The longterm goal of this research is to clarify how endogenous opioid peptides and related genes in identified neurons in the forebrain inhibit the effects of psychostimulants. We have established that the muscarinic cholinergic and dynorphin/kappa opioid systems suppress amphetamine and D1 dopamine agonist effects on behavior and gene expression in striatal medium spiny neurons. In addition, mitogen-activated protein (MAP) kinases were found to mediate PKA and glutamate- induced phosphorylation of cyclase response element binding protein (CREB) and Elk-1, a component of the ternary complex factor, in striatal neurons in vivo. These transcription factors bind to the promoter regions of target genes, such as c-fos and the opioid peptides, preproenkephalin and preprodynorphin, and stimulate their transcription. In this competitive renewal, we propose to solidify and extend these findings using selective pharmacological ligands and enzyme-inhibiting drugs not available previously, as well as dynorphin, kappa opioid and muscarinic receptor knockout mice. In situ hybridization, immunocytochemistry, and microdialysis will be used. To clarify the muscarinic receptor subtypes that mediate the effects of acetylcholine on stimulant-induced striatal gene expression by pharmacological treatment of rats and by using M2 and M4 muscarinic receptor knockout mice, To clarify whether differential release of acetylcholine in the dorsal and ventral striatum underlies differences in D1 and D2 receptor interactions in these structures, To clarify the role of the dynorphin/kappa opioid system on behavior and striatal gene expression after acute and repeated psychostimulant administration in kappa opioid receptor and dynorphin knockout mice, To investigate whether inhibition of MAP kinase pathways augments amphetamine-stimulated behaviors by decreasing CREB and Elk-1 phosphorylation and neuropeptide gene expression in medium spiny neurons. These studies will increase our understanding of transsynaptic and intracellular mechanisms of action of psychostimulants with the potential of identifying novel targets for medicinal development to treat the widespread abuse of psychostimulants.
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