Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA

描述（由申请人提供）：本指导研究科学家发展奖（K01）旨在研究甲基苯丙胺自我服用的神经生理学后果，同时为候选人（Michael Beckstead博士）提供行为神经科学方面的培训。Beckstead博士的近期目标包括学习行为技术，包括立体定向手术、脑部位特异性注射、甲基苯丙胺自我给药程序、精神兴奋剂给药模型的实验设计和解释。除了所提出的研究的科学目的之外，该提案的最终目标是培训研究者的行为技术，以及在电生理学方面的既定专业知识，将形成作为独立研究者职业生涯的基础。职业发展计划包括一位知名的行为神经学家（Gregory Mark博士）对行为技术的指导，同时利用国内顶尖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给药、细胞内钙水平和小鼠腹侧被盖区树突多巴胺传递之间的假设关系。甲基苯丙胺诱导突触可塑性和D2多巴胺自身受体亚敏感，但其机制尚不清楚。此外，还没有研究探讨突触可塑性在甲基苯丙胺自我给药中的作用。利用最近发现的工具，包括多巴胺介导的突触电位和多巴胺突触的一种新形式的可塑性，实验将确定多巴胺可塑性是否在甲基苯丙胺自我给药中起作用。相关性：确定自我给药甲基苯丙胺的神经生理后果是确定预防和治疗人类药物滥用干预策略的第一步。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会对药物上瘾，并可能导致治疗方法帮助患者打破成瘾的艰难循环。

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.