SUBCORTICAL DA FUNCTION IN SCHIZOPHRENIA

精神分裂症的皮质下 DA 功能

• 批准号: 7457808
• 负责人: MARC A LARUELLE
• 金额: $ 20.91万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7457808
• 关键词: Acute; Amphetamines; Amygdaloid structure; Animal Model; Binding; Computer information processing; Corpus striatum structure; Data; Delusions; Development; Disease; Dopamine D2 Receptor; Dorsal; Hallucinations; Hippocampus (Brain); Hyperactive behavior; Lateral; Ligands; Maps; Measurement; Measures; N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; Neurobiology; Noise; Papio; Patients; Positron-Emission Tomography; Prefrontal Cortex; Radiochemistry; Regulation; Resolution; Schizophrenia; Signal Transduction; Symptoms; System; Therapeutic; Ventral Striatum; caudate nucleus; cingulate cortex; insight; instrumentation; mesolimbic system; presynaptic; putamen; radiotracer; transmission process

The "classical" DA (DA) hypothesis of schizophrenia proposed that hyperactivity of DA transmission is responsible for the positive symptoms (hallucinations, delusions) observed in this disorder . Several studies have recently demonstrated that amphetamine-induced DA release, measured at the level of the striatum as a whole, was increased in untreated patients with schizophrenia. These findings suggested an abnormal regulation of striatal DA release in schizophrenia. Two important limitations of these previous studies are that these measurements were restricted to the striatum and to the striatum as a whole. The ligands used did not provide enough signal to noise ratio to quantify D2 receptors in extrastriatal and the cameras used did not have the resolution required to differentiate the signals from ventral and dorsal striata. Recent developments in radiochemistry and instrumentation now permit a much more detailed mapping of DA presynaptic function with PET. We recently obtained evidence that the new PET D2 receptor radiotracer, [tSF]fallypride enable reliable measurements of both striatal and extrastriatal D2 receptors, and that its binding is vulnerable to acute fluctuations in endogenous DA. Furthermore, we recently demonstrated that the PET camera ECAT EXACT HR+ provides tile resolution to Study functional subdivisions of the Striatum. In preiiminary data, we made the observation that DA transmission in schizophrenia is not elevated in the ventral striatum, as anticipated, but rather in the precommiissural dorsal caudate nucleus (preDCA), the Striatal region that processes information; flow from the dorso- lateral prefrontal cortex (DLPFC). Here, we propose to further validate the use of [18F]fallypride to detect changes in endogenous DA in striatal and extrastriatal regions in baboons (specific aim 1) and healthy controls (specific aim 2), and study amphetamine-induced DA release in the nigro-striatal system (caudate and putamen), mesolimbic system (ventral striatum,, hippocampus and amygdala) and mesoeortical system (temporal and cingulate cortices). The hypothesis is that amphetamine-induced DA release will be elevated in the preDCA and blunted in mesocorticat DA system in patients with schizophrenia. Results from this Project will inform animals models developed in Projects by Javitt, Kandel, Rayport, and will provide neurobiological insights about schizophrenia that will be important for the development of more focused therapeutic approaches.

精神分裂症的“经典”DA（DA）假说提出，DA 传输过度活跃是在这种疾病中观察到的阳性症状（幻觉、妄想）的原因。最近的几项研究表明，在未经治疗的精神分裂症患者中，在整个纹状体水平上测量的苯丙胺诱导的 DA 释放增加。这些发现表明精神分裂症患者纹状体 DA 释放存在异常调节。这些先前研究的两个重要局限性是这些测量仅限于纹状体和整个纹状体。使用的配体没有提供足够的信噪比来量化纹状体外的 D2 受体和使用的相机 不具备区分腹侧纹状体和背侧纹状体信号所需的分辨率。放射化学和仪器的最新发展现在允许使用 PET 更详细地绘制 DA 突触前功能。 我们最近获得的证据表明，新型 PET D2 受体放射性示踪剂 [tSF]fallypride 能够可靠地测量纹状体和纹状体外 D2 受体，并且其结合容易受到内源 DA 急剧波动的影响。此外，我们最近证明 PET 相机 ECAT EXACT HR+ 提供切片分辨率来研究纹状体的功能细分。在初步数据中，我们观察到精神分裂症患者的 DA 传输并未像预期的那样在腹侧纹状体中升高，而是在前连合背侧尾状核 (preDCA)（处理信息的纹状体区域）中升高。来自背外侧前额皮质（DLPFC）的流量。 在这里，我们建议进一步验证使用[18F]fallypride来检测狒狒（具体目标1）和健康对照（具体目标2）纹状体和纹状体外区域内源性DA的变化，并研究安非他明诱导的DA释放黑质纹状体系统（尾状核和壳核）、中脑边缘系统（腹侧纹状体、海马体和杏仁核）和中皮层系统（颞叶皮质和扣带皮层）。 假设精神分裂症患者的前 DCA 中安非他明诱导的 DA 释放会升高，而中皮质 DA 系统中的 DA 释放会减弱。 该项目的结果将为 Javitt、Kandel、Rayport 项目中开发的动物模型提供信息，并将提供有关精神分裂症的神经生物学见解，这对于开发更有针对性的治疗方法非常重要。