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.

项目概要 2019 年，估计有 2040 万美国人患有药物滥用障碍 (SUD)，这种疾病会导致 美国每年花费超过 7400 亿美元。更好地识别行为和行为的能力 初次使用药物后发生 SUD 风险增加的神经生物学标志物提供了重要的证据 帮助预防弱势群体发展 SUD 的机会。形成更加连贯的 了解造成脆弱性差异的机制也将有助于推动 对已经患有 SUD 的个体进行更有效的治疗。虽然有些行为特征，例如 感觉寻求，预示着脆弱性的增加，这些背后的神经生物学机制 与脆弱性相关的特征仍不清楚。可以通过检查来模拟啮齿类动物的感觉寻求 对新环境的运动反应。该模型表明，啮齿动物表现出更高的运动能力 与低反应者相比，反应者能够更快、更稳定地获得药物自我给药（SA）。 多项研究发现对新环境的运动反应与中脑边缘之间存在相关性 多巴胺 (DA) 信号传导，对于处理自然奖励和药物奖励以及奖励相关的过程至关重要 提示。例如，具有较高新奇反应的大鼠在全身给药后细胞外 DA 水平增加。 与注射可卡因的大鼠相比，新奇反应较低。更高的新颖性反应也与之相关 具有更高的 DA 转运蛋白水平和更快的 DA 摄取。然而，可能驱动这些的机制 差异 DA 反应和采集率尚未完全了解。这些背后的一种机制 个体差异可能是乙酰胆碱 (ACh) 通过烟碱对 DA 释放的不同驱动 乙酰胆碱受体（nAChR）。我们的实验室已经证明，nAChR 的脱敏或阻断 伏隔核 (NAc) 会增强 HR 脑切片中的相位 DA 信号，但不会增强 LR 脑切片中的相位 DA 信号。我的中央 假设是个体对快速发展的高浓度可卡因的脆弱性存在差异 第一次经历后的摄入量部分是由 ACh 对 NAc DA 信号的差分调制驱动的 作用于 nAChR。拟议的研究计划将研究差异 nAChR 激活在 通过以下目标实现对吸毒的脆弱性：(1) 检查 DA 对吸毒反应的个体差异 奖励相关线索和 nAChR 在可卡因自我给药过程中的作用以及 (2) 评估如何 中脑边缘 DA 和 ACh 的选择性调节会影响大鼠的可卡因获取率 对新奇事物的反应较低。重要的是，调查与漏洞相关的特征背后的机制 使我们能够更好地识别人类药物滥用风险的行为和神经化学标记，并 刺激针对 SUD 的更个性化和更有效的治疗方法的开发。