Specificity of prenatal cocaine on inhibition of locus coeruleus neurite outgrowth
Specificity of prenatal cocaine on inhibition of locus coeruleus neurite outgrowth
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DOI：
10.1016/j.neuroscience.2005.12.053
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Snow, D. M.
中科院分区：
文献类型：
--
作者：
Dey, S.;MacTutus, C. F.;Snow, D. M.
出生前接触可卡因可导致后遗症功能的改变，可能涉及蓝斑去甲肾上腺素能神经元及其投射。以往的报道表明，在体外和体内，胚胎大鼠蓝斑神经元暴露于可卡因后，细胞存活率下降，突起生长受到抑制，且这种影响在妊娠早期最为严重。本研究通过比较神经发生高峰期生理相关剂量的可卡因(500 ng/ml，每天2次，共4天)对蓝斑轴突的形成和伸展与黑质多巴胺能神经元的抑制作用，探讨可卡因抑制作用的特异性。在可卡因处理后，进行免疫细胞化学(抗蓝斑去甲肾上腺素抗体；抗黑质酪氨酸羟化酶抗体)和图像分析，以测量各种轴突生长参数。对于蓝斑神经元，可卡因处理减少了1)启动突起的细胞数量[P<；0.001]，2)平均突起数量[P<；0.0001]，3)平均数量[P<；0.00161]和分支突起长度[P<；0.0006]，以及4)最长突起的平均长度[P<；0.0001]。相比之下，在所检测的任何参数中，黑质神经元都没有受到可卡因的显著影响。更重要的是，观察到可卡因治疗和大脑区域之间的显著相互作用[P<；0.0002]，表明相对于黑质神经元，蓝斑对可卡因暴露更脆弱。这些数据支持我们的假设，即可卡因通过负向调节蓝斑神经元突起来靶向去甲肾上腺素系统，这可能会影响暴露于可卡因的子代的寻路、突触连接，并最终影响注意行为。(C)2006年IBRO。爱思唯尔有限公司出版。保留所有权利。
Prenatal cocaine exposure induces alterations in aftentional function that presumably involve locus coeruleus noradrenergic neurons and their projections. Previous reports indicate that embryonic rat locus coeruleus neurons exposed to cocaine, both in vitro and in vivo, showed in decreased cell survival and inhibition of neurite outgrowth, and that the effects were most deleterious during early gestation. The present study performed in vitro addressed the specificity of the inhibitory effects of cocaine by comparing locus coeruleus neurite formation and extension to that of dopaminergic substantia nigra neurons following exposure to a physiologically-relevant dose of cocaine (500 ng/ml, two times a day, for four days) during peak neuritogenesis. Following cocaine treatment, immunocytochemistry (anti-norepinephrine antibody to locus coeruleus; anti-tyrosine hydroxylase antibody to substantia nigra) and image analysis were performed to measure a variety of neurite outgrowth parameters. For locus coeruleus neurons, cocaine treatment decreased the 1) number of cells initiating neurites [P < 0.001], 2) mean number [P < 0.05] and length of neurites [P < 0.0001], 3) mean number [P < 0.00161 and length of branched neurites [P < 0.0006], and 4) mean length of the longest neurites [P < 0.0001]. In comparison, substantia nigra neurons were not significantly affected by cocaine for any of the parameters examined. More importantly, a significant interaction between cocaine treatment and brain region was observed [P < 0.0002] indicating greater vulnerability of locus coeruleus, relative to substantia nigra neurons, to cocaine exposure. These data support our hypothesis that cocaine targets the noradrenergic system by negatively regulating locus coeruleus neuronal outgrowth, which likely affects pathfinding, synaptic connectivity, and ultimately attentional behavior in cocaine-exposed offspring. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.