The Effects of Nicotine on a Translational Model of Working Memory

描述（由申请人提供）：拟议工作的广泛目标是调查认知增强作为吸烟升级和维持的动机的潜力，与国家药物滥用研究所（NIDA）战略计划的目标之一一致。关于尼古丁对非吸烟者认知能力影响的研究表明，尼古丁通常会增强注意力，但不会增强工作记忆。相比之下，尼古丁给药已显示在非人类动物中产生工作记忆的稳健增强。为了解决这一差异，本研究将研究尼古丁剂量（2 mg、4 mg尼古丁口香糖和安慰剂）对非吸烟者完成动物工作记忆程序（气味跨度任务，OST）的影响。尼古丁已被证明可以增强啮齿动物的OST表现，本研究将确定这种效果是否适用于人类。除了完成OST外，参与者还将完成由临床和实验任务组成的认知电池，以评估工作记忆和注意力。这将允许OST性能与其他常用的人类认知测量进行直接比较。理解OST表现如何与人类认知处理相关，将使研究人员能够更有力地推断在大鼠中发现的OST表现的神经生物学决定因素如何与人类认知处理相关。此外，描述尼古丁增强的人类认知过程是确定认知增强是否介导吸烟行为开始后的升级和维持的关键步骤。作为一个整体，该项目将开发一个转化模型，用于评估尼古丁依赖的新型药理学和行为干预措施的疗效。这是一个重要的考虑因素，因为烟草制品的使用是全世界可预防死亡的主要原因，每年造成500多万人死亡。拟议的研究建立在申请人先前研究药物对动物OST表现的影响的基础上，符合申请人建立物质滥用和认知转化模型的长期目标。为此，申请人还提出了一项旨在培养转化行为神经科学能力的培训计划。这包括在大卫戴蒙德博士的实验室进行监督培训，研究啮齿动物学习/记忆和药物作用的神经生物学决定因素。此外，申请人还将与药物滥用预防模型（Eric Donny博士）、人类认知的神经生物学（Andrew Yonelinas博士）和尼古丁的认知影响（Stephen Heishman博士）领域的专家进行现场实验室咨询。申请人还将完成药理学，研究伦理学，语法和统计方法的课程，并将完成关于使用认知评估的监督神经心理学实习。最后，申请人将获得来自多元化赞助团队的指导，该团队将解决职业发展的关键方面，并在研究成果的展示和出版方面进行合作。

DESCRIPTION (provided by applicant): The broad goal of the proposed work is to investigate the potential of cognitive enhancement as a motivator for the escalation and maintenance of tobacco smoking, consistent with aim one of the strategic plan of the National Institute on Drug Abuse (NIDA). Research concerning the effects of nicotine on cognition in non-smokers has demonstrated that nicotine generally enhances attention but not working memory. In contrast, nicotine administration has been shown to produce robust enhancements in working memory in non-human animals. To address this disparity, the present study will investigate the effects of nicotine dose (2mg, 4mg nicotine gum, and placebo) on the performance of non-smokers completing a working memory procedure developed in animals (the odor span task, OST). Nicotine has been demonstrated to enhance OST performance in rodents and the present study will determine whether this effect generalizes to human performance. In addition to completing the OST, participants will complete a cognitive battery comprised of clinical and experimental tasks which assess working memory and attention. This will allow for a direct comparison of OST performance to other commonly used measures of human cognition. An understanding of how OST performance relates to cognitive processing as it is defined in humans will allow researchers to draw stronger inferences about how the neurobiological determinants of OST performance discovered in rats relate to human cognitive processing. Moreover, delineating the cognitive processes enhanced by nicotine in humans is a critical step in determining whether enhancement of cognition mediates the escalation and maintenance of smoking behavior after initiation. As a whole, the project will develop a translational model for assessing the efficacy o novel pharmacological and behavioral interventions for nicotine dependence. This is an important consideration given that the use of tobacco products is the leading cause of preventable death worldwide and causes over 5 million deaths per year. The proposed study builds upon the applicant's prior research investigating the effects of drugs on OST performance in animals, and fits within the applicant's long-term objective of producing translational models of substance abuse and cognition. Towards this end, the applicant has also proposed a training plan directed at building competency in translational behavioral neuroscience. This includes supervised training in the lab of Dr. David Diamond in methods for investigating the neurobiological determinants of learning/memory and drug effects in rodents. Additionally, the applicant will engage in on-site laboratory consultations with experts in the areas of translationa models of substance abuse (Dr. Eric Donny), the neurobiology of human cognition (Dr. Andrew Yonelinas) and the cognitive effects of nicotine (Dr. Stephen Heishman). The applicant will also complete coursework in pharmacology, research ethics, grantsmanship, and statistical methods, and will complete a supervised neuropsychology practicum on the use of cognitive assessments. Lastly, the applicant will receive mentorship from a diverse sponsorship team who will address critical aspects of career development and collaborate in the presentation and publication of research findings.