Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates

纹状体多巴胺释放的烟碱乙酰胆碱受体差异调节是药物获取率个体差异的机制

• 批准号: 10553611
• 负责人: Amy Claire Leach
• 金额: $ 4.77万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-02 至 2024-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553611
• 关键词: Acetylcholine; Affect; American; Animals; Automobile Driving; Axon; Behavior; Behavioral; Biosensor; Brain; Cocaine; Corpus striatum structure; Cost of Illness; Cues; Data; Development; Disease; Dopamine; Drug Experimentation; Drug Utilization; Drug usage; Effectiveness; Environment; Esthesia; Exhibits; Exposure to; Fiber; Frequencies; Genetic Engineering; Goals; Human; Individual; Individual Differences; Injections; Intake; Interneurons; Measures; Mediating; Modeling; Motivation; Neurobiology; Nicotinic Receptors; Nucleus Accumbens; Pharmaceutical Preparations; Phase; Phenotype; Photometry; Prevention; Prevention strategy; Rattus; Receptor Activation; Recreation; Research; Rewards; Risk; Rodent; Rodent Model; Role; Self Administration; Signal Transduction; Slice; Substance Use Disorder; Substance abuse problem; System; Testing; Time; Translating; United States; Variant; Vulnerable Populations; Work; cholinergic; cocaine self-administration; cost; desensitization; dopamine transporter; dopaminergic neuron; drug abuse vulnerability; drug of abuse; drug reward; drug use vulnerability; effective therapy; experience; extracellular; in vivo; in vivo monitoring; individualized medicine; mesolimbic system; neurobiological mechanism; neurochemistry; novel; optogenetics; personalized approach; prevent; resilience; response; trait; treatment strategy; uptake

Project Summary In 2019, an estimated 20.4 million Americans suffered from a substance use disorder (SUD) - a disease that costs the United States over $740 billion annually. The ability to better identify both behavioral and neurobiological markers of increased risk of developing SUD following initial drug use provides a significant opportunity to help prevent the development of SUD in vulnerable populations. Forming a more coherent understanding of the mechanisms that drive differences in vulnerability will also enable the advancement of more effective treatments for individuals already suffering from SUD. While some behavioral traits, such as sensation seeking, are predictive of increased vulnerability, the neurobiological mechanisms underlying these vulnerability-associated traits remain unclear. Sensation seeking can be modeled in rodents by examining locomotor response to a novel environment. This model has shown that rodents exhibiting higher locomotor response acquire self-administration (SA) of drugs more rapidly and stably compared to low responders. Multiple studies have found correlations between locomotor response to a novel environment and mesolimbic dopamine (DA) signaling, which is integral to processing both natural and drug rewards and reward-associated cues. For example, rats with higher novelty response have increased extracellular DA levels following systemic cocaine injection compared to rats with lower novelty response. Higher novelty response is also associated with higher DA transporter levels and faster DA uptake. However, the mechanisms that may drive these differential DA responses and acquisition rates are not fully understood. One mechanism underlying these individual differences may be differential driving of DA release by acetylcholine (ACh) through nicotinic acetylcholine receptors (nAChRs). Our lab has demonstrated that desensitization or blockade of nAChRs in the nucleus accumbens (NAc) augments phasic DA signals in brain slices of HRs, but not LRs. My central hypothesis is that individual differences in vulnerability to rapidly developing high levels of cocaine intake after first experience are driven, in part, by differential modulation of NAc DA signaling by ACh acting at nAChRs. The proposed research plan will examine the role of differential nAChR activation in vulnerability to drug use through the following aims: (1) Examination of individual differences in DA response to reward-associated cues and the role of nAChRs during cocaine self-administration and (2) Assessment of how selective modulation of mesolimbic DA and ACh affects cocaine acquisition rate in rats with higher versus lower responses to novelty. Importantly, investigating the mechanisms underlying vulnerability-associated traits allows us to better identify behavioral and neurochemical markers of substance abuse risk in humans and to stimulate development of more individualized and effective treatments for SUD.

项目摘要 2019年，估计有2040万美国人患有药物使用障碍（SUD） - 这种疾病 每年使美国超过7400亿美元。更好地识别行为和 最初使用药物后，神经生物学标志物增加了出现SUD的风险增加，这很重要 有助于防止弱势群体中SUD发展的机会。形成更连贯的 了解驱动脆弱性差异的机制也将使 对已经患有SUD的个体更有效的治疗方法。而某些行为特征，例如 寻求感觉，可预测脆弱性的增加，这些机制的神经生物学机制 脆弱性相关的性状尚不清楚。寻求感觉可以通过检查啮齿动物建模 运动对新环境的反应。该模型表明啮齿动物表现出更高的运动 与低反应者相比，反应更快，稳定地获得了药物的自我管理（SA）。 多项研究发现，运动对新环境的运动响应与中边缘之间的相关性 多巴胺（DA）信号传导，这是处理天然和药物奖励和奖励相关的组成部分 提示。例如，具有较高新颖性反应的大鼠在全身后具有升高的细胞外DA水平 与新颖反应较低的大鼠相比可卡因注射。更高的新颖响应也与 具有较高的DA转运蛋白水平和更快的DA摄取。但是，可能会驱动这些机制 差异DA响应和获取率尚不完全了解。这些基础的一种机制 个体差异可能是乙酰胆碱（ACH）通过烟碱释放DA的差异 乙酰胆碱受体（NACHRS）。我们的实验室表明，脱敏或封锁了NACHRS 伏隔核（NAC）增强了HRS的大脑切片中的阶段DA信号，但不能增强LRS的脑切片。我的中央 假设是个体脆弱性迅速发展高水平可卡因的差异 第一次体验后的摄入量部分是通过ACH对NAC DA信号的差异调制来驱动的 在NACHRS上表现。拟议的研究计划将研究差异NACHR激活在 通过以下目的易受药物使用的脆弱性：（1）检查DA反应中的个体差异 奖励相关的提示和NACHR在可卡因自我管理中的作用以及（2）评估如何 选择性调节中脑脱脂DA和ACH会影响较高与较高大鼠的可卡因采集率 对新颖性的反应较低。重要的是，研究与脆弱性相关性状的基本机制 允许我们更好地识别人类药物滥用风险的行为和神经化学标记 刺激对SUD的更个性化和有效治疗的发展。