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

项目总结/摘要 在美国，药物使用障碍（SUD）和药物过量导致的死亡率已经达到流行病的水平; 然而，行为，药理学和神经生物学决定一个人的脆弱性发展的物质使用 疾病还没有得到很好的理解。各种行为和神经化学表型被认为是易感大鼠 根据以下标准，发展成瘾样表型：（1）难以停止药物使用;（2）高 服用药物的动机;（3）尽管有不良后果，但仍继续服用药物。尽管许多研究 表明一部分老鼠在长期或不情愿地接触可卡因后会产生这些成瘾样行为 自我管理，重要的是要注意，这个概念框架不包含SUD的核心特征， 高水平的药物摄入失调事实上，当大鼠在短期接触条件下自我施用可卡因时， 摄入量往往得到很好的调节，受试者之间的差异很小。相反，当老鼠被允许自我管理 3，4-亚甲二氧基吡咯戊酮（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5-羟色胺转运蛋白），其中约40%（即，“高反应者”） 产生异常高水平的药物摄入（即，比“低应答者”高约3倍）。早期的研究还表明， “高应答者”在发出药物不可用信号的期间表现出高应答率（例如，寻求毒品），赚取 在累进比率下的更多输注（例如，增加动机），并且对足部电击的惩罚不太敏感 (e.g.,尽管有不良后果，仍继续服用药物）。 除了重现经常报告的长期或不稳定获得可卡因的成瘾样表型外， 因为MDPV自我给药也可靠地建立了高水平的药物服用失调，这是MDPV的核心特征， 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的因素， 发展成SUD的脆弱性。例如，越来越多的证据表明，高水平的药物摄入和成瘾 药物服用的模式可导致多巴胺的更强的神经可塑性变化（例如，多巴胺D3增加 受体）和血清素（例如，已知在介导炎症反应中起关键作用的 药物的强化作用。该研究项目旨在利用大鼠IV自我给药，以1）确定 短期、长期和间歇性接触MDPV对男性成瘾样表型的影响， 雌性大鼠;和2）确定多巴胺D3和多巴胺2C受体（表达）之间的关系 成瘾样表型的发展或严重程度随药物（MDPV或 可卡因）、访问条件（短访问、长访问、不安全访问）和/或性别。总之，这些研究将提供必要的 关于多巴胺D3和多巴胺2C受体的因果作用以及 吸毒行为失调

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.