Neurobiology of the Cognition Enhancing Actions of Psychostimulants

描述(申请人提供)：精神刺激剂，包括哌醋甲酯(MPH)，是目前最有效的治疗注意力缺陷多动障碍(ADHD)的药物。这些药物改善了ADHD患者依赖前额叶皮质(PFC)的认知/行为过程中的各种缺陷，包括行为抑制/冲动调节、工作记忆和注意力。重要的是，这些行为并不局限于ADHD，在正常的人类和动物中都有很好的记录。尽管这些药物具有临床有效性，但对滥用可能性的担忧引发了对这些药物的广泛使用的担忧，特别是在儿童中。更好地了解精神刺激剂认知增强作用的神经生物学可能有助于发现新的药物治疗方法 用于ADHD和其他与PFC功能障碍相关的疾病。此外，这些信息将增加我们对高等认知过程的神经生物学的理解。在工作记忆的延迟空间交替测试中，系统地给予MPH和所有其他经批准的ADHD药物可以改善大鼠更高的认知功能。最近，申请人证明了PFC内的心理刺激作用，而不是背内侧纹状体，足以改善工作记忆。这项研究的第一个目的是研究PFC内的受体机制，该受体参与了心理刺激剂的认知增强作用。特别是，这些研究将确定PFC内特定的儿茶酚胺受体对于PFC内和全身给药的MPH的认知增强作用的必要性程度。这项拟议研究的第二个目标将确定mph的认知增强作用与额纹状体神经元活动变化的关联程度。这些后一项研究将利用条件强度-一般线性模型来分析参与工作记忆延迟反应任务的动物的药物诱导的额纹状体神经放电的变化。特别是，这一目标将决定在这项任务的延迟间隔期间和之外，认知增强剂量的MPH在多大程度上增加了PFC和背内侧纹状体神经元的经常性激活。这项提议有两个主要的培训目标。首先，它将使APPLANT进一步发展认知增强剂的药理学和神经回路方面的专业知识。其次，它将提供电生理学和统计建模方法方面的培训，以更好地 了解高级认知功能和药物引起的认知功能改变的神经基础。这些研究将极大地帮助申请者成为研究高级认知功能的神经回路/药理学的独立科学家。 公共卫生相关性：注意缺陷多动障碍(ADHD)是一种认知/行为综合征，困扰着3%-8%的人口，并与包括学术、社会和健康相关的多个领域的风险增加有关。虽然精神刺激剂目前是治疗这种疾病的最有效的治疗方法，但滥用的可能性引起了人们对这些药物的广泛使用的担忧，特别是在儿童中。本研究旨在增加我们对精神刺激剂认知增强作用的神经生物学的了解，并促进发现治疗ADHD和其他与PFC功能障碍相关的疾病的新药物。

DESCRIPTION (provided by applicant): Psychostimulants, including methylphenidate (MPH), are currently the most effective treatment for attention-deficit hyperactivity disorder (ADHD). These drugs ameliorate a variety of deficits in cognitive/behavioral processes dependent on the prefrontal cortex (PFC) seen in ADHD patients, including behavioral inhibition/impulsivity regulation, working memory, and attention. Importantly, these actions are not limited to ADHD, having been well documented in normal humans and animals. Despite their clinical effectiveness, concern over abuse potential raises concerns over the widespread use of these drugs, particularly in children. A better understanding of the neurobiology of the cognition-enhancing actions of psychostimulants will likely facilitate the discovery of novel drug treatments for ADHD and other conditions associated with PFC dysfunction. Additionally, such information will increase our understanding of the neurobiology of higher cognitive processes. Systemic administration of MPH and all other approved ADHD medications improves higher cognitive function of rats as measured in a delayed spatial alternation test of working memory. Recently, the applicant demonstrated that psychostimulant action within the PFC, but not dorsomedial striatum, is sufficient to improve working memory. The first aim of the proposed research will investigate the receptor mechanisms within the PFC involved in the cognition enhancing actions of psychostimulants. In particular, these studies will determine the degree to which specific catecholamine receptors within the PFC are necessary for the cognition-enhancing actions of intra-PFC and systemically-administered MPH. The second aim of the proposed research will determine the degree to which the cognition-enhancing actions of MPH are associated with alterations in frontostriatal neuronal activity. These latter studies will utilize a conditional intensity-general linear model to analyze drug-induced alterations in frontostriatal neural discharge in animals engaged in a delayed response tasks of working memory. In particular, this aim will determine the degree to which cognition-enhancing doses of MPH increase recurrent activation of PFC and dorsomedial striatal neurons during and outside the delay interval of this task. This proposal has two primary training goals. First, it will allow the appliant to further develop expertise in the pharmacology and neurocircuitry of cognitive enhancers. Second, it will provide training in electrophysiological and statistical modeling methods to better understand the neural bases of higher cognitive function and drug-induced alterations in cognitive function. These studies will greatly aid the applicant in the progression towards becoming an independent scientist studying the neural circuitry/pharmacology of higher cognitive function. PUBLIC HEALTH RELEVANCE: Attention deficit hyperactivity disorder (ADHD) is a cognitive/behavioral syndrome afflicting 3-8% of the population and associated with an increased risk in a number of domains including academic, social and health-related. While psychostimulants are currently the most effective treatment for this disorder, abuse potential raises concern over the widespread use of these drugs, particularly in children. This research aims to increase our understanding of the neurobiology of the cognition-enhancing actions of psychostimulants and facilitate the discovery of novel drug treatments for ADHD and other conditions associated with PFC dysfunction.