Reid M S, Herrera-Marschitz M, Hökfelt T, Ohlin M, Valentino K L, Ungerstedt U
Department of Pharmacology, Karolinska Institute, Stockholm, Sweden.
Neuroscience. 1990;36(3):643-58. doi: 10.1016/0306-4522(90)90007-q.
The functional role of striatonigral neurokinins were studied by analysing the effects of intranigral injections of substance P and neurokinin A on the extracellular level of dopamine and dihydroxyphenylacetic acid in the striatum, as measured by in vivo microdialysis in rats. Two substance P antagonists, substance P D-Pro2 D-Trp7,9 and substance P D-Arg1 D-Trp7,9 Leu11 were tested and analysed for their ability to block the neurokinin effects. Unilateral injections of substance P (0.00007-7.0 nmol injected in 0.2 microliter) as well as neurokinin A (0.009-9.0 nmol) into the substantia nigra, pars reticulata of halothane anaesthetized rats produced long-lasting increases in ipsilateral striatal dopamine and dihydroxyphenylacetic acid levels. The dose-response relationship for substance P on dopamine was biphasic, with maximal effects occurring after the middle dose (0.007-0.07 nmol). The dose-response relationship for neurokinin A was monophasic. Intranigral injections of substance P D-Pro2 D-Trp7,9 (0.07-0.7 nmol) or substance P D-Arg1 D-Trp7,9 Leu11 (0.07-0.7 nmol) produced a decrease in striatal dopamine, but an increase in striatal dihydroxyphenylacetic acid. At a low dose (0.07 nmol) substance P D-Pro2 D-Trp7,9 enhanced the dopamine increase produced by intranigral substance P (0.07 nmol) or neurokinin A (0.09), while at a high dose (0.7 nmol) it blocked both substance P and neurokinin A effects. Both doses of substance P D-Arg1 D-Trp7,9 Leu11 (0.07 and 0.7 nmol) blocked the substance P- but not the neurokinin A-induced increase in striatal dopamine. Immunohistochemical analysis revealed that high doses of substance P (7.0 nmol) and neurokinin A (0.9 and 9.0 nmol), as well as substance P D-Pro2 D-Trp7,9 and substance P D-Arg1 D-Trp7,9 Leu11 (0.07 and 0.7 nmol), induced a restricted loss of tyrosine hydroxylase in dendrites and cells, and neuropeptide K in terminals, at the site of injection. Further analysis shows that co-administration of substance P (0.07 nmol) or neurokinin A (0.09 nmol) did not modify the extent of the depletion of both immunoreactivities induced by substance P D-Arg1 D-Trp7,9 Leu11 (0.7 nmol). The extent of the effect produced by substance P D-Arg1 D-Trp7,9 Leu11 (0.7 nmol) was, however, smaller than the spread of intranigral injection of [125I]Bolton-Hunter-labelled substance P D-Arg1 D-Trp7,9 Leu11, and it is suggested that the "neurotoxic" effects of the substance P antagonists are not primarily involved in their abilities to inhibit striatal dopamine release and block the stimulation of dopamine after intranigral substance P and neurokinin A.(ABSTRACT TRUNCATED AT 400 WORDS)
通过分析向大鼠黑质内注射P物质和神经激肽A对纹状体中多巴胺和二羟基苯乙酸细胞外水平的影响，研究了纹状体黑质神经激肽的功能作用，该水平通过体内微透析进行测量。测试并分析了两种P物质拮抗剂，即P物质D - Pro2 D - Trp7,9和P物质D - Arg1 D - Trp7,9 Leu11阻断神经激肽作用的能力。向氟烷麻醉大鼠的黑质网状部单侧注射P物质（0.2微升中注射0.00007 - 7.0纳摩尔）以及神经激肽A（0.009 - 9.0纳摩尔），可使同侧纹状体多巴胺和二羟基苯乙酸水平产生持久升高。P物质对多巴胺的剂量 - 反应关系呈双相性，中等剂量（0.007 - 0.07纳摩尔）后出现最大效应。神经激肽A的剂量 - 反应关系呈单相性。向黑质内注射P物质D - Pro2 D - Trp7,9（0.07 - 0.7纳摩尔）或P物质D - Arg1 D - Trp7,9 Leu11（0.07 - 0.7纳摩尔）可使纹状体多巴胺减少，但使纹状体二羟基苯乙酸增加。低剂量（0.07纳摩尔）的P物质D - Pro2 D - Trp7,9可增强黑质内注射P物质（0.07纳摩尔）或神经激肽A（0.09）所产生的多巴胺增加，而高剂量（0.7纳摩尔）时则阻断P物质和神经激肽A的作用。两种剂量的P物质D - Arg1 D - Trp7,9 Leu11（0.07和0.7纳摩尔）均可阻断P物质诱导的纹状体多巴胺增加，但不能阻断神经激肽A诱导的增加。免疫组织化学分析显示，高剂量的P物质（7.0纳摩尔）和神经激肽A（0.9和9.0纳摩尔），以及P物质D - Pro2 D - Trp7,9和P物质D - Arg1 D - Trp7,9 Leu11（0.07和0.7纳摩尔），在注射部位可诱导树突和细胞中的酪氨酸羟化酶以及终末中的神经肽K出现局限性缺失。进一步分析表明，联合给予P物质（0.07纳摩尔）或神经激肽A（0.09纳摩尔）不会改变P物质D - Arg1 D - Trp7,9 Leu11（0.7纳摩尔）诱导的两种免疫反应性耗竭程度。然而，P物质D - Arg1 D - Trp7,9 Leu11（0.7纳摩尔）产生的效应范围小于向黑质内注射[125I]博尔顿 - 亨特标记的P物质D - Arg1 D - Trp7,9 Leu11的扩散范围，提示P物质拮抗剂的“神经毒性”效应并非主要涉及其抑制纹状体多巴胺释放以及阻断黑质内注射P物质和神经激肽A后多巴胺刺激的能力。（摘要截选至400字）
