Role of dopamine D3 and serotonin 2C receptors in the development of an addiction-like phenotype in rats

多巴胺 D3 和血清素 2C 受体在大鼠成瘾样表型发展中的作用

• 批准号: 10057748
• 负责人: Michelle Riane Doyle
• 金额: $ 5.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057748
• 关键词: Agonist; Behavior; Behavioral; Binding; Cessation of life; Cocaine; Development; Dopamine; Drug usage; Effectiveness; Epidemic; Exhibits; FDA approved; Female; Future; Individual Differences; Infusion procedures; Intake; Measures; Mediating; Modeling; Motivation; Neurobiology; Neuronal Plasticity; Norepinephrine; Overdose; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Public Health; Punishment; Quantitative Autoradiography; Rattus; Recording of previous events; Reporting; Research; Research Project Grants; Role; Self Administration; Serotonin; Serotonin Receptor 5-HT2C; Severities; Shock; Signal Transduction; Substance Use Disorder; System; Testing; Time; United States; Yawning; addiction; adverse outcome; base; bath salts; behavioral pharmacology; dopamine D3 receptor; foot; male; neurochemistry; novel; pramipexol; receptor; receptor density; receptor expression; receptor function; response; serotonin transporter; sex; stimulant use disorder; uptake

PROJECT SUMMARY/ABSTRACT Rates of substance use disorders (SUDs) and deaths by drug overdose in the United States have reached epidemic levels; yet, the behavioral, pharmacological, and neurobiological determinants of one’s vulnerability to develop a substance use disorder are not well understood. A variety of behavioral and neurochemical phenotypes are thought to predispose rats to developing addiction-like phenotypes based on the following criteria: (1) difficulty stopping drug use; (2) high motivation to take the drug; and, (3) continued drug-taking despite adverse consequences. Though a number of studies suggest that a subset of rats will develop these addiction-like behaviors following long- or intermittent-access to cocaine self-administration, it is important to note that this conceptual framework does not incorporate a core feature of SUDs, high levels of dysregulated drug intake. Indeed, when rats self-administer cocaine under short-access conditions, drug intake tends to be well-regulated, with little inter-subject variability. Conversely, when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV; a synthetic cathinone that selectively inhibits uptake at dopamine and norepinephrine relative to serotonin transporters) under short-access conditions, ~40% of them (i.e., “high-responders”) develop unusually high levels of drug intake (i.e., ~3-fold greater than “low-responders”). Early studies also suggest that “high-responders” exhibit high rates of responding during periods of signaled drug unavailability (e.g., drug-seeking), earn more infusions under a progressive ratio (e.g., increased motivation), and are less sensitivity to punishment by foot shock (e.g., continue drug-taking despite adverse consequences). In addition to recapitulating the addiction-like phenotype often reported with long- or intermittent-access to cocaine, because MDPV self-administration also reliably establishes high levels of dysregulated drug-taking, a core feature of addiction, we believe that our model provides a novel and robust approach to study the factors that impact one’s vulnerability to develop a SUD. For instance, mounting evidence suggests that high levels of drug intake and addiction-like patterns of drug taking can result in more robust neuroplastic changes in dopamine (e.g., increases in dopamine D3 receptors) and serotonin (e.g., decreases in serotonin2C receptors) systems that are known to play key roles in mediating the reinforcing effects of drugs. The research project aims to utilize IV self-administration in rats to 1) determine the impact of short-, long-, and intermittent access to MDPV on the development of addiction-like phenotypes in male and female rats; and 2) determine whether the relationship between the dopamine D3 and serotonin2C receptors (expression and function) and the development or severity of addiction-like phenotypes varies as a function of drug (MDPV or cocaine), access condition (short-, long-, intermittent-access), and/or sex. Together, these studies will provide essential information about the causal role of dopamine D3 and serotonin2C receptors and the development or manifestation of dysregulated drug-taking behavior.

项目摘要/摘要 美国药物使用障碍（SUD）和药物过量的死亡率已达到流行水平； 然而，行为，药物和神经生物学决定者的脆弱性开发底物使用 疾病不太了解。各种行为和神经化学表型被认为易感大鼠 根据以下标准开发成瘾样表型：（1）难以停止使用药物； （2）高 服用药物的动机； （3）继续吸毒目的地不利后果。虽然许多研究 表明一部分大鼠会在可卡因长期或间歇性访问后发展这些成瘾的行为 自我管理，重要的是要注意，这个概念框架并不包含Suds的核心特征， 高水平的药物摄入量。实际上，当大鼠在短期呼吸条件下自我管理可卡因时，药物 摄入量往往受到良好的调节，几乎没有受试者间的可变性。相反，当允许大鼠自我管理时 3,4-甲基二甲基甲甲甲甲基酮（MDPV；一种合成的天酮，有选择地抑制多巴胺的摄取和 在短呼吸条件下，去甲肾上腺素相对于5-羟色胺转运蛋白，其中约40％（即“高响应者”） 产生很少水平的药物摄入量（即比“低响应者”大约3倍）。早期研究还表明 “高响应者”在签署的药物不可用时表现出很高的响应率（例如，寻求毒品） 在渐进式比率下的更多输注（例如，动机的增加），对脚部的惩罚较少敏感 （例如，持续吸毒目的地广告后果）。 除了概括类似成瘾的表型外，还经常报告可卡因的长期或间歇性访问 因为MDPV自我给药也可靠地确立了高水平的药物吸毒，这是 成瘾，我们认为我们的模型提供了一种新颖而强大的方法来研究影响一个人的因素 发展SUD的脆弱性。例如，越来越多的证据表明高水平的药物摄入量和成瘾状 服用药物的模式会导致多巴胺的更强大的神经塑性变化（例如，多巴胺D3的增加 受体）和5-羟色胺（例如，血清素2c受体的降低）系统已知在介导中起关键作用 药物的增强作用。该研究项目旨在利用大鼠的静脉自我给药至1）确定 短期，长和间歇访问MDPV对男性和类似成瘾表型发展的影响 雌鼠； 2）确定多巴胺D3和5-羟色胺2C受体之间的关系（表达 和功能），成瘾表型的发展或严重程度随着药物的函数而变化（MDPV或 可卡因），访问条件（短，长，间歇性）和/或性别。这些研究将共同​​提供必不可少的 有关多巴胺D3和5-羟色胺2C受体的因果作用的信息以及发育或表现 吸毒行为失调。