Synaptic Mechanisms of Dopaminergically Mediated MRI Signal Changes

多巴胺能介导的 MRI 信号变化的突触机制

• 批准号: 6358943
• 负责人: Bruce G Jenkins
• 金额: $ 16.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6358943
• 关键词: amphetamines; apomorphine; bioimaging /biomedical imaging; brain circulation; brain imaging /visualization /scanning; brain mapping; cocaine; dopamine receptor; dopamine transporter; drug addiction; functional magnetic resonance imaging; hemodynamics; laboratory rat; microdialysis; neuropharmacology; neurotransmitter metabolism; oxygen tension; positron emission tomography; receptor binding; receptor sensitivity; synapses

The underlying goal of this project is to understand the molecular and synaptic processes that drive the hemodynamic response to a dopaminergic stimulus. This knowledge is crucial to proper interpretation of the changes observed in humans after pharmacologic challenges such as cocaine or amphetamine. First, we will study the effects of blockers of the dopamine transporter (DAT) (such as cocaine or amphetamine) on the regional distribution of hemodynamic responses in rat brains using pharmacological MRI (phMRI) measurements of blood oxygenation level dependent (BOLD) contrast or relative cerebral blood volume (rCBV). Then we will test the ability of selective dopamine D1 and D2 antagonists to block the phMRI signal changes. These experiments will be followed by study of the hemodynamic consequences of the interactions between dopamine receptors and adenosine receptors by selective antagonism of the adenosine system in combination with stimulus delivered using DAT blockers. Concurrently, we will test the hypothesis that hemodynamic changes are proportional to dopamine concentrations by making microdialysis measurements of dopamine concentrations in striatum and frontal cortex. Then we will preform selective pre-synaptic dopamine fiber lesions using unilateral injections of 6-hydroxydopamine in the substantia nigra, and selective unilateral lesioning of the post-synaptic striatal neurons using quinolinic acid injections. Then we will perform rCBV measurements in these animals After stimulus using DAT blockers to test whether the origins of the phMRI signals are pre-or post-synaptic. We will also perform correlative positron emission tomography (PET) measurements of DAT, and D1 and D2 receptors to determine their correlations with the phMRI. Then, we will examine the role of receptor supersensitivity using the lesion models above to determine the quantitative differences between the two striata after stimulation with apomorphine or amphetamine, two compounds known to elicit opposite behavioral effects in these lesion models based upon dopamine receptor supersensitivity. These results will be correlated with quantitative PET measurements in the same animals of dopamine receptor binding properties. Lastly, these studies will be followed by quantitative PET measurements in rats who chronically self administer cocaine to determine what changes in dopamine receptor binding properties accompany chronic cocaine administration. These studies should lead to a fundamental understanding of the synaptic and molecular underpinnings of behavioral-metabolic coupling which is crucial to developing a biological basis for understanding of human drug abuse.

这个项目的基本目标是了解分子和突触过程，驱动血液动力学反应多巴胺能刺激。这些知识对于正确解释在人体中观察到的可卡因或安非他明等药理学挑战后的变化至关重要。首先，我们将研究多巴胺转运蛋白（DAT）的阻滞剂（如可卡因或安非他明）对大鼠大脑中的血液动力学反应的区域分布的影响，使用药理学MRI（phMRI）测量血氧水平依赖（BOLD）对比度或相对脑血容量（rCBV）。然后，我们将测试选择性多巴胺D1和D2拮抗剂阻断phMRI信号变化的能力。在这些实验之后，将通过腺苷系统的选择性拮抗作用与使用DAT阻断剂递送的刺激相结合，研究多巴胺受体和腺苷受体之间相互作用的血流动力学后果。同时，我们将测试的假设，即血流动力学的变化是成正比的多巴胺浓度的纹状体和额叶皮质的多巴胺浓度的微透析测量。然后，我们将预制选择性突触前多巴胺纤维病变，使用6-羟基多巴胺在黑质的单侧注射，和选择性单侧病变的突触后纹状体神经元，使用喹啉酸注射。然后，我们将在这些动物中使用DAT阻断剂进行刺激后的rCBV测量，以测试phMRI信号的起源是突触前还是突触后。我们还将对DAT、D1和D2受体进行相关正电子发射断层扫描（PET）测量，以确定它们与phMRI的相关性。然后，我们将使用上述损伤模型来检查受体超敏性的作用，以确定用阿扑吗啡或安非他明刺激后两个纹状体之间的定量差异，这两种化合物已知在这些基于多巴胺受体超敏性的损伤模型中引起相反的行为效应。这些结果将与多巴胺受体结合特性的相同动物中的定量PET测量相关联。最后，这些研究将在长期自我施用可卡因的大鼠中进行定量PET测量，以确定多巴胺受体结合特性的变化伴随着长期可卡因施用。这些研究应导致对行为代谢耦合的突触和分子基础的基本理解，这对于建立理解人类药物滥用的生物学基础至关重要。