomotor activity in experimental animals (Vacher and Miller, 1968; Brown and Engel, 1973; Brown et al., 1975). It is reported that the same type of behavioral distur- bances can also be induced by some drugs, such as reserpine and a-methyl-p-tyrosine (Seiden and Carls- son, 1964; Weissman and Koe, 1965), that depress the activity of catecholaminergic neurons in the brain by depleting catecholamines (Nagatsu et al., 1964; Carls- son, 1966). Furthermore, these drug-induced behav- ioral disturbances are reported to be improved by ad- ministration of ~-3,4-dihydroxyphenylalanine, a pre- cursor for catecholamines (Seiden and Carlsson, 1964; Corrodi and Hanson, 1966), as are those induced by hypoxia (Brown and Engel, 1973; Brown et al., 1973, 1975). From these results, the hypoxia-induced behav- ioral disturbances are considered to be the result of decreased activity of catecholaminergic neurons. In fact, several investigators reported that under hypoxic conditions, the turnover rate of 3,4-dihydroxyphen- ylethylamine (dopamine) is depressed, whereas that of noradrenaline is unchanged (Davis and Carlsson, 1973; Brown et al., 1974, 1975; Miwa et al., 1986). Thus, it is now considered that the disruption of behavior ob- served under hypoxia may be related to decreased do- paminergic neuronal activity. ~ ~~ Received June 18, 1990; revised manuscript received December 20, 1990; accepted February zyxwvutsrq 15, 199 1. Address correspondence and reprint requests to Dr. Y. Akiyama at Department of Neurosurgery, Kyoto University Faculty of Med- icine, Kyoto 606, Japan. Abbreviations used: dopamine, 3.4-dihydroxyphenylethylamine; MAO, monoamine oxidase; Pao2, oxygen tension in arterial blood; TTX, tetrodotoxin. 99 7