Dopamine pathology in schizophrenia: analysis of total and phosphorylated tyrosine hydroxylase in the substantia nigra.
Dopamine pathology in schizophrenia: analysis of total and phosphorylated tyrosine hydroxylase in the substantia nigra.
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DOI：
10.3389/fpsyt.2012.00031
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发表时间：
2012
影响因子：
4.7
通讯作者：
Roberts RC
中科院分区：
文献类型：
--
作者：
Perez-Costas E;Melendez-Ferro M;Rice MW;Conley RR;Roberts RC
尽管多巴胺神经传递在精神分裂症中的重要性，但很少有研究涉及黑质/腹侧被盖区（SN/VTA）中脑多巴胺能神经元的异常。酪氨酸羟化酶（TH）是多巴胺生成的限速酶，可能是精神分裂症中多巴胺能神经传递异常的一个原因。目的：在本研究中，我们有三个目的：(1)比较精神分裂症和对照组死后样本中SN/VTA中TH的表达（mRNA和蛋白）。(2)评估抗精神病药物对SN/VTA中TH表达的影响。(3)检查SN/VTA内TH表达异常可能存在的区域差异。方法：为了实现这些目标，进行了三项独立研究：(1)比较精神分裂症和对照组死后样本SN/VTA中TH mRNA和TH蛋白水平的初步研究。(2)通过啮齿动物慢性治疗研究，评估抗精神病药物对SN/VTA内TH蛋白水平的影响。(3)在两种类型的样本中进行了第二次尸检研究，以评估TH和磷酸化的TH蛋白水平：精神分裂症和对照组样本包含整个SN/VTA的上尾端范围，精神分裂症和对照组样本只包含SN/VTA的中尾端区域。结果和结论：我们的研究表明，精神分裂症患者多巴胺能系统的损伤可能主要（或完全）位于SN/VTA的吻侧区域。我们的研究还表明，精神分裂症患者TH蛋白水平明显异常，而mRNA表达水平未受影响，提示该区域TH病理可能发生在转录后。最后，我们的抗精神病动物治疗研究表明，抗精神病药物对TH蛋白水平没有显著影响，这表明这些异常是一种内在病理，而不是治疗效果。
Introduction: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. Objectives: In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. Methods: To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. Results and Conclusion: Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect.