Dysfunctions in dopamine systems and ADHD: evidence from animals and modeling.
Dysfunctions in dopamine systems and ADHD: evidence from animals and modeling.
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DOI：
10.1155/np.2004.97
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发表时间：
2004
影响因子：
3.1
通讯作者：
Sadile, Adolfo
中科院分区：
文献类型：
--
作者：
Viggiano, Davide;Vallone, Daniela;Sadile, Adolfo
动物模型可用于表征神经精神障碍的神经基质。已经提出了几种模型用于研究注意缺陷多动障碍（ADHD）。这些模型可以分为不同的组：（i）遗传来源的多动症/注意力不集中，（ii）药物干预后显示症状的动物模型，以及（iii）基于随机群体中自发变化的模型。自发性高血压（SHR）和那不勒斯高兴奋性（NHE）大鼠表现出人类ADHD主要方面的行为特征，但多巴胺（DA）系统表现出不同的变化。事实上，酪氨酸羟化酶在NHE大鼠中高表达，而在SHR中低表达。DA转运蛋白在两种细胞系中均高表达，但在SHR中，DAT活性较低（DA摄取减少）。纹状体和前额叶皮质中的DA水平在幼年SHR中增加，但在处理的年轻和非处理的老年动物中降低。D1 DA受体mRNA在SHR前额叶皮质上调，在NHE下调。D2 DA受体可能在SHR中功能低下，尽管实验证据不是单一的，而它们的mRNA在NHE中高表达。因此，在SHR的中皮层和mesolimbic DA通路似乎参与，而在NHE只有中皮层系统。为了了解哌醋甲酯，选择性ADHD药物治疗人类，在一个功能失调的DA系统的影响，我们实现了一个简单的数学模型的DA调节的基础上，从电生理学，循环伏安法和微透析研究的实验数据。该模型允许估计SHR大鼠DA神经元的较高放电频率，并表明哌甲酯通过调节DA神经元的放电频率来增加注意过程。
Animal models are useful for characterizing neural substrates of neuropsychiatric disorders. Several models have been proposed for the study of Attention Deficit Hyperactivity Disorder (ADHD). The models can be divided into various groups: (i) genetically derived hyperactivity/ inattention, (ii) animal models showing symptoms after pharmacological intervention, and (iii) those based on spontaneous variations in a random population. Spontaneously hypertensive (SHR) and Naples High Excitability (NHE) rats show behavioral traits featuring the main aspects of ADHD in humans but show different changes in dopamine (DA) systems. In fact, the enzyme tyrosine hydroxylase is hyperexpressed in NHE rats and hypoexpressed in SHR. The DA transporter is hyperexpressed in both lines, although in the SHR, DAT activity is low (reduced DA uptake). The DA levels in the striatum and prefrontal cortex are increased in the juvenile SHR, but are decreased in handled young and non-handled older animals. The mRNA of the D1 DA receptor is upregulated in the prefrontal cortex of SHR and downregulated in NHE. The D2 DA receptors are likely to be hypofunctioning in SHR, although the experimental evidence is not univocal, whereas their mRNA is hyperexpressed in NHE. Thus, in SHR both the mesocortical and mesolimbic DA pathways appear to be involved, whereas in NHE only the mesocortical system. To understand the effects of methylphenidate, the elective ADHD drug treatment in humans, in a dysfunctioning DA system, we realized a simple mathematical model of DA regulation based on experimental data from electrophysiological, cyclic voltammetry, and microdialysis studies. This model allows the estimation of a higher firing frequency of DA neurons in SHR rats and suggests that methylphenidate increases attentive processes by regulating the firing rate of DA neurons.