Nissbrandt H, Engberg G, Wikström H, Magnusson T, Carlsson A
Department of Pharmacology, University of Göteborg, Sweden.
Naunyn Schmiedebergs Arch Pharmacol. 1988 Aug;338(2):148-61. doi: 10.1007/BF00174863.
The accumulation rates of 3,4'-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after inhibition of aromatic amino acid decarboxylase (AADC) by 3-hydroxybenzylhydrazine (NSD 1015) or 1-(DL-seryl)-2- (2,3,4-trihydroxybenzyl)hydrazine (Ro 4-4602) have widely been used as measurements of the in vivo synthesis rates of monoamines. However, the values of dopamine (DA) turnover in rat striatum obtained using these drugs are much lower than values obtained by other methods. This discrepancy prompted us to further investigate the AADC inhibitor 1-(3-hydroxybenzyl)-1-methylhydrazine (NSD 1034) which earlier has been shown to give a DOPA accumulation rate in the striatum of the same magnitude as other measures of DA turnover. NSD 1034 was found to give a more than twofold higher DOPA accumulation rate than NSD 1015, NSD 1024, NSD 1039, NSD 1055 and Ro 4-4602 in the striatum. Also, in the limbic region and the hemispheres, but not in the substantia nigra, the DOPA accumulation was higher after NSD 1034 than after NSD 1015, but the difference was less pronounced. There was, however, no difference in 5-HTP accumulation between the drugs in any of the brain parts investigated. Although the DOPA accumulation rates are higher after NSD 1034 than after NSD 1015, the NSD 1015-induced DOPA accumulation seems to be more sensitive to changes in dopamine receptor occupancy. The different DOPA accumulation rates obtained with NSD 1015 and NSD 1034 are not due to differences in MAO inhibition, to interference with classical DA receptors, or to different degrees of AADC inhibition, but to an ability of NSD 1034 to stimulate DA synthesis. In addition, under certain conditions NSD 1034 also has a DA releasing action, like amphetamine. It is proposed that NSD 1034 and amphetamine stimulate DA synthesis and release by a common mechanism. The low value of DA synthesis rate, obtained when measured as DOPA accumulation after NSD 1015, is due to a substantial efflux of DOPA from the brain. The efflux of DOPA is equally large after NSD 1034 but the loss is compensated for by an increase in DOPA synthesis.
用3-羟基苄肼（NSD 1015）或1-(DL-丝氨酰基)-2-(2,3,4-三羟基苄基)肼（Ro 4-4602）抑制芳香族氨基酸脱羧酶（AADC）后，3,4'-二羟基苯丙氨酸（DOPA）和5-羟色氨酸（5-HTP）的积累率已被广泛用作单胺体内合成率的测量指标。然而，使用这些药物获得的大鼠纹状体中多巴胺（DA）周转值远低于通过其他方法获得的值。这种差异促使我们进一步研究AADC抑制剂1-(3-羟基苄基)-1-甲基肼（NSD 1034），此前已表明该抑制剂在纹状体中产生的DOPA积累率与DA周转的其他测量指标相当。研究发现，NSD 1034在纹状体中产生的DOPA积累率比NSD 1015、NSD 1024、NSD 1039、NSD 1055和Ro 4-4602高出两倍多。此外，在边缘区域和大脑半球，而非黑质，NSD 1034后的DOPA积累高于NSD 1015后的，但差异不太明显。然而，在所研究的任何脑区，这些药物之间的5-HTP积累没有差异。尽管NSD 1034后的DOPA积累率高于NSD 1015后的，但NSD 1015诱导的DOPA积累似乎对多巴胺受体占有率的变化更敏感。NSD 1015和NSD 1034获得的不同DOPA积累率并非由于单胺氧化酶（MAO）抑制的差异、对经典DA受体的干扰或AADC抑制程度的不同，而是由于NSD 1034刺激DA合成的能力。此外，在某些条件下，NSD 1034也具有类似苯丙胺的DA释放作用。有人提出，NSD 1034和苯丙胺通过共同机制刺激DA合成和释放。当以NSD 1015后DOPA积累来测量时，获得的低DA合成率是由于DOPA从大脑大量外流。NSD 1034后DOPA外流同样很大，但损失通过DOPA合成增加得到补偿。
