Calcium-related Neurotoxicity of Cocaine

可卡因与钙相关的神经毒性

基本信息

批准号：
8607920
负责人：
Congwu Du
金额：
$ 41.17万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607920
关键词：
Acute Affect Animal Model Animals Blood Blood Vessels Blood Volume Blood flow Brain Brain Diseases Brain Injuries Brain region Calcium Calcium Channel Blockers Catheters Cerebrovascular Circulation Cerebrum Cessation of life Chronic Cocaine Cocaine Abuse Complement Core-Binding Factor Coupling Detection Drug Exposure Event Fluorescence Frequencies Functional Magnetic Resonance Imaging Functional disorder Goals Hemoglobin Hemorrhage Human Hypoxia Image Imaging Device Imaging Techniques Individual Intravenous Ischemia Lasers Lead Maps Measures Medial Modality Neurobiology Neurons Nucleus Accumbens Optical Coherence Tomography Optics Oxygen Pathology Pilot Projects Positron-Emission Tomography Prefrontal Cortex Probability Ramp Rattus Resolution Rodent Self Administration Self-Administered Stroke Syndrome Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect addiction base brain tissue capillary bed cerebrovascular channel blockers cocaine exposure cocaine use deoxyhemoglobin digital drug of abuse efficacy testing fluorescence imaging hemodynamics in vivo in vivo imaging insight medical complication neuroimaging neurotoxic neurotoxicity novel optical imaging prevent response spatiotemporal tissue oxygenation tool treatment strategy vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Cocaine-induced stroke and hemorrhage in the brain are among the most serious medical complications. The mechanisms underlying these effects are poorly understood but are likely to reflect in part its vasoactive effects that may be exacerbated with repeated drug exposures. Our poor understanding of the cerebrovascular effects of cocaine are due in part to technological limitations in our ability to concurrently assess and thus distinguish cocaine's neuronal effects from its vascular effects. Here we aim to apply our newly developed optical/ fluorescence imaging techniques (OFIs), to study separately the neuronal and cerebrovascular effects of acute and chronic cocaine exposures. OFIs integrate (1) dual-wavelength laser speckle imaging to enable concurrent detection of cerebral blood flow (CBF), blood volume (CBV), and tissue hemoglobin oxygenation (StO2) at high spatiotemporal resolutions across a large field of view, (2) digital-frequency-ramping Doppler optical coherence tomography for in vivo 3D quantitative imaging of the neurovascular network, (3) Rhod2 fluorescence imaging to measure intracellular calcium ([Ca2+]i), and (4) a micro-catheter probe (mOFI) to assess cocaine's effects on subcortical brain regions in real time and at high spatiotemporal resolution. Our pilot study has shown that acute cocaine decreases CBF while increasing deoxyhemoglobin content and increasing intracellular Ca content and that there is sensitization to these effects with repeated exposures. Since increases in intracellular [Ca2+]i are associated with neuronal death following ischemia, we hypothesize that these sensitized responses with chronic cocaine exposures increase the vulnerability of neuronal tissue to damage from hypoxia. To test these hypotheses, we will use OFIs to concurrently measure the effects of acute and chronic cocaine on cerebrovascular responses (CBF, CBV), tissue oxygenation (StO2) and neuronal [Ca2+]i changes in cortical and subcortical brain regions. We will use an animal model of compulsive cocaine self- administration (short and long access) that mimics key aspects of human addiction. In addition, we will examine the efficacy of calcium channel blockers in preventing cocaine-induced increases in intracellular Ca2+ content, as a potential therapeutic strategy to reduce cocaine's cerebrovascular toxicity. We propose the following Specific Aims: Assess the neuronal and vascular effects of acute and chronic cocaine on cortical (using OFI, Aim 1) and subcortical regions (using mOFI, Aim 2); Characterize the 'ischemia-like' neurovascular dysfunction resulting from chronic cocaine exposure (Aim 3), and examine the efficacy of calcium channel blockers to ameliorate cocaine-induced intracellular [Ca2+]i and hemodynamic changes in brain (Aim 4). The proposed studies will provide a better understanding of the mechanisms that underlie cocaine's cerebrovascular toxicity, which could help develop therapeutic interventions to counteract this toxicity. In addition, the proposed studies will introduce an imaging capability that could be applied to studies of the effects of other drugs of abuse and to studies of other brain disorders for which there are pertinent animal models.

描述（由申请人提供）：可卡因引起的中风和脑出血是最严重的医疗并发症之一。这些作用背后的机制尚不清楚，但可能部分反映了其血管活性作用，而反复接触药物可能会加剧这种作用。我们对可卡因的脑血管作用了解甚少，部分原因是我们同时评估并区分可卡因的神经元作用与其血管作用的能力受到技术限制。在这里，我们的目标是应用我们新开发的光学/荧光成像技术（OFI）来分别研究急性和慢性可卡因暴露对神经元和脑血管的影响。 OFI 集成 (1) 双波长激光散斑成像，能够在大视场中以高时空分辨率同时检测脑血流量 (CBF)、血容量 (CBV) 和组织血红蛋白氧合 (StO2)，(2)用于神经血管网络体内 3D 定量成像的数字频率斜坡多普勒光学相干断层扫描，(3) 用于测量细胞内钙的 Rhod2 荧光成像([Ca2+]i)，(4) 微导管探针 (mOFI)，用于实时、高时空分辨率评估可卡因对皮层下大脑区域的影响。我们的初步研究表明，急性可卡因会降低 CBF，同时增加脱氧血红蛋白含量和细胞内 Ca 含量，并且反复接触会对这些影响敏感。由于细胞内 [Ca2+]i 的增加与缺血后神经元死亡有关，因此我们假设长期接触可卡因引起的这些敏化反应增加了神经元组织对缺氧损伤的脆弱性。为了检验这些假设，我们将使用 OFI 同时测量急性和慢性可卡因对脑血管反应 (CBF、CBV)、组织氧合 (StO2) 以及皮质和皮质下脑区域神经元 [Ca2+]i 变化的影响。我们将使用强迫性可卡因自我给药（短期和长期使用）的动物模型来模拟人类成瘾的关键方面。此外，我们将检查钙通道阻滞剂在预防可卡因引起的细胞内 Ca2+ 含量增加方面的功效，作为减少可卡因脑血管毒性的潜在治疗策略。我们提出以下具体目标：评估急性和慢性可卡因对皮质（使用 OFI，目标 1）和皮质下区域（使用 mOFI，目标 2）的神经元和血管影响；描述慢性可卡因暴露导致的“缺血样”神经血管功能障碍（目标 3），并检查钙通道阻滞剂改善可卡因诱导的细胞内 [Ca2+]i 和大脑血流动力学变化的功效（目标 4）。拟议的研究将更好地了解可卡因脑血管毒性的机制，这可能有助于开发治疗干预措施来抵消这种毒性。此外，拟议的研究将引入一种成像功能，可应用于其他滥用药物的影响的研究以及有相关动物模型的其他脑部疾病的研究。