Dopaminergic modulation of frontostriatal function

描述（由申请人提供）：众所周知，黑质纹状体和中皮层多巴胺系统在工作记忆和认知控制的认知过程中发挥重要作用。然而，越来越多的证据表明多巴胺能药物的作用是复杂的：它们可以改善或损害认知功能。在年轻的健康志愿者和帕金森病（PD）患者中都观察到了这种对比效应，帕金森病是一种以严重的多巴胺耗竭为特征的运动障碍。最近的进展表明，多巴胺和认知表现之间的关系至少有三个因素。首先，药物的作用似乎取决于任务的类型：虽然多巴胺能药物的管理可以提高某些任务的性能，但它可以同时损害同一受试者的其他任务的性能。第二，效果取决于所研究药物的多巴胺受体选择性。因此，多巴胺D1和D2受体的刺激对不同的认知功能具有可分离的作用。第三，多巴胺能药物可以改善某些个体的功能，同时损害其他个体的相同功能。拟议的实验旨在表征这些复杂的，有时矛盾的影响多巴胺能药物在健康受试者和PD患者作为一个功能的任务要求，受体特异性和个体差异的基线能力。将评估表现和大脑活动（使用fMRI和PET）。更具体地说，根据任务是否需要运动与认知过程，以及任务是否需要认知灵活性与认知稳定性，预计药物作用会有所不同。我们预测，这些可分离的影响反映了纹状体与前额叶脑区多巴胺的差异调制。此外，它们可能反映了多巴胺对D1和D2受体的差异调节。最后，假设药物作用根据与基线多巴胺功能相关的基线工作记忆容量的个体差异而不同。多巴胺对多种神经行为障碍如PD、注意缺陷多动障碍、精神分裂症和药物成瘾的病因学具有根本重要性。进一步了解多巴胺和认知之间的关系，应该进一步了解这些疾病中认知和行为缺陷的机制，并提供针对特定神经递质系统的药物治疗这种缺陷的新方法。

DESCRIPTION (provided by applicant): The nigrostriatal and mesocortical dopamine systems are well known to play an important role in the cognitive processes of working memory and cognitive control. However, accumulating evidence indicates that the effects of dopaminergic drugs are complex: They can improve or impair cognitive function. Such contrasting effects have been observed both in young healthy volunteers, as well as in patients with Parkinson's disease (PD), a movement disorder characterized by severe dopamine depletion. Recent progress reveals that the relationship between dopamine and cognitive performance is qualified by at least three factors. First, drug effects appear dependent on the type of task: while administration of dopaminergic drugs can improve performance on some tasks, it can simultaneously impair performance on other tasks in the same subjects. Second, the effects vary depending on dopamine receptor selectivity of the drug under study. Thus, stimulation of dopamine D1 and D2 receptors has dissociable effects on distinct cognitive functions. Third, dopaminergic drugs can improve function in some individuals while impairing the same function in other individuals. The proposed experiments aim to characterize these complex, sometimes paradoxical effects of dopaminergic drugs in both healthy subjects and PD patients as a function of task demands, receptor specificity and individual differences in baseline capacity. Both performance and brain activity (using fMRI and PET) will be assessed. More specifically, drug effects are predicted to differ depending on whether the task requires motor versus cognitive processes, and whether the task requires cognitive flexibility versus cognitive stability. We predict that these dissociable effects reflect differential modulation by dopamine of striatal versus prefrontal brain regions. In addition, they may reflect differential modulation by dopamine at D1 and D2 receptors. Finally, drug effects are hypothesize to differ depending on individual variation in baseline working memory capacity, associated with baseline dopamine function. Dopamine is of fundamental importance to the etiology of a wide variety of neurobehavioral disorders such as PD, attention deficit hyperactivity disorder, schizophrenia and drug addiction. A further understanding of the relationship between dopamine and cognition should further our understanding of the mechanisms underlying cognitive and behavioral deficits in these disorders and provide insight into novel approaches to treating such deficits with medications targeted at specific neurotransmitter systems.