Murphy B L, Arnsten A F, Goldman-Rakic P S, Roth R H
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510-8001, USA.
Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1325-9. doi: 10.1073/pnas.93.3.1325.
The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex.
轻度应激对前额叶皮质多巴胺系统的选择性激活可被致焦虑的β-咔啉（如FG7142）模拟。为了研究前额叶皮质中多巴胺周转率升高的功能相关性，本研究考察了FG7142对大鼠和猴子空间工作记忆任务表现的影响。FG7142选择性地增加了大鼠前额叶皮质的多巴胺周转率，并显著损害了大鼠和猴子在空间工作记忆任务中的表现。空间辨别任务（对大鼠而言，具有相似的运动和动机要求）或零秒延迟后的延迟反应表现（对猴子而言）不受FG7142影响。此外，对大鼠的生化分析显示，前额叶皮质中的多巴胺周转率与延迟交替任务中的认知障碍之间存在显著正相关。大鼠和猴子的认知缺陷可通过用苯二氮䓬受体拮抗剂RO15 - 1788预处理来预防，RO15 - 1788可阻断多巴胺周转率的增加，多巴胺受体拮抗剂氟哌啶醇、氯氮平和SCH23390也有同样效果。这些发现表明，前额叶皮质中多巴胺活性过高对由前额叶皮质介导的认知功能有害。
