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“古典” DA（DA）假设提出，DA传播的多动症是导致在这种疾病中观察到的正症状（幻觉，妄想）。最近的几项研究表明，未经治疗的精神分裂症患者在整个纹状体水平上测量的苯丙胺诱导的DA释放增加了。这些发现表明，精神分裂症中纹状体DA释放的异常调节。这些先前研究的两个重要局限性是，这些测量值仅限于纹状体和整个纹状体。所使用的配体没有提供足够的信号与噪声比来量化外牙和所用相机中的D2受体 没有将信号与腹侧和背纹状体区分开所需的分辨率。现在，放射化学和仪器的最新发展允许使用PET对DA前功能进行更详细的映射。 我们最近获得了证据表明，新的PET D2受体放射性示踪剂[TSF] FallyPride可以对纹状体和层表外D2受体进行可靠的测量，并且其结合容易受到内源性DA中急性波动的影响。此外，我们最近证明了PET摄像机ECAT精确的HR+提供了瓷砖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，正如预期的那样，精神分裂症中的DA传播并未升高，而是在杂前的背侧尾状核（PARECCA）中，这是处理信息的纹状体区域；从侧侧前额叶皮层（DLPFC）流动。 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杏仁核）和中层系统（时间和扣带皮层）。 假设是，苯丙胺诱导的DA释放将升高在PERDCA中，并在精神分裂症患者的中皮层DA系统中钝化。 该项目的结果将告知Javitt，Kandel，Rayport在项目中开发的动物模型，并将提供有关精神分裂症的神经生物学见解，这对于开发更为集中的治疗方法至关重要。