Huotari M, Passlin M, Nordberg H L, Forsberg M, Kotisaari S, Tuomisto L, Shintani F, Tanaka K F, Reenilä I, Laitinen K, Männistö P T
Department of Pharmacology and Toxicology, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland.
J Neurosci Methods. 2001 Aug 15;109(1):47-52. doi: 10.1016/s0165-0270(01)00400-9.
6-Nitronoradrenaline, a bioactive compound recently identified in the brain, is known to inhibit catechol-O-methyltransferase. To study its effect on dopamine metabolism, it was administered into rat striatum via a microdialysis probe. Other nitrated catechols (6-nitrodopamine, 6-nitro-DOPAC and 5-nitro-HVA) were studied for comparison. Tolcapone, a selective catechol-O-methyltransferase inhibitor, was used as a positive reference compound. Both 6-nitronoradrenaline and tolcapone increased striatal extracellular dopamine levels during the perfusion (at 100 microM concentration but not at 10 microM) and decreased the efflux of homovanillic acid. Tolcapone, but not other nitrated catechols, increased 3,4-dihydroxyphenylacetic acid efflux. None of the compounds inhibited MAO-B activity at 100 microM or lower. At 1 mM, 6-nitrodopamine inhibited MAO-B by 60%. Compared to tolcapone, other nitrated catechols were very weak COMT inhibitors in vitro. Neither tolcapone nor 6-nitronoradrenaline modified the metabolism of L-dopa which was given peripherally. In binding studies, both 6-nitronoradrenaline and other nitrocatechols failed to affect the dopamine transporter even at high micromolar concentrations. In conclusion, exogenous 6-nitronoradrenaline can act as a COMT inhibitor in the striatum and elevate striatal dopamine levels without inhibiting dopamine reuptake. Whether endogenous 6-nitronoradrenaline can be formed also in vivo in the striatum and act as a regulator of dopaminergic tone remains to be determined.
6-硝基去甲肾上腺素是一种最近在大脑中发现的生物活性化合物，已知它能抑制儿茶酚-O-甲基转移酶。为了研究其对多巴胺代谢的影响，通过微透析探针将其注入大鼠纹状体。还研究了其他硝化儿茶酚（6-硝基多巴胺、6-硝基-3,4-二羟基苯乙酸和5-硝基高香草酸）以作比较。托卡朋，一种选择性儿茶酚-O-甲基转移酶抑制剂，用作阳性对照化合物。在灌注期间（浓度为100微摩尔时，但10微摩尔时未出现此现象），6-硝基去甲肾上腺素和托卡朋均提高了纹状体细胞外多巴胺水平，并降低了高香草酸的流出量。托卡朋增加了3,4-二羟基苯乙酸的流出量，但其他硝化儿茶酚没有此作用。在100微摩尔或更低浓度时，这些化合物均未抑制单胺氧化酶B（MAO-B）的活性。在1毫摩尔时，6-硝基多巴胺对MAO-B的抑制率为60%。与托卡朋相比，其他硝化儿茶酚在体外是非常弱的儿茶酚-O-甲基转移酶抑制剂。托卡朋和6-硝基去甲肾上腺素均未改变外周给予的左旋多巴的代谢。在结合研究中，即使在高微摩尔浓度下，6-硝基去甲肾上腺素和其他硝基儿茶酚也未能影响多巴胺转运体。总之，外源性6-硝基去甲肾上腺素可在纹状体中作为儿茶酚-O-甲基转移酶抑制剂发挥作用，并提高纹状体多巴胺水平而不抑制多巴胺再摄取。内源性6-硝基去甲肾上腺素是否也能在纹状体中体内形成并作为多巴胺能张力的调节剂仍有待确定。
