Cellular Biology and Pharmacology Core

翻译成瘾科学中心的细胞生物学和药理学核心(核心B) (TASC)旨在搭建科学项目之间的桥梁，通过减少跨越 从细胞到人类的界限。TASC的中心研究主题是冲动动作和提示 反应性与5-羟色胺(5-羟色胺)通过5-羟色胺(5-HT2a)的神经传递障碍有关 受体(5-HT2AR)和5-HT2cR定位于皮质纹状体回路。收购新的蜂窝和 5-HT2AR：5-HT2CR平衡的分子知识对于理解5-HT2AR：5-HT2CR平衡是必要的 导致临床上的脆弱性特征和成瘾。证据表明，5-HT2AR和5-HT2cR 相反的影响对冲动和线索反应都有影响。然而，潜在的神经生物学基础 这种对立并不被很好地理解，特别是因为这些高度同源的受体通过 类似的下行信令机制。为了解决这一根本差距，更好地理解 这些受体的区域、细胞定位和神经元分布，以及对其他 影响受体功能状态的因素，如配体定向信号(项目3)， 受体多态(项目1)和受体寡聚(项目2，项目3)是必要的。这个 核心B的主要目标是作为一个集中的、综合的细胞生物学和 药理学知识和技术专长，以最大限度地了解神经生物学和 5-HT2AR的药理学特征：5-HT2CR功能调节参与干扰 总冲动性/线索反应性的动态平衡。为了这个目的。核心B将：开发一个库 使用生物反应试验筛选配体的稳定转染5-HT2R细胞系(项目3) 对表型和治疗反应的功能选择性(项目1和2)；进行基因分型 测定(项目1)；5-HT2AR：5-HT2CR在细胞和区域的MAP激活和共定位 脉冲大鼠前额-纹状体-丘脑环路中的水平；利用生物反应分析 确定项目3中的哪些新配体将在动物行为模型(项目2)中进行测试 塑造未来的人体实验(项目1)；确定5-HT2A2CR二聚体在控制 受体功能以及新合成的二价5-HT2R配体的作用(项目3)。这个强大的 将遗传学、化学和功能筛选与新药分析相结合的方法将所有 TASC项目并将提供不可或缺的信息基础，以便能够证明5 HT2AR：5-HT2CR稳态失衡是可卡因依赖行为表现的基础， 恢复5-HT2AR：5-HT2CR平衡将修复皮质纹状体缺陷，改善复发。 相关性： 目前还没有有效的、可获得的治疗兴奋剂成瘾的药物。vbl.使用 培养细胞，我们将筛选新发明的药物，以在啮齿动物实验中测试它们的潜力 人类服用药物，并最终作为治疗兴奋剂成瘾的新药进入临床试验。

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. RELEVANCE: 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.