Calcium-related neurotoxicity of cocaine

可卡因与钙相关的神经毒性

• 批准号: 10133028
• 负责人: Congwu Du
• 金额: $ 40.44万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10133028
• 关键词: 3-Dimensional; Acute; Affect; Angiography; Animal Model; Animals; Astrocytes; Behavioral; Blood Vessels; Brain; Brain Diseases; Calcium; Caliber; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Cocaine; Cocaine Dependence; Complement; Consumption; Development; Doppler tomography; Fluorescence; Functional disorder; Glial Fibrillary Acidic Protein; Hemoglobin; Human; Image; Imaging Techniques; Impairment; Individual; Intake; Intervention; Ischemia; Knowledge; Measures; Mediating; Modality; Multi-modal optical imaging; Mus; Neuroglia; Neurons; Optics; Paralysed; Pharmaceutical Preparations; Pilot Projects; Play; Prefrontal Cortex; Reporting; Resolution; Role; Self Administration; Severities; Techniques; Transient Ischemic Attack; addiction; cerebral hemodynamics; cocaine self-administration; cocaine use; designer receptors exclusively activated by designer drugs; efficacy testing; fluorescence imaging; imaging platform; imaging study; improved; in vivo; insight; neuroimaging; neurotoxic; neurotoxicity; neurovascular; neurovascular coupling; novel; novel imaging technique; prevent; quantitative imaging; response; vasoconstriction

Disfunction of the prefrontal cortex (PFC), plays a crucial role in compulsive cocaine use and addiction. The role of glia in addition to that of neurons and vascular networks in cocaine-induced PFC dysfunction remains elusive. In the completing R01, we showed that the neurotoxic effects of cocaine were associated with persistent decreases in cerebral blood flow (CBF) and an elevation in intracellular calcium in cortex; however, we did not assess the role of glia versus that of neurons on the CBF decreases. This renewal application, "Calcium-related neurotoxicity of cocaine", will assess the effects of acute and chronic cocaine on astrocytic Ca2+ and its role on the CBF deficits and neuronal Ca2+ increases in PFC and their association with cocaine intake in an animal model of compulsive-like cocaine self-administration. Specifically, we will apply multimodality optical imaging (MOI) in combination with genetically-encoded Ca2+ indicators to capture activities in neurons (jRGECO1a) and astrocytes (GCaMP6f) and ultrahigh- resolution optical coherence angiography and Doppler tomography (µODT) for quantitative imaging of 3D CBF networks in PFC of GFAP cre mice (Aim 1). We will apply chemogenetics with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to manipulate astrocytic Ca2+ accumulation while assessing its consequences on acute and chronic cocaine’s vascular and neuronal effects and cocaine intake (Aim 2, Aim 3). These studies will be valuable for understanding how astrocyte and neuronal networks in the PFC interact and mediate the associated local neurovascular responses to cocaine and how they contribute to compulsive-like drug consumption, providing knowledge to guide development of novel addiction interventions.

前额叶皮层（PFC）的不函数在强迫可卡因的使用和成瘾中起着至关重要的作用。 除了可卡因诱导的PFC功能障碍中神经元和血管网络的作用外 仍然难以捉摸。在完成R01中，我们表明可卡因的神经毒性作用是相关的 脑血流（CBF）持续下降，皮质中细胞内钙的升高； 但是，我们没有评估神经胶质与神经元在CBF下降中的作用。这个更新 应用“与钙相关的可卡因的神经毒性”将评估急性和慢性可卡因的影响 关于星形胶质细胞CA2+及其在CBF上的作用定义了PFC及其关联的神经元Ca2+增加 在强迫性可卡因自我管理的动物模型中可卡因摄入量。 具体而言，我们将与一般编码的多模式光学成像（MOI）一起应用 CA2+指标捕获神经元（JRGECO1A）和星形胶质细胞（GCAMP6F）和Ultrahigh-的活动 分辨率光相干血管造影和多普勒层析成像（µODT）用于3D定量成像 GFAP CRE小鼠PFC中的CBF网络（AIM 1）。我们将与设计器受体应用化学遗传学 由设计师药物（Dreadds）专门激活，以操纵星形胶质细胞CA2+积累 评估其对急性和慢性可卡因血管和神经元作用以及可卡因的后果 进气（AIM 2，AIM 3）。 这些研究对于了解PFC中的星形胶质细胞和神经元网络将是有价值的 相互作用并调解相关的局部神经血管对可卡因的反应，以及它们如何贡献 强迫性药物消耗，提供知识来指导新成瘾的发展 干预措施。