Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT1A or 5-HT1B receptor knockout mice
Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT1A or 5-HT1B receptor knockout mice
复制标题
DOI：
10.1046/j.1471-4159.2000.0752415.x
复制
发表时间：
2000-12-01
影响因子：
4.7
通讯作者：
Descarries, L
中科院分区：
文献类型：
--
作者：
Ase, AR;Reader, TA;Descarries, L
采用高效液相色谱法测定129/Sv菌株5-HT1A或5-HT1B敲除小鼠和野生型小鼠的16个脑区和脊髓中5-羟色胺（5-HT）、多巴胺（DA）、去甲肾上腺素以及5-HT和DA代谢物的含量。在5-HT1A基因敲除中，5-HT浓度始终不变，但5-HT代谢物水平高于野生型中叶背/内侧核、嗅球、黑质和蓝斑。这被认为是5-羟色胺转换增加的迹象，反映了中脑中脑神经元的基础活性增强，从而增加了它们的体突和轴突末端的5-羟色胺释放。这为5-HT1A基因敲除小鼠中观察到的焦虑样行为增加提供了可能的解释。DA含量的增加和/或DA周转量的增加被解释为DA去抑制的结果，而在蓝斑突起的一些区域，去甲肾上腺素浓度的增加可能反映了其神经元活性的降低。在5-HT1B。敲除后，5-HT在伏隔核、蓝斑、脊髓以及其他一些5-HT神经支配区域的浓度低于野生型。在伏隔核中测量到DA的减少与DA周转的增加有关。5-HT和DA代谢的这些变化与5-HT1B基因敲除小鼠的侵袭性增加和对可卡因的超敏感性一致。因此，CNS单胺代谢的显著不同改变可能导致这两种基因敲除的相反行为表型。
Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT1A or 5-HT1B knockout and wild-type mice of the 129/Sv strain. In 5-HT1A knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT1A knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT1B. knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT1B knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts.