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导致残疾，部分原因是执行认知功能受损。此外，精神分裂症患者产生可卡因依赖的风险也在增加。当戒断可卡因时，合并症患者表现出症状减轻，但执行认知功能比其他精神分裂症患者差。本研究探讨精神分裂症与可卡因依赖的交互认知神经科学。这一发现建立在我们已故同事Patricia Goldman-Rakic的研究基础上，她在猴子身上发现，工作记忆维持阶段的前额叶皮层（PFC）活动依赖于多巴胺D1受体的功能，而工作记忆反应选择阶段的PFC活动依赖于D2受体的功能。我们建议使用功能性磁共振成像（fMRI）来比较健康个体、戒断可卡因依赖个体、精神分裂症患者和戒断可卡因依赖精神分裂症患者四组受试者中与WM和皮质功能连通性相关的PFC活动。我们的试点数据表明，在WM维持阶段，共病组比任何单一诊断组显示更大的PFC活性缺陷，这可能与PFC D1受体功能更大的缺陷有关。然而，合并症组表现出比单一诊断组或健康受试者更大的反应期活性，提示可卡因使用相关的PFC D2受体功能增强。通过强调导致与精神分裂症和可卡因依赖相互作用相关的认知功能障碍的新电路适应，该应用可能为PFC机制提供新的思路，该机制导致与精神分裂症、可卡因依赖及其合并症相关的较差认知结果。这个项目可以帮助我们了解精神分裂症和可卡因滥用是如何影响前额叶功能的，这些因素在精神分裂症和可卡因依赖并存的人身上是如何相互作用的。这些知识可以帮助我们为那些同时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.