Neurobiology of the Cognition Enhancing Actions of Psychostimulants

描述（由申请人提供）：精神兴奋剂，包括哌甲酯（MPH），是目前治疗注意力缺陷多动障碍（ADHD）最有效的药物。这些药物改善了ADHD患者中依赖于前额叶皮层（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，这些行为不仅限于ADHD，在正常人类和动物中已有很好的记录。尽管其临床有效性，但对滥用可能性的担忧引起了对这些药物广泛使用的担忧，特别是在儿童中。更好地理解精神兴奋剂的认知增强作用的神经生物学将可能促进新药物治疗的发现 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级认知过程的神经生物学的理解。 MPH和所有其他经批准的ADHD药物的全身给药改善了大鼠的更高认知功能，如在工作记忆的延迟空间交替测试中所测量的。最近，申请人证明，PFC内的精神兴奋剂作用，而不是背内侧纹状体，足以改善工作记忆。本研究的第一个目的是探讨前额叶皮层中参与精神兴奋剂认知增强作用的受体机制。特别是，这些研究将确定PFC内特定的儿茶酚胺受体对PFC内和全身给药MPH的认知增强作用所必需的程度。这项研究的第二个目的是确定MPH的认知增强作用与额纹状体神经元活动改变的相关程度。后一项研究将利用条件强度-一般线性模型分析药物诱导的参与工作记忆延迟反应任务的动物的额纹状体神经放电变化。特别是，这一目标将确定在何种程度上认知增强剂量的MPH增加PFC和背内侧纹状体神经元的经常性激活期间和以外的延迟间隔的这项任务。这项建议有两个主要的培训目标。首先，它将允许申请人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，它将提供电生理和统计建模方法的培训，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人成为研究高级认知功能的神经回路/药理学的独立科学家。

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.