Lapish C C, Ahn S, Evangelista L M, So K, Seamans J K, Phillips A G
Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver BCV6T2A1, Canada.
Psychopharmacology (Berl). 2009 Jan;202(1-3):521-30. doi: 10.1007/s00213-008-1342-1. Epub 2008 Oct 15.
Genetic variations in catechol-O-methyl transferase (COMT) or administration of COMT inhibitors have a robust impact on cognition and executive function in humans. The COMT enzyme breaks down extracellular dopamine (DA) and has a particularly important role in the prefrontal cortex (PFC) where DA transporters are sparse. As such, the beneficial cognitive effects of the COMT inhibitor tolcapone are postulated to be the result of increased bioavailability of DA in the PFC. Furthermore, it has been shown previously that COMT inhibitors increase pharmacologically evoked DA but do not affect basal levels in the PFC.
The current study characterized the ability of tolcapone to increase DA release in response to behaviorally salient stimuli and improve performance of the delayed spatial win-shift (DSWSh) task.
Tolcapone enhanced PFC DA efflux associated with the anticipation and consumption of food when compared to saline controls. Chronic and acute treatment with tolcapone also reduced the number of errors committed during acquisition of the DSWSh. However, no dissociable effects were observed in experiments designed to selectively assay encoding or recall in well-trained animals, as both experiments showed improvement with tolcapone treatment. Taken together, these data suggest a generalized positive influence on cognition. Furthermore, these data support the conclusion of Apud and Weinberger (CNS Drugs 21:535-557, 2007) that agents which selectively potentiate PFC DA release may confer cognitive enhancement without the unwanted side effects produced by drugs that increase basal DA levels in cortical and subcortical brain regions.
儿茶酚-O-甲基转移酶（COMT）的基因变异或给予COMT抑制剂对人类认知和执行功能有显著影响。COMT酶分解细胞外多巴胺（DA），在多巴胺转运体稀少的前额叶皮质（PFC）中发挥着特别重要的作用。因此，推测COMT抑制剂托卡朋的有益认知作用是PFC中DA生物利用度增加的结果。此外，先前已表明COMT抑制剂可增加药理学诱发的DA，但不影响PFC中的基础水平。
本研究表征了托卡朋响应行为显著刺激增加DA释放的能力，以及改善延迟空间赢-转换（DSWSh）任务表现的能力。
与生理盐水对照组相比，托卡朋增强了与食物预期和摄取相关的PFC DA流出。托卡朋的慢性和急性治疗还减少了DSWSh习得过程中犯下的错误数量。然而，在旨在选择性检测训练有素动物的编码或回忆的实验中未观察到可分离的效应，因为两个实验均显示托卡朋治疗有改善。综上所述，这些数据表明对认知有普遍的积极影响。此外，这些数据支持了阿普德和温伯格（《中枢神经系统药物》21:535 - 557，2007年）的结论，即选择性增强PFC DA释放的药物可能带来认知增强，而不会产生增加皮质和皮质下脑区基础DA水平的药物所带来的不良副作用。
