Individual Differences in Cocaine Activation/Reward and the Dopamine Transporter

可卡因激活/奖励和多巴胺转运蛋白的个体差异

• 批准号: 7924302
• 负责人: Nancy Rutledge Zahniser
• 金额: $ 6.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924302
• 关键词: Acute; Address; Adult; Agonist; Animal Model; Area; Arts; Award; Behavior; Behavioral; Binding; Biological; Biological Assay; Brain; Brain Chemistry; Brain Diseases; CCRL2 gene; Cell surface; Classification; Cocaine; Cocaine Abuse; Corpus striatum structure; Coupling; Cues; DRD2 gene; Development; Disease; Dopamine; Dopamine Receptor; Dorsal; Dose; Down-Regulation; Exhibits; Female; GPR37 receptor; GTP-Binding Proteins; Goals; In Vitro; Incentives; Individual; Individual Differences; Injection of therapeutic agent; Investigation; Kinetics; Measures; Methods; Microdialysis; Mining; Modeling; Motivation; Motor Activity; Nucleus Accumbens; Pharmaceutical Preparations; Phenotype; Predictive Value; Psychological reinforcement; Public Health; Quantitative Autoradiography; Regulation; Reinforcement Schedule; Request for Applications; Rewards; Self Administration; Self-Administered; Signal Transduction; Sprague-Dawley Rats; Technology; Time; Up-Regulation; addiction; base; dopamine system; dopamine transporter; extracellular; human GPRC5C protein; in vivo; insight; male; novel; preference; prevent; radioligand; research study; response; stimulant abuse; trafficking; uptake

DESCRIPTION (provided by applicant): This application requests renewal of a NIDA-sponsored MERIT Award as a R01. The overall goal is to under- stand why individuals differ in cocaine-induced activation and, specifically, i) how the dopamine (DA) trans- porter (DAT) contributes to this differential responsiveness and ii) how this individual variability is predictive of cocaine abuse liability. Adult outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their differential open-field locomotor activity following a low dose cocaine injection. These initial differences in cocaine activation are explained, in part, by how effectively cocaine inhibits the DAT in dorsal striatum (dSTR) and nucleus accumbens (NAc). This classification also predicts repeated cocaine-induced behaviors associated with reward and reinforcement, in that LCRs, more than HCRs, exhibit locomotor sensitization, conditioned place preference and motivation to self- administer cocaine. Differential LCR/HCR DAT inhibition would be expected to result in differences in extra- cellular DA levels and DA receptor (R) stimulation. Aim 1 will use i) in vivo microdialysis to define the overall relationship between endogenous extracellular DA in dSTR and NAc core and acute and repeated cocaine- induced locomotor activation in LCRs and HCRs and ii) new state-of-the-art in vivo electrochemical recording technology to assess real-time changes in cocaine-induced endogenous extracellular DA levels in dSTR and subregions of NAc (core and shell) in freely-behaving LCRs and HCRs. Aim 2 will explore potential differences between LCRs and HCRs in cocaine-induced i) rapid DAT regulation (trafficking) in dSTR and NAc and ii) longer-term DAT and DA R regulation that could help to explain the behavioral differences. These experiments will measure open-field activity, cell surface DAT levels, [3H]DA uptake kinetics, and levels of the orphan G- protein-coupled receptor GPR37. Quantitative autoradiographic analysis of in vitro radioligand binding will be used to assess regulation of DATs, D1Rs, D2Rs and agonist-stimulated G-protein coupling. Aim 3 will deter- mine how LCR/HCR classification predicts addiction-related effects of cocaine by measuring i) sensitization during acquisition of cocaine self-administration and cocaine pre-exposure, ii) sensitization to motivational effects of cocaine measured under a progressive ratio schedule of reinforcement, and iii) incentive sensiti- zation in the context of cue-elicited reinstatement of responding for cocaine and responding under a second- order schedule of reinforcement. Concurrent in vivo electrochemical recording will be used to address particular questions in the self-administration experiments. Together, the results will provide novel insights as to why initial insensitivity to cocaine locomotor activation is associated with the more "addiction prone" pheno- type, how both rapid and longer-term DAT adaptations and their consequences contribute to this individual variability, and how sensitization impacts cocaine self-administration. Understanding the biological bases for individual differences in cocaine abuse/addiction is of fundamental importance for treating this disease. Individuals vary markedly in their vulnerability to cocaine abuse and addiction. This project will use an animal model to explore how individual differences in normal brain chemistry can contribute to variability in cocaine-induced activation and addiction-like behaviors. Understanding the biological bases for individual differences in cocaine abuse/addiction is of fundamental importance for developing new ways to treat, and ultimately prevent, this devastating brain disease and public health problem.

描述（由申请人提供）：本申请要求将 NIDA 赞助的 MERIT 奖续期为 R01。总体目标是了解为什么个体在可卡因诱导的激活方面存在差异，特别是，i）多巴胺（DA）转运蛋白（DAT）如何促成这种不同的反应性，以及ii）这种个体差异如何预测可卡因滥用责任。成年远交雄性 Sprague-Dawley 大鼠可根据低剂量可卡因注射后不同的开放场运动活动分为低可卡因反应者或高可卡因反应者（分别为 LCR 或 HCR）。可卡因激活的这些最初差异部分可以通过可卡因如何有效地抑制背侧纹状体 (dSTR) 和伏隔核 (NAc) 中的 DAT 来解释。这种分类还预测了与奖励和强化相关的重复可卡因诱导行为，因为 LCR 比 HCR 更表现出运动敏化、条件性位置偏好和自我服用可卡因的动机。差异性 LCR/HCR DAT 抑制预计会导致细胞外 DA 水平和 DA 受体 (R) 刺激的差异。目标 1 将使用 i) 体内微透析来定义 dSTR 和 NAc 核心中的内源性细胞外 DA 与 LCR 和 HCR 中急性和重复的可卡因诱导的运动激活之间的总体关系，以及 ii) 最先进的体内电化学记录技术可评估自由行为时 dSTR 和 NAc 子区域（核心和外壳）中可卡因诱导的内源性细胞外 DA 水平的实时变化LCR 和 HCR。目标 2 将探讨 LCR 和 HCR 在可卡因诱导的 i）dSTR 和 NAc 中的快速 DAT 调节（贩运）和 ii）长期 DAT 和 DA R 调节方面的潜在差异，这有助于解释行为差异。这些实验将测量旷场活性、细胞表面 DAT 水平、[3H]DA 摄取动力学以及孤儿 G 蛋白偶联受体 GPR37 的水平。体外放射性配体结合的定量放射自显影分析将用于评估 DAT、D1R、D2R 和激动剂刺激的 G 蛋白偶联的调节。目标 3 将确定 LCR/HCR 分类如何通过测量 i）在获得可卡因自我给药和可卡因预暴露过程中的敏化，ii）在渐进比例表下测量的对可卡因激励作用的敏化来预测可卡因的成瘾相关效应。的强化，以及 iii) 在提示引发的恢复可卡因响应和根据二阶时间表响应的背景下的激励敏化加固。并行体内电化学记录将用于解决自我给药实验中的特定问题。总之，这些结果将提供新的见解，解释为什么最初对可卡因运动激活不敏感与更“容易成瘾”的表型相关，快速和长期的 DAT 适应及其后果如何导致这种个体差异，以及如何致敏影响可卡因的自我给药。了解可卡因滥用/成瘾个体差异的生物学基础对于治疗这种疾病至关重要。个体对可卡因滥用和成瘾的脆弱性存在显着差异。该项目将使用动物模型来探索正常大脑化学物质的个体差异如何导致可卡因诱导的激活和成瘾样行为的变异性。了解可卡因滥用/成瘾个体差异的生物学基础对于开发治疗并最终预防这种毁灭性脑部疾病和公共卫生问题的新方法至关重要。