IMMUNOHISTOCHEMICAL ANALYSIS OF THE NEUROTOXIC EFFECTS OF DSP-4 IDENTIFIES 2 POPULATIONS OF NORADRENERGIC AXON TERMINALS
IMMUNOHISTOCHEMICAL ANALYSIS OF THE NEUROTOXIC EFFECTS OF DSP-4 IDENTIFIES 2 POPULATIONS OF NORADRENERGIC AXON TERMINALS
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DOI：
10.1016/0306-4522(89)90364-3
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发表时间：
1989-01-01
期刊：
影响因子：
3.3
通讯作者：
GRZANNA, R
中科院分区：
文献类型：
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作者：
FRITSCHY, JM;GRZANNA, R
N-(2-氯乙基)-N-乙基-2-溴苄胺 (DSP-4) 是一种有效且高度选择性的神经毒素，可诱导去甲肾上腺素能轴突变性。 DSP-4的作用在不同的大脑区域有很大差异：该药物在新皮质、海马体、小脑和脊髓中几乎完全耗尽去甲肾上腺素，但在下丘脑和脑干中仅部分耗尽。在本研究中，我们采用免疫组织化学方法评估 DSP-4 对大鼠中枢去甲肾上腺素能神经元结构完整性的神经毒性作用，并鉴定 DSP-4 治疗 2-4 周后仍保留在中枢神经系统中的去甲肾上腺素能轴突。染色结果表明去甲肾上腺素能轴突末端是 DSP-4 的主要作用位点；去甲肾上腺素能细胞体和前终末轴突没有受到明显影响。 DSP-4 对不同大脑区域的去甲肾上腺素能轴突末端几乎产生全部或全部神经毒性作用。新皮质、海马、嗅球、丘脑、顶盖、小脑和脊髓背角中几乎所有去甲肾上腺素能轴突末端均被破坏。相反，基底前脑、下丘脑、网状结构、脑干运动核和脊髓腹角的大多数去甲肾上腺素能轴突未受影响。这些剩余的去甲肾上腺素能轴突末端在形态上与敏感轴突的不同之处在于它们的厚度、大小和静脉曲张的间距以及它们在末端区域内的密集的树枝化。对 DSP-4 敏感的去甲肾上腺素能轴突的分布与蓝斑轴突的分布非常密切相关，并且去甲肾上腺素能末端不受 DSP-4 影响的所有区域可能都接收来自非蓝斑神经元的主要去甲肾上腺素能输入。这项研究提供了第一个直接证据，证明 DSP-4 会破坏蓝斑神经元的去甲肾上腺素能轴突末端，但不会破坏非蓝斑神经元的去甲肾上腺素轴突末端。去甲肾上腺素能轴突对 dSP-4 的这种显着差异敏感性与它们的形态和地形投影的明显差异相匹配。结果支持这样的观点：蓝斑和非蓝斑去甲肾上腺素能神经元构成两个独立的子系统，它们不仅在投影上不同，而且在轴突末端的药理学特性上也不同。
N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a potent and highly selective neurotoxin which induces degeneration of noradrenergic axons. The effects of DSP-4 vary considerably in different brain regions: the drug produces nearly complete depletion of noraderenaline in neocortex, hippocampus, cerebellum and spinal cord, but only partial depletion in hypothalamus and brainstem. In this study we have employed an immunohistochemical method to assess the neurotoxic effects of DSP-4 on the structural integrity of central noradrenergic neurons in the rat, and to identify those noradrenergic axons that remain in the central nervous system 2-4 weeks after DSP-4 treatment. The staining results identified noradrenergic axons terminals as the principal site of action of DSP-4; noradrenergic cell bodies and preterminal axons were not noticeably affected. DSP-4 produced an almost all or none neurotoxic effect on noradrenergic axon terminals in different brain regions. Nearly all noradrenergic axon terminals were destroyed in the neocortex, hippocampus, olfactory bulb, thalamus, tectum, cerebellum and spinal cord dorsal horn. In contrast, most noradrenergic axons were unaffected in the basal forebrain, hypothalamus, reticular formation, brainstem motor nuclei and spinal cord ventral horn. These remaining noradrenergic axon terminals differed morphologically from sensitive axons by their thickness, size and spacing of their varicosities and their dense arborizations within terminal fields. The distribution of noradrenergic axons susceptible to DSP-4 correlates very closely with the distribution of locus coeruleus axons and possibly all regions in which noradrenergic terminals are unaffected by DSP-4 receive their major noradrenergic input from non-locus coeruleus neurons. This study provides the first direct evidence that DSP-4 destroys noradrenergic axon terminals from the locus coeruleus, but not those from non-locus coeruleus neurons. This profound differential sensitivity of noradrenergic axons to dSP-4 is matched by distinct differences in their morphology and their topographic projections. The results support the view that locus coeruleus and non-locus coeruleus noradrenergic neurons constitute two separate subsystems, which differ not only in their projections but also with respect to the pharmacological properties of their axon terminals.