Adenosine has been shown to be an inhibitory neuromodulator, which acts by decreasing the release of the excitatory neurotransmitters glutamate and aspartate. Adenosine is likely to play an important role in normal synaptic transmission, but also in pathological states such as epilepsy and stroke. Despite the importance of adenosine in health and disease, the cellular mechanisms regulating extracellular adenosine accumulation are not well understood. The experiments described here are aimed at elucidating the mechanisms of extracellular adenosine accumulation in cerebral cortex. Previous studies by the P.I. have shown that beta adrenergic receptor stimulation causes the accumulation of extracellular cyclic AMP and adenosine in rat cerebral cortex in dissociated cell culture. The specific hypothesis to be tested in this project is that beta adrenergic receptor mediated secretion of cyclic AMP followed by extracellular hydrolysis of cyclic AMP is a significant mechanism regulating extracellular adenosine concentrations in the cerebral cortex. The specific aims of this study are to: 1) determine whether extracellular adenosine, which is increased by beta adrenergic stimulation of cortical cultures, is actually derived from extracellular cAMP; 2) characterize other sources of extracellular adenosine in the cerebral cortex; 3) use microdialysis techniques in vivo to determine whether beta-adrenergic stimulation of extracellular adenosine accumulation can be demonstrated in living animals. The long-term objective of the present proposal is to understand the cellular mechanisms regulating extracellular adenosine accumulation in the CNS. It is expected that this information will help us to understand the mechanisms modulating synaptic transmission under normal circumstances as well as during seizures and hypoxic/ischemic insults to the brain.