Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA

描述（由申请人提供）：该指导研究科学家发展奖（K01）建议调查甲基苯丙胺自我管理的神经生理学后果，同时为候选人（Michael Beckstead博士）提供行为神经科学培训。Beckstead博士的近期目标包括学习行为技术，包括立体定位手术，大脑部位特异性注射，甲基苯丙胺自我管理程序，以及精神兴奋剂管理模型的实验设计和解释。除了所提出的研究的科学目的外，该提案的最终目标是培训研究人员的行为技术，沿着已建立的电生理学专业知识，将成为独立研究人员职业生涯的基础。职业发展计划包括从一位成熟的行为神经科学家（格雷戈里·马克博士）那里获得行为技术方面的指导，同时利用该国顶级行为部门之一的资源和专业知识。实验程序将探讨甲基苯丙胺自我管理，细胞内钙离子水平，和树突多巴胺传输在小鼠腹侧被盖区之间的假设关系。甲基苯丙胺诱导突触可塑性和D2多巴胺自身受体亚敏感性，但所涉及的机制知之甚少。此外，还没有研究探讨突触可塑性对甲基苯丙胺自我管理的作用。使用最近发现的工具，包括多巴胺介导的突触电位和多巴胺突触可塑性的新形式，实验将确定多巴胺可塑性是否在甲基苯丙胺自我给药中发挥作用。相关性：确定甲基苯丙胺自我管理的神经生理后果是确定干预策略，以防止和治疗人类药物滥用的第一步。更好地了解与药物使用和管理相关的神经适应可能有助于解释为什么一些甲基苯丙胺使用者对药物成瘾，并可能导致治疗，以帮助患者打破成瘾的困难循环。

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award (K01) proposes to investigate the neurophysiological consequences of methamphetamine self-administration while providing the candidate (Dr. Michael Beckstead) with training in behavioral neuroscience. Dr. Beckstead's immediate goals include learning behavioral techniques including stereotaxic surgeries, brain site-specific injections, methamphetamine self administration procedures, and experimental design and interpretation of models of psychostimulant administration. In addition to the scientific aims of the studies presented, the ultimate goal of the proposal is to train the investigator with behavioral techniques that, along with established expertise in electrophysiology, will form the basis for a career as an independent investigator. The career development plan involves mentorship in behavioral techniques from an established behavioral neuroscientist (Dr. Gregory Mark) while utilizing the resources and expertise of one of the top behavioral departments in the country. The experimental procedures will investigate the hypothesized relationship between methamphetamine self-administration, intracellular calcium levels, and dendrodendritic dopamine transmission in the ventral tegmental area of mice. Methamphetamine induces synaptic plasticity and D2 dopamine autoreceptor subsensitivity, but the mechanisms involved are poorly understood. Furthermore, no study has investigated the role of synaptic plasticity on methamphetamine self-administration. Using recently discovered tools including a synaptic potential mediated by dopamine and a novel form of plasticity at dopamine synapses, the experiments will determine if dopamine plasticity plays a role in methamphetamine self-administration. Relevance: Determining the neurophysiological consequences of methamphetamine self-administration is the first step in identifying intervention strategies to prevent and treat human drug abuse. A better understanding of the neural adaptations associated with drug use and administration may help to explain why some methamphetamine users become addicted to the drug, and may lead to treatments to help patients break the difficult cycle of addiction.