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

项目摘要 在2019年，估计有2040万美国人患有物质使用障碍（SUD）-一种疾病， 每年花费美国超过7400亿美元。能够更好地识别行为和 首次用药后发生SUD风险增加的神经生物学标志物提供了一个显著的 有机会帮助预防弱势群体发生SUD。形成一个更加连贯的 了解导致脆弱性差异的机制也将有助于促进 更有效的治疗已经患有SUD的人。而一些行为特征，如 感觉寻求，是增加脆弱性的预测，这些潜在的神经生物学机制， 与能力相关的特征仍不清楚。感觉寻求可以在啮齿类动物中建模， 对新环境的自发反应该模型表明，表现出较高运动能力的啮齿动物 与低应答者相比，应答者获得药物的自我给药（SA）更快速和稳定。 多项研究发现，对新环境的运动反应与中脑边缘系统之间存在相关性。 多巴胺（DA）信号，这是必不可少的处理自然和药物的奖励和奖励相关的 线索例如，具有较高新奇反应的大鼠在全身性刺激后细胞外DA水平增加， 可卡因注射相比，大鼠具有较低的新奇反应。更高的新奇反应也与 多巴胺转运蛋白水平更高多巴胺吸收更快然而，可能驱动这些的机制 不同的DA反应和获得率还没有完全了解。其中一个机制是 个体差异可能是由乙酰胆碱（ACh）通过烟碱释放DA的差异驱动。 乙酰胆碱受体（nAChRs）。我们的实验室已经证明，nAChR的脱敏或阻断可以在 延髓核（NAc）增强HR脑片中的DA时相信号，但不增强LR。我的中枢 一种假设是，个体对快速发展的高水平可卡因的脆弱性存在差异， 第一次经验后摄入部分是由ACh对NAc DA信号传导的差异调节驱动的， 作用于nAChRs。拟议的研究计划将研究差异nAChR激活在以下方面的作用： （1）通过以下目的来评估对药物使用的脆弱性： 奖励相关的线索和nAChRs在可卡因自我管理过程中的作用，以及（2）评估如何 选择性调节中脑边缘DA和ACh影响大鼠可卡因获得率， 对新奇事物的反应较低。重要的是，调查潜在的机制与能力相关的性状， 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志物， 刺激开发更加个性化和有效的SUD治疗方法。

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.