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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要美国的物质使用障碍（SUD）率和药物过量死亡率已达到流行病水平；然而，行为、药理学和神经生物学因素决定了一个人是否容易形成药物滥用多种行为和神经化学表型被认为会诱发大鼠。根据以下标准发展成瘾样表型：(1) 难以停止吸毒；(2) 高度戒毒；服用药物的动机；以及，(3) 尽管有许多研究结果，但仍继续服用药物。表明一部分老鼠在长期或间歇性接触可卡因后会出现这些成瘾样行为自我管理，值得注意的是，这个概念框架并未纳入 SUD 的核心特征，事实上，当老鼠在短期接触条件下自行服用可卡因时，药物摄入量会出现严重失调。当允许大鼠自我给药时，摄入量趋势得到良好调节，受试者间的差异很小。 3,4-亚甲基二氧基吡咯戊酮（MDPV；一种合成卡西酮，选择性抑制多巴胺和去甲肾上腺素（相对于血清素转运蛋白）在短距离条件下，约 40% 的人（即“高反应者”）早期研究还表明，药物摄入量异常高（即比“低反应者”多约 3 倍）。 “高反应者”在药物不可用期间（例如寻求药物）表现出高反应率，赚取在渐进比例下进行更多输注（例如，增加动力），并且对足部电击惩罚的敏感性较低（例如，尽管有不良后果，仍继续吸毒）。除了重现长期或间歇性获取可卡因时经常报道的成瘾样表型之外，因为 MDPV 自我给药也可靠地建立了高水平的药物滥用失调，这是成瘾，我们相信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成瘾的因素例如，越来越多的证据表明，高水平的药物摄入和类似成瘾的风险。吸毒模式可能会导致多巴胺的神经塑性变化（例如，多巴胺 D3 增加）受体）和血清素（例如，血清素2C受体减少）系统已知在介导中发挥关键作用该研究项目旨在利用大鼠静脉注射的自我给药来 1) 确定药物的增强作用。短期、长期和间歇性使用 MDPV 对男性和女性成瘾样表型发展的影响雌性大鼠；2) 确定多巴胺 D3 和血清素 2C 受体（表达和功能），成瘾样表型的发展或严重程度随药物（MDPV 或这些研究将共同提供重要的信息。有关多巴胺 D3 和 5-羟色胺 2C 受体的因果作用以及以下疾病的发展或表现的信息吸毒行为失调。