Calcium-related Neurotoxicity of Cocaine

可卡因与钙相关的神经毒性

• 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
• 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

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大脑出血是最严重的医疗并发症之一。这些作用的基础机制知之甚少，但很可能部分反映了其血管活性作用，可能会因反复的药物暴露而加剧。我们对可卡因脑血管作用的不良理解部分是由于我们同时评估可卡因的神经元作用与其血管作用的技术局限性。在这里，我们旨在应用新开发的光学/荧光成像技术（OFIS），以分别研究急性和慢性可卡因暴露的神经元和脑血管效应。 OFIS整合（1）双波长激光斑点成像，以在高时空分辨率上同时检测大脑血流（CBF），血容量（CBV）和组织血红蛋白氧合（STO2），并在高时空分辨率上进行高度时空的分辨率（2）数字化量化量的数字化量化，以供数字化的数字化量化量表神经血管网络的（3）Rhod2荧光成像，以测量细胞内钙（[CA2+] I），以及（4）微型导管探针（MOFI），以评估可卡因实时和高时空分辨率的可卡因对皮质下脑区域的影响。 我们的试点研究表明，急性可卡因会降低CBF，同时增加脱氧血红蛋白含量并增加细胞内Ca含量，并且随着反复的暴露对这些影响具有敏感性。由于缺血后的细胞内[Ca2+] I的增加与神经元死亡有关，因此我们假设这些慢性可卡因暴露的敏化反应增加了神经元组织对缺氧损害的脆弱性。为了检验这些假设，我们将使用IS同时测量急性和可卡因对脑血管反应（CBF，CBV），组织氧合（STO2）和神经元[CA2+] I的影响。我们将使用一种强迫性可卡因自我给药（短而长）的动物模型，该模型模仿了人类成瘾的关键方面。此外，我们将研究钙通道阻滞剂在防止可卡因诱导的细胞内Ca2+含量增加的功效，这是降低可卡因脑血管毒性的潜在治疗策略。我们提出以下特定目的：评估急性和可卡因对皮质（使用OFI，AIM 1）和皮层下区域（使用MOFI，AIM 2）的神经元和血管作用；表征慢性可卡因暴露引起的“缺血状”神经血管功能障碍（AIM 3），并检查钙通道阻滞剂改善可卡因可卡因诱导的细胞内[Ca2+] I和大脑血液动力学变化的疗效（AIM 4）。 拟议的研究将更好地理解可卡因脑血管毒性基础的机制，这可能有助于开发治疗干预措施以抵消这种毒性。此外，拟议的研究将引入成像能力，可以应用于其他滥用药物的作用以及对存在相关动物模型的其他脑疾病的研究。