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尼古丁的反应仅略高于 生理盐水，并且通常对尼古丁剂量的变化不敏感。事实上，尼古丁是一种弱的主要代谢物， 这与它是滥用最严重的物质之一的事实有些不一致。尼古丁的广泛使用 产品已被归因于尼古丁奖励的复杂性质，涉及遗传，生物， 学习和药理学方面的知识。尼古丁的药理作用可以作为 一种内感受性刺激（CS），可以与环境中的其他强化事件相关联 (US例如，食物，酒精，工作休息，同伴互动），并通过联想过程可以获得额外的 可能导致尼古丁使用永久化的特性。先前的研究表明， 尾壳核（dmCPu）在功能上参与尼古丁刺激的学习。我们也知道 前（a-）和后（p-）dmCPu不同地参与该学习的各个阶段。a侧和 p-dmCPu接受来自前额叶皮层的兴奋性输入，并向黑质提供抑制性输出 通过直接（D1驱动）或间接（D2驱动）的网状部/内侧苍白球复合体（SNr/GPi） 途径。我们不知道的是这些传入和传出连接到dmCPu如何有助于 学习尼古丁刺激。因此，本申请的总体目标是研究功能性 在尼古丁刺激的学习过程中，dmCPu的传入和传出连接的参与- 特异性化学遗传学方法。本申请中提出的实验将首次识别 与任何药物状态关联学习的直接回路。更好地了解 尼古丁刺激下的联想学习的神经生物学机制可能为 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.