Acquisition of new cellular and molecular knowledge of the serotonin (5-HT) system is necessary to understand how 5-HT neurobiology drives clinical vulnerability profiles and addiction. The objective of the Molecular and Cell Biology Core (Core B) of the Translational Center for Serotonin and Stimulant Addiction (TCSSA) is to maximize therapeutic advances by tying clinical observations to parallel cellular and molecular biology knowledge. To this end, Core B will (1) develop a library of stably-transfected cell lines of native 5- HT2AR and 5-HT2CR and select polymorphisms and isoforms for screening ligands (Project 3) to relate to endophenotypes and treatment responses (Projects 1 and 2);(2) initiate and coordinate genotype determinations in humans (Project 1) and rats (Project 2), and to correlate genotype with endophenotype in parallel with 5-HT^R and/or 5-HT2CR expression in platelets;(3) measure functional activity of 5-HT2R ligands (Project 3) in cellular 5-HT2AR and/or 5-HT2CR models using intracellular (Ca,++) mobilization and/or inositol phosphate accumulation assays and immunoprecipitation assays to determine association with Gproteins and other binding partners;(4) correlate 5-HT2AR and/or 5-HT2CR expression and function in specific brain regions of rats identified by endophenotype (Project 2) using assays paralleling those in humans and in cultured cells;(5) utilize these functional activity assays to determine which new ligands from Project 3 will be tested in animal behavioral models (Project 2) as we shape future experiments in humans (Project 1). Screening to determine the potency, efficacy and specificity of extant and new ligands (Project 3) will provide the objective basis for deciding which new molecules to test in the rodent behavior (in vivo) models (Project 2). Combined data from cultured cells, animal models and human subjects will aid in developing a comprehensive functional picture of extant and novel (Project 3) 5-HT2AR and 5-HT2CR ligands and will assure advancements in all Projects to develop innovative new pharmacotherapeutic approaches to cocaine addiction. Lav Abstract. No effective, accessible medication for the treatment of stimulant addiction is currently available. Using cultured cells, we will screen newly created drugs for their potential to be tested in rodent assays that model human drug-taking and ultimately in clinical trials as novel medications for treatment of stimulant addiction.
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