Calcium-related neurotoxicity of cocaine

可卡因与钙相关的神经毒性

• 批准号: 9886788
• 负责人: Congwu Du
• 金额: $ 42.87万
• 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/9886788
• 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 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.

前额皮质（PFC）功能障碍在强迫性可卡因使用和成瘾中起着至关重要的作用。