Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
PLoS One. 2013 Apr 16;8(4):e61839. doi: 10.1371/journal.pone.0061839. Print 2013.
The catechol-O-methyltransferase (COMT) enzyme metabolises catecholamines. COMT inhibitors are licensed for the adjunctive treatment of Parkinson's disease and are attractive therapeutic candidates for other neuropsychiatric conditions. COMT regulates dopamine levels in the prefrontal cortex (PFC) but plays a lesser role in the striatum. However, its significance in other brain regions is largely unknown, despite its links with a broad range of behavioural phenotypes hinting at more widespread effects. Here, we investigated the effect of acute systemic administration of the brain-penetrant COMT inhibitor tolcapone on tissue levels of dopamine, noradrenaline, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). We examined PFC, striatum, hippocampus and cerebellum in the rat. We studied both males and females, given sexual dimorphisms in several aspects of COMT's function. Compared with vehicle, tolcapone significantly increased dopamine levels in the ventral hippocampus, but did not affect dopamine in other regions, nor noradrenaline in any region investigated. Tolcapone increased DOPAC and/or decreased HVA in all brain regions studied. Notably, several of the changes in DOPAC and HVA, particularly those in PFC, were more prominent in females than males. These data demonstrate that COMT alters ventral hippocampal dopamine levels, as well as regulating dopamine metabolism in all brain regions studied. They demonstrate that COMT is of significance beyond the PFC, consistent with its links with a broad range of behavioural phenotypes. Furthermore, they suggest that the impact of tolcapone may be greater in females than males, a finding which may be of clinical significance in terms of the efficacy and dosing of COMT inhibitors.
儿茶酚-O-甲基转移酶（COMT）酶代谢儿茶酚胺。COMT 抑制剂被许可用于辅助治疗帕金森病，并且是其他神经精神疾病的有吸引力的治疗候选药物。COMT 调节前额叶皮层（PFC）中的多巴胺水平，但在纹状体中作用较小。然而，尽管其与广泛的行为表型相关，暗示着更广泛的影响，但它在其他脑区的意义在很大程度上尚不清楚。在这里，我们研究了脑穿透性 COMT 抑制剂托卡朋急性全身给药对多巴胺、去甲肾上腺素以及多巴胺代谢物 3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）的组织水平的影响。我们检查了大鼠的 PFC、纹状体、海马体和小脑。我们研究了雄性和雌性动物，因为 COMT 的功能在几个方面存在性别二态性。与载体相比，托卡朋显着增加了腹侧海马体中的多巴胺水平，但未影响其他区域的多巴胺，也未影响任何研究区域中的去甲肾上腺素。托卡朋增加了所有研究区域中的 DOPAC 和/或降低了 HVA。值得注意的是，DOPAC 和 HVA 的几种变化，特别是 PFC 中的变化，在雌性中比雄性更为明显。这些数据表明 COMT 改变了腹侧海马体中的多巴胺水平，并且还调节了所有研究脑区中的多巴胺代谢。它们表明 COMT 的意义超出了 PFC，这与其与广泛的行为表型相关。此外，它们表明托卡朋的影响在女性中可能比男性更大，这一发现可能在 COMT 抑制剂的疗效和剂量方面具有临床意义。
