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The Journal of Neuroscience, April 1, 2001, 21(7):2298-2307

A Depletable Pool of Adenosine in Area CA1 of the Rat Hippocampus

Tim Pearson², Feruza Nuritova², Darren Caldwell², Nicholas Dale¹, and Bruno G. Frenguelli²

¹ Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom, and ² Department of Pharmacology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom

Adenosine plays a major modulatory and neuroprotective role in the mammalian CNS. During cerebral metabolic stress, such as hypoxia or ischemia, the increase in extracellular adenosine inhibits excitatory synaptic transmission onto vulnerable neurons via presynaptic adenosine A₁ receptors, thereby reducing the activation of postsynaptic glutamate receptors. Using a combination of extracellular and whole-cell recordings in the CA1 region of hippocampal slices from 12- to 24-d-old rats, we have found that this protective depression of synaptic transmission weakens with repeated exposure to hypoxia, thereby allowing potentially damaging excitation to both persist for longer during oxygen deprivation and recover more rapidly on reoxygenation. This phenomenon is unlikely to involve A₁ receptor desensitization or impaired nucleoside transport. Instead, by using the selective A₁ antagonist 8-cyclopentyl-1,3-dipropylxanthine and a novel adenosine sensor, we demonstrate that adenosine production is reduced with repeated episodes of hypoxia. Furthermore, this adenosine depletion can be reversed at least partially either by the application of exogenous adenosine, but not by a stable A₁ agonist, N⁶-cyclopentyladenosine, or by endogenous means by prolonged (2 hr) recovery between hypoxic episodes. Given the vital neuroprotective role of adenosine, these findings suggest that depletion of adenosine may underlie the increased neuronal vulnerability to repetitive or secondary hypoxia/ischemia in cerebrovascular disease and head injury.

Key words: adenosine; hypoxia; ischemia; sensor; depletion; replenishment; glutamate; hippocampus; head injury; TBI; stroke; TIA; neuroprotection; adenosine deaminase; nucleoside phosphorylase; xanthine oxidase

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2172298-10$05.00/0

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