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

项目摘要 2019年，估计有2040万美国人患有物质使用障碍(SUD)--一种 每年给美国造成的损失超过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记物提供了显著的 有机会帮助预防弱势人群中的严重急性呼吸窘迫综合征。形成更连贯的 了解导致脆弱性差异的机制也将有助于推动 对已经患有SUD的个人进行更有效的治疗。而一些行为特征，如 感觉寻求，预示着脆弱性的增加，其背后的神经生物学机制 与脆弱性相关的特征仍不清楚。感觉寻求可以在啮齿类动物身上通过检查 对新环境的运动反应。这个模型已经表明，啮齿动物表现出更强的运动性 与低反应者相比，响应者更快、更稳定地获得药物的自我给药(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，这是处理自然和药物奖励以及与奖励相关的不可或缺的信号 暗示。例如，具有较高新颖性反应的大鼠在全身反应后细胞外DA水平增加。 注射可卡因与大鼠相比具有较低的新颖性反应。更高的新颖性反应也与 具有更高的DA转运体水平和更快的DA摄取。然而，可能推动这些变化的机制 不同的DA反应和采集率还没有完全理解。这些问题背后的一个机制 个体差异可能是乙酰胆碱(ACh)通过烟碱释放DA的差异驱动因素 乙酰胆碱受体(NAChRs)。我们的实验室已经证明，nAChRs的脱敏或阻断在 伏隔核(NAC)增强HR脑片中的时相DA信号，但不增强LR。我的中央 假设是个体对快速发展的高水平可卡因的易感性存在差异 第一次体验后的摄入量，部分是由ACh对NAC DA信号的差异调制驱动的 在nAChRs工作。拟议的研究计划将检查差异nAChR激活在 通过以下目标易受药物使用的影响：(1)审查个人对药物滥用反应的差异 奖赏相关线索和nAChRs在可卡因自我给药中的作用和(2)如何评估 选择性调节中脑边缘DA和ACh对大鼠可卡因获得率的影响 对新奇事物的反应较低。重要的是，研究与脆弱性相关的特征背后的机制 使我们能够更好地识别人类滥用药物风险的行为和神经化学标记物，并 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.