common shared clinical question of the Translational Center for Serotonin and Stimulant Addiction(TCSSA) is the role of 5-HT neurobiology in impulsivity and cue reactivity endophenotypes which associatewith cocaine addiction. Project 2 will employ and refine behavioral measures of impulsivity and cue reactivityin rats, mechanistically link the status of 5-HT^R and/or 5-HT2cR expression and function to specificbehavioral profiles, and test the hypothesis that treatment with M100907 (selective S-HT^R antagonist),WAY 470 (selective 5-HT2cR agonist) or their combination will normalize behavioral and molecular patternsof expression. We will initially identify the endophenotype for impulsivity based upon the degree of responseinhibition in the differential reinforcement of low rates schedule (DRL-20) task and for cue reactivity basedupon lever responses reinforced by drug-associated cues during forced abstinence from a well-definedcocaine self-administration paradigm. We will also investigate how basal levels of impulsivity interact with theprogression of drug-taking and drug-seeking. In concert with Project 3, we propose that gains in treatmenteffectiveness will be possible with the selective homo- and/or heterodimeric 5-HT2R ligands. Promisingcompounds will be evaluated for in vivo bioavailability in a stairstep approach utilizing simple rodent assaysthat will also serve as dose-ranging studies for the more intensive assessment of their effectiveness inmodels of impulsivity and cue reactivity. Project 2 will be driven and adapted directly from the clinicalneurobiology insight (Project 1) and take a molecular-level view to elaborating the role of 5-HT in targetedendophenotypes (Project 3, Core B). Careful analyses of the status of 5-HT^R and 5-HT2CR expression andfunction and the effects of treatment with extant and novel selective 5-HT^R and 5-HT2cR ligands or theircombination, in rodent models will shape the rationale for future hypothesis-driven neurobiological studies inhumans (Project 1) and clinical assessments of new selectively-targeted serotonergic drugs (Project 3).Lav Abstract. No effective, accessible medication for the treatment of stimulant addiction is currentlyavailable. We will establish the ability of existing and newly designed drugs to suppress relapse in rodentassays which model human drug-taking.
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