Neuropathology of dopamine systems in schizophrenia

精神分裂症多巴胺系统的神经病理学

• 批准号: 7171934
• 负责人: Rosalinda C Roberts
• 金额: $ 27.56万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7171934
• 关键词: Accounting; Actins; Adverse effects; Affect; Animals; Antipsychotic Agents; Area; Autopsy; Basal Ganglia; Behavior; Brain; Cells; Cellular Morphology; Cessation of life; Chlorpromazine; Chromosome Pairing; Clozapine; Cognition; Cognitive; Corpus striatum structure; Cytoskeletal Proteins; Data; Development; Devices; Disease; Dopamine; Dopamine D2 Receptor; Dyskinetic syndrome; Electrons; Emotional; Enzymes; Exhibits; Functional disorder; Genetic Transcription; Glutamates; Haloperidol; Heterogeneity; Housing; Human; Hyperactive behavior; Image; In Situ Hybridization; Knowledge; Label; Lesion; Light; Localized; Location; Measures; Messenger RNA; Methods; Microscopic; Midbrain structure; Morphology; Motor; Movement Disorders; Neurons; Normal tissue morphology; Nucleus Accumbens; Numbers; Organelles; Parents; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Population; Production; Proteins; Published Comment; Publishing; Rattus; Role; Sales; Schizophrenia; Screening procedure; Series; Site; Staining method; Stains; Structure; Study Section; Substantia nigra structure; Symptoms; Synapses; System; Techniques; Testing; Therapeutic Effect; Time; Time Study; Tissues; Tyrosine 3-Monooxygenase; Variant; Ventral Tegmental Area; Week; Western Blotting; Work; atypical antipsychotic; base; case control; density; design; dopamine system; dopamine transporter; dopaminergic neuron; human tissue; in vivo; insight; neuropathology; pars compacta; prevent; research study; response; size

DESCRIPTION (provided by applicant): Schizophrenia is a devastating illness, with unknown pathophysiology, that affects 1% of the world's population. The experiments in the following revised proposal will focus on the basal ganglia and dopamine (DA) pathology in schizophrenia (SA1) and relate these changes to those occurring in rats treated with antipsychotic drugs (APDs) (SA2). Our preliminary data shows abnormalities in morphology of DAergic neurons in the substantia nigra (SN) and in the number of TH+ striatal synapses in electron microscopic (EM) studies of postmortem tissue from subjects with schizophrenia (SZ), similar structural changes and a decrease in number of TH+ cells in rats treated with APD. SA1 tests the hypothesis that the DA system is perturbed in the basal ganglia of SZ, using tissue from normal controls, SZ treated with typical or atypical APDs or off-drug. SA2 tests the hypothesis that anatomical changes observed in SN and ventral tegmental area (VTA) of SZ are the results, in part, of APDs, and will determine the contributing physiological mechanisms. In both aims, we will determine if the morphological alterations seen will show regional variations that are consistent with the differential effects of typical and atypical APDs on the activity of midbrain DA neurons. In this revision, we have modified the EM analysis of the SN and added 3 parallel experiments in both the human tissue and rats (treated with haloperidol or clozapine or controls). In SA1a the synaptic organization of DA labeled profiles will be analyzed in the human striatum at the EM level. In SA1b & SA2a, the number and size of Nissl stained, and TH+ cells double labeled with the DA transporter (DAT), or a selective marker of DA cells, SK3, will be determined using stereological methods in the SN/VTA. In SA1c & SA2b at the EM level, the integrity of subcellular organelles and the synaptic organization to the TH+ neurons (also labeled with DAT or SK3) will be studied. Using in situ hybridization SA1d & SA2e will determine if TH synthesis is affected at the level of transcription. SA1c & SA2d will determine if cytoskeletal proteins are upregulated. SA1f & SA2e will determine if the loss of TH in neurons is due to changes at the translational level by using Western blot analysis. SA2f will study the time course of the anatomical changes observed during APD treatment and relate these changes to the development of depolarization (DP) block. SA2g tests the hypothesis that morphological alterations in SN/VTA neurons will not occur in rats treated with APD if DP block is prevented (with a unilateral striatal lesion).

描述(申请人提供)：精神分裂症是一种毁灭性的疾病，病理生理未知，影响世界1%的人口。以下修订提案中的实验将侧重于精神分裂症(SA1)中的基底节和多巴胺(DA)病理，并将这些变化与抗精神病药物(APDS)治疗的大鼠(SA2)中发生的变化联系起来。我们的初步数据显示，在精神分裂症(SZ)患者死后组织的电子显微镜(EM)研究中，黑质(SN)中的DA能神经元的形态和TH+纹状体突触的数量出现了异常，类似的结构变化和经apd处理的大鼠的TH+细胞数量减少。SA1使用正常对照组、典型或非典型APDS或非药物治疗的SZ的组织，检验了SZ基底节DA系统受到干扰的假设。SA2验证了这样一种假设，即在SZ的SN和腹侧被盖区(VTA)观察到的解剖学变化部分是APDS的结果，并将确定其起作用的生理机制。在这两个目标中，我们将确定所看到的形态变化是否会显示出与典型和非典型APD对中脑DA神经元活动的不同影响相一致的区域性差异。在这次修订中，我们修改了对SN的EM分析，并在人类组织和大鼠(用氟哌啶醇或氯氮平或对照治疗)中增加了3个平行实验。在SA1a中，DA标记轮廓的突触组织将在EM水平上在人类纹状体中进行分析。在SA1b和SA2a中，Nissl染色的数量和大小以及TH+细胞与DA转运体(DAT)或DA细胞的选择性标记SK3的双重标记将在SN/VTA中用体视学方法确定。在EM水平的SA1c和SA2b中，将研究亚细胞器的完整性和与TH+神经元(也被DAT或SK3标记)的突触组织。通过原位杂交，SA1d和SA2e将确定TH的合成是否在转录水平上受到影响。SA1c和SA2d将决定细胞骨架蛋白是否上调。SA1f和SA2e将通过蛋白质印迹分析来确定神经元TH的丢失是否是由于翻译水平的变化。SA2f将研究APD术期间观察到的解剖变化的时间进程，并将这些变化与去极化(DP)传导阻滞的发展联系起来。SA2g测试了一种假设，即如果阻止了DP阻断(伴有单侧纹状体损害)，则在接受雪崩治疗的大鼠中，SN/VTA神经元不会发生形态变化。