The overall goal of this project is to increase our understanding of the role of adenosine in the brain's response to metabolic stress, specifically hypoxia. This knowledge may contribute to our understanding of the pathophysiology of cerebral stroke and ischemia. The mechanisms underlying hypoxia-induced depression of neuronal activity and subsequent neuronal survival are not clear. Preliminary results indicate that the endogenous inhibitory neuromodulator adenosine plays a central role in the initial depression of neuronal function during exposure to hypoxia. It is postulated that the release of adenosine and the subsequent depression of neuronal activity represents a mechanism for decreasing ATP consumption and improving neuronal survivability during periods of metabolic stress. Adenosine, for a variety of reasons, appears to play a particularly important role in regulating excitability in the isolated hippocampal brain slice. The amplitude of the evoked orthodromic synaptic response is depressed during hypoxia and adenosine antagonists essentially block this depression. Levels of adenosine in the slice can be qualitatively assessed by monitoring changes in neuronal excitability and efflux can be quantitatively measured using radiolabelled precursor in combination with HPLC detection. Tissue partial pressure of oxygen (p02) is inversely related to oxygen consumption and can be continuously monitored with an oxygen microelectrode. Experiments are designed to address the following specific aims. 1. Show that adenosine underlies the early hypoxia-induced depression of the evoked response in the superfused hippocampal slice. 2. Show that tissue partial pressure of oxygen (p02) regulates adenosine release and that the decline in p02 is not directly responsible for early inhibition of the evoked response. 3. Investigate adenosine's role in the development of post-hypoxia hyperexcitability and in recovery of neuronal function following prolonged hypoxia.
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