Serotonergic changes in the frontal cortex during methamphetamine reinstatement

描述(由申请者提供)：我的总体职业目标是在一所大学工作，在那里我可以在成瘾和复发的潜在神经化学、成瘾的潜在干预措施以及成瘾的行为后果方面追求我的研究兴趣。K99/R00独立之路奖是实现这一目标的重要一步。拟议的奖项将使我能够通过指导、合作、研究和新的研究技能以及拨款撰写，在学术研究领域实现独立的职业生涯。犹他大学可以提供设施和设备、指导和协作研究环境，不仅可以实现K99奖的建议研究，还可以开启我作为独立调查员的职业生涯。犹他大学在甲基苯丙胺(冰毒)毒性领域有许多杰出的研究人员，他们致力于最大限度地发挥我作为研究人员的潜力。我的导师弗莱肯斯坦博士和汉森博士帮助我实现了博士后生涯的目标，即提高我研究与吸毒成瘾相关的神经化学变化的能力。我的导师和指导委员会(Bevins&Wilkins博士)以及顾问(Yamamoto博士、LaLumiere博士、Keefe&Wilcox博士)提供的支持将使我能够通过学习光遗传学和放射自显影来扩展我的研究技术，提高我的赠款撰写和实验室管理技能，并增强我教育和指导后代的能力。这项拟议的研究将使我能够通过研究额叶皮质的神经化学变化在冰毒自我管理和恢复中的作用，扩大我导师关于纹状体冰毒自我管理(SA)的神经化学效应的研究范围。由于在人类冰毒成瘾者中观察到了额叶皮质的变化，并与药物滥用相关的认知缺陷有关，因此更好地了解这些变化对于理解成瘾和复发非常重要。这将由1进行评估。)确定冰毒后额叶皮质中发生的特定的5-羟色胺能变化；研究内侧前额叶皮质兴奋性活动在冰毒恢复过程中的作用；4.研究5-羟色胺和谷氨酸的释放以及5-HT2A受体刺激在冰毒恢复过程中内侧前额叶皮质的作用；研究5-羟色胺能功能的性别差异是否会导致吸食冰毒的性别差异。目前的提议将提供对额叶皮质变化在冰毒复发中的作用的洞察，并允许有针对性地开发潜在的治疗方法。这也将为进一步调查药物滥用中的性别差异奠定基础。除了进行这项重要的研究外，这笔赠款还将使我能够根据拟议研究的结果，向试点数据提交R03拨款，以研究冰毒SA和R01拨款后神经化学变化的行为影响。这项研究建议，除了所描述的指导外，将增强我成为一名成功的独立研究人员调查药物成瘾的潜力。

DESCRIPTION (provided by applicant): My overall career goal is to work in a university setting where I can pursue my research interests in the neurochemistry underlying addiction and relapse, potential interventions for addiction, and the behavioral consequences of addiction. The K99/R00 Pathways to Independence award is an important step in achieving this goal. The proposed award would allow me to achieve an independent career in academic research through mentoring, collaboration, research and new research skills, and grant writing. The University of Utah can provide the facilities and equipment, mentoring, and collaborative research environment to not only achieve the research proposed for the K99 award, but also launch my career as an independent investigator. The University of Utah has many prominent researchers in the field of methamphetamine (METH) toxicity that are committed to maximizing my potential as a researcher. My mentors, Dr. Fleckenstein and Hanson, have been instrumental in helping me achieve my postdoctoral career goal of enhancing my ability to study the neurochemical changes associated with drug addiction. The support provided by my mentors and mentoring committee (Drs. Bevins & Wilkins), and consultants (Drs. Yamamoto, LaLumiere, Keefe & Wilcox) will allow me to expand my research techniques by learning optogenetics and autoradiography, improve my grant writing and laboratory management skills, and enhance my abilities to teach and mentor future generations. The proposed research will allow me to expand beyond the scope of my mentors' research on the neurochemical effects METH self-administration (SA) in the striatum by investigating the role of neurochemical changes in the frontal cortex in METH SA and reinstatement. Since changes in the frontal cortex have been observed in human METH addicts and are implicated in the cognitive deficits associated with drug abuse, better understanding these changes are important for understanding addiction and relapse. This will be assessed by 1.) identifying the specific serotonergic changes that occur in the frontal cortex following METH SA; 2.) investigating the role of excitatory activity in the medial prefrontal cortex during the reinstatement of METH- seeking; 3.) investigating the role of serotonin and glutamate release and 5HT2A receptor stimulation in the medial prefrontal cortex during the reinstatement of METH-seeking; and 4.) investigating if sex differences in serotonergic function contribute to sex differences in METH-seeking. The current proposal will provide insight into the role of changes in the frontal cortex i the relapse of METH addiction and allow for the targeted development of potential therapeutics. It will also set the foundation to further investigate sex differences in drug abuse. In addition t conducting this important research, this grant will help enable me to submit an R03 grant to pilot data of the behavioral effects of the neurochemical changes following METH SA and R01 grant based on the findings of the proposed studies. The research proposed, in addition to the mentoring described, will enhance my potential to become a successful independent researcher investigating drug addiction.