Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex.
Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex.
复制标题
托莫西汀可逆转内侧前额叶皮层去甲肾上腺素能传入神经阻滞所产生的注意力缺陷。
DOI：
10.1007/s00213-008-1097-8
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发表时间：
2008
影响因子：
3.4
通讯作者：
McGaughy,Jill
中科院分区：
文献类型：
--
作者：
Newman,LoriA;Darling,Jenna;McGaughy,Jill
背景大多数评估注意缺陷障碍(ADD)执行功能的研究表明，使用威斯康星卡片分类任务或维度内/维度外集合转移任务(ID/ED)的注意集合转移存在缺陷。人类、灵长类和啮齿类动物前额叶皮质的损伤会损害次元外(ED)移位。去甲肾上腺素能耗竭大鼠的内侧前额叶皮质足以损害注意定势转移。托莫西汀是一种选择性去甲肾上腺素(NE)再摄取抑制剂，被认为是通过增加额叶皮质NE的释放而对ADD患者产生有益的影响。材料和方法我们评估了系统给予正常和去甲肾上腺素(NE-LX)大鼠(NE-LX)的托莫西汀(0.0、0.1、0.3和0.9 mg/kg/ml)对注意定势转移的影响。结果托莫西汀纠正了NE-LX大鼠的注意定势转移障碍，但损害了非损毁大鼠的ED表现。讨论虽然托莫西汀在神经化学上是选择性的，但在0.3 mg/kg剂量下并不是完全特异的。所有剂量的药物在逆转ED缺陷方面的疗效相似，但0.1 mg/kg剂量的有效性支持了这样的假设，即仅增加前额叶NE就足以改善NE-LX大鼠的注意力。此外，该药物在非损毁大鼠身上的有害影响支持这样的假设，即前额叶皮质中适宜的去甲肾上腺素水平对注意力定势转移至关重要，高于和低于最佳水平的NE都会产生注意力障碍。
BackgroundThe majority of studies assessing executive function in attention deficit disorder (ADD) have shown deficits in attentional set shifting using either the Wisconsin card sorting task or the intra-dimensional/extra-dimensional set-shifting task (ID/ED). Damage to the prefrontal cortex in humans, primates, and rodents impairs extra-dimensional (ED) shifts. Noradrenergic depletion of the medial prefrontal cortex in rats is sufficient to impair attentional set shifting. Atomoxetine, a selective norepinephrine (NE) re-uptake inhibitor, is hypothesized to produce beneficial effects in patient with ADD by augmenting NE release in prefrontal cortex.Materials and methodsWe assessed the effects of systemic administration of atomoxetine (0.0, 0.1, 0.3, and 0.9 mg/kg/ml) in normal and noradrenergically lesioned (NE-LX) rats on attentional-set shifts. We replicated findings showing NE-LX rats are selectively impaired on the ED shifts but not reversals or other discriminations.ResultsAtomoxetine remediated the attentional set-shifting impairments in NE-LX rats but impaired ED performance of non-lesioned rats.DiscussionThough atomoxetine is neurochemically selective, it is not wholly specific at doses >0.3 mg/kg. All doses of the drug were similar in their efficacy in reversing the ED deficit, but the effectiveness of the 0.1 mg/kg dose supports the hypothesis that increases in prefrontal NE alone are sufficient to improve attention in NE-LX rats. Moreover, the detrimental effects of the drug in non-lesioned rats support the hypothesis that optimal levels of NE in prefrontal cortex are critical to attentional set shifting with both supra- and sub-optimal levels producing attentional impairments.