Astrocyte-mediated mechanisms of cocaine seeking

星形胶质细胞介导的可卡因寻求机制

基本信息

批准号：
9902393
负责人：
Kathryn Joanna Reissner
金额：
$ 33.64万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902393
关键词：
Abstinence Address Affect Agonist Area Astrocytes Award Bathing Behavioral Biology Brain Ceftriaxone Cells Cellular biology Characteristics Chemosensitization Chronic Cocaine Communication D-Amino Acid Dehydrogenase Data Development Down-Regulation Drug Exposure Drug usage Electrophysiology (science)Enzymes Extinction (Psychology)Frequencies Glial Fibrillary Acidic Protein Glutamate Transporter Glutamates Goals Grant Homeostasis Impairment Intervention Investigation Label Mediating Modeling Morphology N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Nucleus Accumbens Outcome Pathology Pharmaceutical Preparations Phase Property Psychostimulant dependence Public Health Rattus Recombinants Relapse Research Resolution Response to stimulus physiology Saline Self Administration Serine Signal Transduction Site Specificity Structure Substance Use Disorder Surface Synapses Testing Therapeutic Intervention Time Withdrawal addiction behavior measurement cocaine exposure cocaine use design drug of abuse experience experimental study extracellular fluorescence imaging glutamatergic signaling high resolution imaging insight neurotransmission novel patch clamp receptor function response restoration reward circuitry voltage

项目摘要

Project Summary/Abstract Propensity toward relapse is a hallmark feature of addiction. Hence, understanding the cellular mechanisms responsible for relapse vulnerability represents an important focus of addiction research. One significant and long-lasting cellular adaptation observed in response to multiple drugs of abuse is downregulation of astroglial glutamate transporter GLT-1. However, relatively very little is known about how drug self-administration affects astrocytes beyond GLT-1 expression, or how astrocytes may contribute to mechanisms of drug seeking. Results collected during the preceding K99/R00 award indicate that restored expression of GLT-1 is pivotal to the mechanism of action of multiple compounds that reduce behavioral measures of relapse in the rat self- administration and reinstatement model of addiction. Preliminary data also indicate that downregulation of GLT-1 by cocaine is accompanied by reduced expression of glial fibrillary acidic protein (GFAP) and a retraction of astrocytes in the nucleus accumbens core. Astrocyte retraction is characterized by decreased surface area, volume, and decreased synaptic contacts. This finding represents a heretofore-unappreciated fundamental consequence of cocaine use on astrocyte cell biology. Thus, decreased GLT-1 expression is a component of larger-scale adaptions in astrocyte biology that occur following chronic cocaine use. These findings have led to the hypothesis that astrocyte retraction in the nucleus accumbens of cocaine-withdrawn rats contributes to synaptic adaptations that drive cocaine seeking. In order to test this hypothesis, the specific goals of this proposal are: (1) to determine when during the addiction cycle the morphological effects on astrocytes are induced (2) to determine the functional relationship between astrocyte retraction and synaptic adaptations believed to underlie cocaine seeking, and (3) to determine the relationship between astrocyte retraction and drug seeking after cessation of drug use. These questions will be addressed by combining rat cocaine self-administration with behavioral measures of cocaine seeking, high-resolution imaging of fluorescently labeled astrocytes, and whole cell patch-clamp electrophysiology. These studies will provide novel insight into how cocaine-dependent adaptations in astrocyte dynamics contribute to the cellular and behavioral pathologies characteristic of psychostimulant addiction. These studies will also provide important information toward the translational potential of astrocytes as a pharmacotherapeutic target for substance use disorders.

项目概要/摘要复发倾向是成瘾的一个标志性特征。因此，了解细胞机制造成复吸脆弱性的原因是成瘾研究的一个重要焦点。一项重要且针对多种滥用药物观察到的持久细胞适应是星形胶质细胞的下调谷氨酸转运蛋白 GLT-1。然而，对于自我给药如何影响药物知之甚少。星形胶质细胞超越 GLT-1 表达，或星形胶质细胞如何促进药物寻找机制。在之前的 K99/R00 颁奖期间收集的结果表明，GLT-1 表达的恢复对于多种化合物减少大鼠自我复发行为指标的作用机制成瘾的管理和恢复模型。初步数据还表明，下调可卡因引起的 GLT-1 伴随着胶质纤维酸性蛋白 (GFAP) 表达的减少和伏隔核核心星形胶质细胞回缩。星形胶质细胞回缩的特点是减少表面积、体积和突触接触减少。这一发现代表了迄今为止未被重视的使用可卡因对星形胶质细胞生物学的根本后果。因此，GLT-1 表达减少是长期使用可卡因后发生的星形胶质细胞生物学大规模适应的组成部分。这些研究结果得出这样的假设：可卡因戒断后伏核中的星形胶质细胞收缩老鼠有助于突触适应，从而驱动可卡因的寻找。为了验证这一假设，具体该提案的目标是：（1）确定成瘾周期中形态学对成瘾周期的影响。诱导星形胶质细胞 (2) 以确定星形胶质细胞回缩和突触之间的功能关系适应被认为是可卡因寻求的基础，并且（3）确定星形胶质细胞之间的关系戒毒后的退缩和寻求药物。这些问题将通过结合大鼠可卡因自我管理与可卡因寻求的行为测量，高分辨率成像荧光标记的星形胶质细胞和全细胞膜片钳电生理学。这些研究将提供关于星形胶质细胞动力学中可卡因依赖性适应如何促进细胞和精神兴奋剂成瘾的行为病理学特征。这些研究还将提供重要的关于星形胶质细胞作为物质使用药物治疗靶点的转化潜力的信息失调。