Dopaminergic signaling in striatum is involved in neuropsychiatric disease, including drug abuse and psychosis. Stimulants, antipsychotics and other drugs targeting the dopaminergic system regulate transcription in striatal neurons, but the underlying molecular mechanisms are not completely understood. Gaining a better understanding of how dopaminergic drugs induce transcription of early response and other genes should broaden the range and efficacy of treatments. The proposed experiments are designed to examine the dopaminergic regulation of covalent histone modifications in striatum, using acute and chronic paradigms. Histones are, together with DNA that wraps around them, the fundamental structural unit of chromatin and thus regulate gene expression, DNA repair and chromosome segregation, among others. Specifically, a """"""""histone code"""""""" has been established, associating the sitespecific acetylation, methylation and phosphorylation of the amino-terminal tails of two core histones, H3 and H4, either to open chromatin and active gene expression or to silenced, inactive and condensed chromatin. Our central goals are 1) to examine on a molecular and cellular level dynamic changes in histone acetylation, methylation and phosphorylation after single or repeated administration of stimulants, DI agonists and D2-like antagonists (Specific Aims 1 and 2) and to identify intracellular messenger pathways that couple dopamine receptor signaling to the chromatin-remodeling complex in the nucleus (Specific Aim 3). These experiments are guided by preliminary data demonstrating that DI agonist- and D2-like antagonist-induced striatal transcription is accompanied by dynamic changes in open chromatin-associated histone acetylation, phospho-acetylation and methylation at the corresponding gene promoters. Therefore, our central hypothesis is that histone modifications defining open and closed chromatin are differentially regulated by stimulant drugs, D1 agonists and D2-like antagonists. Our experiments will rely on chromatin immunoprecipitation assays and immunoblotting, and laser capturemicrodissections of cells labeled with anti-histone antibodies that selectively recognize site-specific modifications at the NH2-terminal tails of H3 and H4. It is expected that these novel approaches will provide a clear picture on the dopaminergic regulation of the """"""""histone code"""""""" in striatal neurons and will establish the epigenetic modification of striatal chromatin as a novel mechanism of action for stimulant drugs and also for conventional antipsychotics acting as D2-like antagonists. ? ?
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