Acquisition of new cellular and molecular knowledge of the serotonin (5-HT) system is necessary tounderstand how 5-HT neurobiology drives clinical vulnerability profiles and addiction. The objective of theMolecular 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 molecularbiology 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 toendophenotypes and treatment responses (Projects 1 and 2); (2) initiate and coordinate genotypedeterminations in humans (Project 1) and rats (Project 2), and to correlate genotype with endophenotype inparallel with 5-HT^R and/or 5-HT2CR expression in platelets; (3) measure functional activity of 5-HT2Rligands (Project 3) in cellular 5-HT2AR and/or 5-HT2CR models using intracellular (Ca,++) mobilization and/orinositol phosphate accumulation assays and immunoprecipitation assays to determine association with Gproteinsand other binding partners; (4) correlate 5-HT2AR and/or 5-HT2CR expression and function in specificbrain regions of rats identified by endophenotype (Project 2) using assays paralleling those in humans and incultured cells; (5) utilize these functional activity assays to determine which new ligands from Project 3 willbe 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 providethe objective basis for deciding which new molecules to test in the rodent behavior (in vivo) models (Project2). Combined data from cultured cells, animal models and human subjects will aid in developing acomprehensive functional picture of extant and novel (Project 3) 5-HT2AR and 5-HT2CR ligands and willassure advancements in all Projects to develop innovative new pharmacotherapeutic approaches to cocaineaddiction.Lav Abstract. No effective, accessible medication for the treatment of stimulant addiction is currentlyavailable. Using cultured cells, we will screen newly created drugs for their potential to be tested in rodentassays that model human drug-taking and ultimately in clinical trials as novel medications for treatment ofstimulant addiction.
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