STRIATAL AND EXTRASTRIATAL DOPAMINERGIC NEUROTRANSMISSION IN SCHIZOPHRENIA

精神分裂症的纹状体和纹状体外多巴胺能神经传递

• 批准号: 6111449
• 负责人: ROBERT B INNIS
• 金额: $ 30.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-26 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6111449
• 关键词: baboons; blood chemistry; clinical research; corpus striatum; dopamine; dopamine receptor; dopamine transporter; human subject; image processing; magnetic resonance imaging; neuropathology; neurotransmitter biosynthesis; radiotracer; receptor expression; schizophrenia; single photon emission computed tomography; statistics /biometry; synapses; temporal lobe /cortex; thalamus

Striatal and Extrastriatal Dopaminergic Neurotransmission to Schizophrenia The dopamine (DA) hypothesis of schizophrenia, formulated more than 30 years ago, still lacks definitive experimental validation and must be modified to account for the diversity and complexity of DA transmission in cortical and subcortical regions of the brain. Using state-of the-art radio-tracer imaging techniques, this project will assess dopaminergic function in both cortex and striatum of patients with schizophrenia compared to healthy thalamus, and striatum but also, using a novel pharmacological approach, the synaptic levels of the neurotransmitter itself, i.e. dopamine. These studies will provide information never previously obtained in either schizophrenic or healthy subjects and will directly test theories of dopamine's involvement in the pathophysiology of psychosis. Using SPECT (single photon emission computed tomography) D2 receptor imaging in the striatum combined with an amphetamine challenge, we previously found that schizophrenic patients have an elevated release of dopamine and that transient increases in psychotic symptoms were correlated with the amount of DA receptors in thalamus and temporal cortex and by measuring baseline synaptic DA levels. D2 receptors will be imaged with an equilibrium paradigm using the high affinity tracer [123I]epidepride (EPID). Synaptic levels of DA will be assessed with a second [123I]EPID scan, obtained after DA depletion induced by two days treatment with the synthesis inhibitor alpha-methyl-paratyrosine (AMPT). We have shown that treatment of both baboons and healthy subjects with AMPT depletes DA levels, "unmasks" receptors which were occupied by the transmitter; and, thereby, increases radio-tracer binding to the D2 receptor. We hypothesize that patients with schizophrenia will show a dysregulated of cortical and subcortical DA transmission. Specifically, patients will show higher DA transmission in temporal cortex than striatum, which will be assessed as the % D2 receptors unmasked in temporal cortex compared to % D2 receptors unmasked in striatum. Furthermore, the comparison of schizophrenic patients and healthy subjects on scan 1 alone will provide new imaging data (not previously published) on the baseline levels of extrastriatal D2 receptors in this disorder.

精神分裂症的纹状体和纹状体外多巴胺能神经传递 精神分裂症的多巴胺（DA）假说，制定了30多个 多年前，仍然缺乏明确的实验验证，必须 修改以考虑DA传输的多样性和复杂性， 大脑的皮质和皮质下区域。使用最先进的 放射性示踪剂成像技术，该项目将评估多巴胺能 精神分裂症患者皮层和纹状体功能的研究 与健康的丘脑和纹状体相比， 药理学方法，神经递质的突触水平 本身，即多巴胺。这些研究将提供信息， 之前在精神分裂症患者或健康受试者中获得过，并且将 直接测试多巴胺参与的病理生理学理论， 精神病 使用SPECT（单光子发射计算机断层扫描）D2受体 在纹状体成像结合安非他明的挑战，我们 以前发现精神分裂症患者有一个升高的释放 多巴胺和精神病症状的短暂增加， 与丘脑和颞叶皮层DA受体数量相关 以及测量突触DA水平的基线。D2受体将成像 使用高亲和力示踪剂的平衡范例 [123 I]马普莱德（EPID）。DA的突触水平将用 第二次[123I] EPID扫描，在两天诱导DA耗竭后获得 用合成抑制剂α-甲基-对酪氨酸（AMPT）处理。 我们已经表明，狒狒和健康受试者的治疗， AMPT消耗DA水平，"暴露"受体，这些受体被 发射器;并由此增加放射性示踪剂与D2的结合 受体的我们假设精神分裂症患者会表现出 皮质和皮质下DA传递失调。具体地说， 患者在颞叶皮层中的DA传递高于 纹状体，其将被评估为% D2受体未掩蔽， 与纹状体中未掩蔽的% D2受体相比，颞叶皮层。 此外，精神分裂症患者和健康人的比较 仅扫描1将提供新的成像数据（以前未发表） 纹状体外D2受体的基线水平。