5-HT2R NEUROBIOLOGY IN ANIMAL MODELS OF ADDICTION

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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 associate with cocaine addiction. Project 2 will employ and refine behavioral measures of impulsivity and cue reactivity in rats, mechanistically link the status of 5-HT^R and/or 5-HT2cR expression and function to specific behavioral 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 patterns of expression. We will initially identify the endophenotype for impulsivity based upon the degree of response inhibition in the differential reinforcement of low rates schedule (DRL-20) task and for cue reactivity based upon lever responses reinforced by drug-associated cues during forced abstinence from a well-defined cocaine self-administration paradigm. We will also investigate how basal levels of impulsivity interact with the progression of drug-taking and drug-seeking. In concert with Project 3, we propose that gains in treatment effectiveness will be possible with the selective homo- and/or heterodimeric 5-HT2R ligands. Promising compounds will be evaluated for in vivo bioavailability in a stairstep approach utilizing simple rodent assays that will also serve as dose-ranging studies for the more intensive assessment of their effectiveness in models of impulsivity and cue reactivity. Project 2 will be driven and adapted directly from the clinical neurobiology insight (Project 1) and take a molecular-level view to elaborating the role of 5-HT in targeted endophenotypes (Project 3, Core B). Careful analyses of the status of 5-HT^R and 5-HT2CR expression and function and the effects of treatment with extant and novel selective 5-HT^R and 5-HT2cR ligands or their combination, in rodent models will shape the rationale for future hypothesis-driven neurobiological studies in humans (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 currently available. We will establish the ability of existing and newly designed drugs to suppress relapse in rodent assays which model human drug-taking.