Adenosine has been shown in a number of preparations derived from the central nervous system to inhibit transmitter release, and may do so by inhibiting presynaptic calcium influx. In addition, adenosine has been shown to modulate glycogen metabolism. Despite the potential importance of adenosine as modulator both of neuronal activity and of glial energy metabolism, little is known about the mechanisms by which adenosine accumulates extracellularly in the central nervous system. Adenosine has often been shown to accumulate extracellularly following various methods of stimulation. However, important questions remain to be answered, namely from which cells does adenosine derive; by what mechanisms of release; as a consequence of what signals? It is also unclear whether adenosine itself is transported or whether and to what extent extracellular adenosine derives from adenosine nucleotides. Finally, does adenosine fulfill the requirements for being called an intrinsic neuromodulator as well as a modulator of glial function? the hypothesis to be tested by the experiments to be described in this proposal is that in cerebral cortex adenosine accumulates in the extracellular space by at least two routes: 1) derived from neurons as a consequence of neuronal depolarization: and 2) following adrenergic stimulation which yields adenosine by degradation of secreted cAMP. This research will demonstrate and characterize these mechanisms of extracellular adenosine accumulation and will localize the sources and sinks of adenosine involved. In addition the possibility that anticonvulsant interact with these mechanisms or with adenosine receptors will be tested. The significance of this work is that the accumulation of adenosine or other purines in the extracellular space may subserve a signalling function in the cerebral cortex. This signalling function may be important in mediating some effects of certain neurotransmitters, coordinating neuronal activity and astrocyte metabolism, and providing a safety mechanism for inhibiting synaptic transmission during excessive neuronal discharge, for example during epileptic discharges. It may be particularly relevant to an understanding of seizure termination to understand the mechanisms resulting in extracellular adenosine accumulation. The failure of these mechanisms, either because of the pathophysiology of certain forms of epilepsy, or because of withdrawal from anticonvulsant medication, might be responsible for status epilepticus. The model system for these studies will be rat cerebral cortex in dissociated cell culture, ideal for combining biochemical and physiological approaches.
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