Huotari M, Gainetdinov R, Männistö P T
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Pharmacol Toxicol. 1999 Nov;85(5):233-8. doi: 10.1111/j.1600-0773.1999.tb02014.x.
To elucidate the importance of catechol-O-methyltransferase, we performed striatal microdialysis studies in conscious rats given tolcapone, an inhibitor of catechol-O-methyltransferase, together with four compounds each of which elevates the extracellular dopamine content through a different mechanism. Tolcapone itself did not alter dopamine levels in the striatal microdialysis fluid but increased DOPAC and decreased homovanillic acid levels. However, tolcapone pretreatment (30 mg/kg) multiplied the already high dopamine levels after levodopa, and less so the moderately elevated dopamine levels after GBR-12909 (at 20 mg/kg) alone, but the minor (insignificant) dopamine-elevating effects of haloperidol and (+)-U232 were not altered. In all cases, a tolcapone pretreatment decreased homovanillic acid levels and elevated DOPAC levels. In further combination studies, GBR-12909 did not alter significantly the effects of levodopa/carbidopa on dopamine, DOPAC and homovanillic acid levels. In these rats, tolcapone enhanced the effect of GBR-12909 on extracellular dopamine but not on DOPAC. In conclusion, when levodopa and carbidopa are given together, COMT inhibition becomes extremely meaningful, and dopamine levels are multiplied by tolcapone. Otherwise, tolcapone is able to further elevate extracellular dopamine levels only when dopamine turnover is normal or low but not when it is high. Overall, the role of COMT in the elimination of synaptic dopamine remains minor compared to the dominance of the reuptake process.
为阐明儿茶酚-O-甲基转移酶的重要性，我们对清醒大鼠进行了纹状体微透析研究，给大鼠注射托卡朋（一种儿茶酚-O-甲基转移酶抑制剂），同时注射四种化合物，每种化合物通过不同机制提高细胞外多巴胺含量。托卡朋本身并未改变纹状体微透析液中的多巴胺水平，但增加了3,4-二羟基苯乙酸（DOPAC）水平并降低了高香草酸水平。然而，托卡朋预处理（30mg/kg）使左旋多巴给药后本已较高的多巴胺水平进一步升高，对单独给予GBR-12909（20mg/kg）后适度升高的多巴胺水平的增强作用较小，但对氟哌啶醇和(+)-U232轻微（不显著）的多巴胺升高作用没有影响。在所有情况下，托卡朋预处理均降低了高香草酸水平并提高了DOPAC水平。在进一步的联合研究中，GBR-12909对左旋多巴/卡比多巴对多巴胺、DOPAC和高香草酸水平的影响没有显著改变。在这些大鼠中，托卡朋增强了GBR-12909对细胞外多巴胺的作用，但对DOPAC没有影响。总之，当同时给予左旋多巴和卡比多巴时，儿茶酚-O-甲基转移酶抑制变得极具意义，托卡朋可使多巴胺水平升高。否则，只有当多巴胺周转正常或较低时，托卡朋才能进一步提高细胞外多巴胺水平，而当多巴胺周转较高时则不能。总体而言，与再摄取过程的主导作用相比，儿茶酚-O-甲基转移酶在消除突触多巴胺中的作用仍然较小。
