The Interactive Impact of Cocaine and Schizophrenia on Prefrontal Function

描述（由申请人提供）：精神分裂症和可卡因依赖产生残疾，部分原因是损害了执行认知功能。此外，精神分裂症患者患可卡因依赖症的风险增加。当戒除可卡因时，共病患者的症状减轻，但执行认知功能比其他精神分裂症患者差。该建议探讨了精神分裂症和可卡因依赖的交互认知神经科学。它建立在我们已故同事帕特里夏·戈德曼-拉基奇（Patricia Goldman-Rakic）的工作基础上，她在猴子身上发现，在工作记忆（WM）的维持阶段，前额叶皮层（PFC）的活动依赖于多巴胺D1受体的功能，而在WM的反应选择阶段，PFC的活动依赖于D2受体的功能。我们建议使用功能磁共振成像（fMRI）比较PFC活动与WM和皮质功能连接在四组受试者：健康人，戒毒可卡因依赖的个人，精神分裂症患者，戒毒可卡因依赖的精神分裂症患者。我们的试点数据表明，共病组显示更大的PFC活动赤字在维持阶段的WM比任何单一的诊断组，可能与更大的赤字PFC D1受体功能。然而，共病组显示出比单一诊断组或健康受试者更大的反应期活动，表明可卡因使用相关的PFC D2受体功能增强。通过突出新的电路适应，有助于与精神分裂症和可卡因依赖的相互作用相关的认知功能障碍，这种应用程序可能会揭示PFC机制，有助于与精神分裂症，可卡因依赖和他们的合并症相关的认知结果较差。公共卫生相关性这个项目可以帮助我们了解精神分裂症和可卡因滥用如何影响前额叶功能，这些因素如何在精神分裂症和可卡因依赖共病的人中相互作用。这些知识可能有助于我们为那些患有精神分裂症和可卡因依赖的人开发更好的治疗方法。

DESCRIPTION (provided by applicant): Schizophrenia and cocaine dependence produce disability, in part, by impairing executive cognitive function. Also, schizophrenic patients are at increased risk for developing cocaine dependence. When abstinent from cocaine, comorbid patients show reduced symptoms, but poorer executive cognitive function than other schizophrenic patients. This proposal probes the interactive cognitive neuroscience of schizophrenia and cocaine dependence. It builds on the work of our late colleague, Patricia Goldman-Rakic, who showed in monkeys that prefrontal cortex (PFC) activity during the maintenance phase of working memory (WM) was dependent upon dopamine D1 receptor function, while PFC activity during the response selection phase of WM was dependent upon D2 receptor function. We propose to use functional magnetic resonance imaging (fMRI) to compare PFC activity associated with WM and cortical functional connectivity in four groups of subjects: healthy individuals, abstinent cocaine dependent individuals, schizophrenia patients, and abstinent cocaine dependent schizophrenic patients. Our pilot data suggest that the comorbid group shows greater PFC activity deficits in the maintenance phase of WM than either single diagnosis group, perhaps related to greater deficits in PFC D1 receptor function. However, the comorbid group shows greater response phase activity than either single diagnosis group or healthy subjects, suggestive of a cocaine use-related enhancement of PFC D2 receptor function. By highlighting novel circuit adaptations that contribute to cognitive dysfunction associated with the interplay of schizophrenia and cocaine dependence, this application may shed new light on PFC mechanisms that contribute to poorer cognitive outcomes associated with schizophrenia, cocaine dependence, and their comorbidity. PUBLIC HEALTH RELEVANCE This project may help us to understand how schizophrenia and cocaine abuse affect prefrontal function how these factors interact in those who are co-morbid for schizophrenia and cocaine dependence. Such knowledge may help us to develop better treatments for those who are comorbid for schizophrenia and cocaine dependence.