The Cellular Biology and Pharmacology Core (Core B) of the Translational Addiction Sciences Center (TASC) is designed to bridge the scientific projects and engender synergy by mitigating barriers across the boundaries from cells to humans. The central research theme ot the TASC is that impulsive action and cue reactivity are mechanistically linked to disrupted serotonin (5-HT) neurotransmission through the 5-HT2A receptor (5-HT2AR) and 5-HT2cR localized to the corticostriatal circuitry. The acquisition of new cellular and molecular knowledge of the 5-HT2AR:5-HT2CR balance is necessary to understand how 5-HT neurobiology drives clinical vulnerability profiles and addiction. Evidence indicates that 5-HT2AR and 5-HT2cR exert opposing influence upon both impulsivity and cue reactivity. However, the neurobiological basis underlying this opposition is not well understood, particularly since these highly homologous receptors work through similar downstream signaling mechanisms. To address this fundamental gap, a greater understanding of the regional, cellular localization and neuronal distribution of these receptors, as well as an assessment of other factors that influence the functional status of the receptors, such as ligand directed signaling (Project 3), receptor polymorphisms (Project 1) and receptor oligomerization (Project 2, Project 3), is needed. The primary objective tor Core B is to serve as a centralized, integrative source of cellular biology and pharmacology knowledge and technical expertise, to maximize our understanding of the neurobiological and pharmacological features of 5-HT2AR:5-HT2CR functional regulation that contribute to the disruption of homeostatic balance in aggregate impulsivity/cue reactivity. To this end. Core B will: develop a library of stably-transfected 5-HT2R cell lines for screening ligands (Project 3) using bioresponsive assays to relate functional selectivity to phenotypes and treatment responses (Projects 1 and 2);conduct genotype determinations (Project 1);map activation and co-localization of 5-HT2AR:5-HT2CR at the cellular and regional levels within the prefrontal-striatal-thalamic circuits of impulsive rats;utilize bioresponsive 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);determine the role of 5-HT2A+2CR dimerization in control of receptor function as well as effects of newly synthesized bivalent 5-HT2R ligands (Project 3). This powerful approach combining genetics, chemical and functional screens with new drug analyses ties together all of the TASC Projects and will provide an indispensable foundation of information to allow demonstration that 5 HT2AR:5-HT2CR homeostatic imbalance underlies behavioral manifestations of cocaine dependence and that restoration of the 5-HT2AR:5-HT2CR balance will repair corticostriatal deficits and ameliorate relapse.
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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