Adenosine is an inhibitory neuromodulator that has been postulated to be involved in behavioral state control in several regions of the brain, including the cortex, thalamus, basal forebrain and lateral dorsal tegmental nucleus/pedunuculopontine tegmental nucleus (LDT/PPT). Adenosine inhibits firing of cholinergic cells of the adenosine levels in the extracellular space in any brain region. Recently it has been found that monoamines, peptides and metabotropic glutamate agonists regulate adenosine levels by a mechanism dependent upon cycle AMP metabolism. In addition, in cortical cultures, and in the hippocampal and LDT/PPT slice preparations, all derived from the rat, the cyclic nucleotide phosphodiesterase inhibitor zaprinast evokes significant extracellular adenosine accumulation. Since the LDT/PPT receives glutamatergic, monoaminergic, and peptidergic inputs, our specific hypothesis is that mechanisms linking adenosine accumulation with neurotransmitter control of cyclic nucleotide metabolism may be important in regulating extracellular adenosine in the LDT/PPT.
The specific aims of this project are to: 1) determine the origin of zaprinast evoked extracellular adenosine accumulation; 2) identify phosphodiesterases present in the LDT/PPT; 3) characterize the effect of phosphodiesterase inhibitors on cyclic nucleotide metabolism and adenosine accumulation in the LDT/PPT; 4) characterize the effects of endogenous neuromodulators of cyclic nucleotide metabolism and adenosine accumulation in the LDT/PPT. This work should improve our understanding of how adenosine levels are regulated at a molecular level, how elevations in adenosine levels might be produced in brain regions involved in state control and whether such changes play a causal role in the determination of behavioral state.
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