Role of striatal pathways in learning with nicotine stimulus

项目摘要 与可卡因或甲基苯丙胺等其他兴奋剂相比，尼古丁是一种温和的兴奋剂。的确， 临床前自我给药研究中对尼古丁的反应仅略高于对尼古丁的反应 生理盐水，通常对尼古丁剂量的变化不敏感。尼古丁是一种微弱的主要增强剂，这一事实是 这与它是被滥用最多的物质之一的事实有些不符。尼古丁的广泛使用 产品被归因于尼古丁奖励的复杂性质，涉及遗传，生物， 学习和药理学方面，仅举几例。尼古丁的药理作用可作为 一种可与环境中其他强化事件相关联的内感刺激(CS) (美国；例如，食物、酒精、工作休息、同伴互动)，并通过联合过程可以获得更多 可能导致尼古丁长期使用的特性。先前的研究表明，背内侧 尾壳核(DmCPu)在尼古丁刺激下参与学习。我们也知道， 前侧(a-)和后侧(p-)dmCPU不同程度地参与学习的不同阶段。既是-也是 P-dmCPU接受前额叶皮质的兴奋性输入，并向黑质提供抑制性输出 网状部/苍白球内侧复合体(SNR/GPI)通过直接(d1驱动)或间接(d2驱动) 小路。我们不知道的是，这些传入和传出dmcpu的连接如何有助于 在尼古丁刺激下学习。因此，此应用程序的总体目标是研究 对dmcpu的传入和传出联系参与尼古丁刺激学习的通路-- 特殊的化学发生方法。这项申请中提出的实验将是第一个确定 与任何药物状态有关的联想学习的即时回路。更好地理解 尼古丁刺激与联想学习有关的神经生物学机制可能会为 研究尼古丁依赖的神经基础的临床前或临床研究。

Project Summary Nicotine is a mild stimulant when compared to other stimulants like cocaine or methamphetamine. Indeed, responding for nicotine in preclinical self-administration studies is only marginally higher than responding for saline and is often insensitive to variation in nicotine dose. The fact that nicotine is a weak primary reinforcer is somewhat incongruent with the fact that it is one of the most abused substances. The wide use of nicotine products has been attributed to the complex nature of nicotine reward that involves genetic, biological, learning, and pharmacological dimensions, to name a few. The pharmacological effects of nicotine can serve as an interoceptive stimulus (CS) that can come into association with other reinforcing events in the environment (US; e.g., food, alcohol, work breaks, peer interaction) and through associative processes can acquire additional properties that likely contribute to perpetuation of nicotine use. Previous studies show that dorsomedial caudate-putamen (dmCPu) is functionally involved in learning with nicotine stimulus. We also know that anterior (a-) and posterior (p-) dmCPu are differentially involved in various stages of that learning. Both a- and p-dmCPu receive excitatory input from the prefrontal cortex and provide inhibitory output to substantia nigra pars reticulata/globus pallidus internus complex (SNr/GPi) via direct (D1 driven) or indirect (D2 driven) pathways. What we do not know is how these afferent and efferent connections to dmCPu contribute to learning with nicotine stimulus. Thus, the overall objective of this application is to investigate the functional involvement of afferent and efferent connections to dmCPu in learning with nicotine stimulus using pathways- specific chemogenetic approach. The experiments proposed in this application will be the first to identify immediate circuitry involved in associative learning with any drug state. A better understanding of neurobiological mechanisms involved in associative learning with nicotine stimulus may open new avenues in preclinical or clinical research investigating the neural underpinnings of nicotine dependence.