Dopaminergic modulation of frontostriatal function

描述(申请人提供)：众所周知，黑质纹状体和中皮质多巴胺系统在工作记忆和认知控制的认知过程中发挥着重要作用。然而，越来越多的证据表明，多巴胺能药物的影响是复杂的：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氏病(PD)患者中都观察到了这种反差效应，帕金森病是一种以严重的多巴胺耗尽为特征的运动障碍。最近的研究表明，多巴胺和认知能力之间的关系至少受三个因素的制约。首先，药物效应似乎取决于任务的类型：尽管服用多巴胺能药物可以提高某些任务的表现，但它同时也会影响同一受试者在其他任务中的表现。其次，根据研究药物对多巴胺受体的选择性，效果会有所不同。因此，刺激多巴胺D1和D2受体对不同的认知功能有分离的影响。第三，多巴胺能药物可以改善某些人的功能，而损害另一些人的相同功能。拟议的实验旨在将多巴胺能药物在健康受试者和帕金森病患者身上的这些复杂的、有时是矛盾的影响表征为任务需求、受体特异性和基线能力的个体差异的函数。将对性能和大脑活动(使用功能磁共振成像和PET)进行评估。更具体地说，药物效应预计会有所不同，这取决于这项任务是否需要运动过程与认知过程，以及该任务是否需要认知灵活性与认知稳定性。我们预测，这些可分离的效应反映了多巴胺对纹状体和前额叶脑区的不同调制。此外，它们可能反映了多巴胺在D1和D2受体上的差异调制。最后，药物效应被假设为根据基线工作记忆容量的个体差异而不同，这与基线多巴胺功能有关。多巴胺对帕金森病、注意缺陷多动障碍、精神分裂症和药物成瘾等多种神经行为障碍的病因学具有重要作用。进一步了解多巴胺和认知之间的关系将有助于我们进一步了解这些疾病中认知和行为缺陷的潜在机制，并为通过针对特定神经递质系统的药物治疗此类缺陷提供新的方法。

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.