Astrocyte-mediated mechanisms of cocaine seeking

星形胶质细胞介导的可卡因寻求机制

• 批准号: 9193717
• 负责人: Kathryn Joanna Reissner
• 金额: $ 32.11万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193717
• 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); Employee Strikes; Enzymes; Extinction (Psychology); Frequencies; Glial Fibrillary Acidic Protein; Glutamate Transporter; Glutamates; Goals; Grant; Homeostasis; Image; Intervention; Investigation; Label; Mediating; Modeling; 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; abstracting; addiction; behavior measurement; cocaine exposure; cocaine use; design; drug mechanism; drug of abuse; experience; extracellular; fluorescence imaging; glutamatergic signaling; insight; neurotransmission; novel; patch clamp; receptor function; research study; response; restoration; reward circuitry; voltage

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.

项目摘要/摘要 复发的倾向是成瘾的标志性特征。因此，了解细胞机制 负责复发脆弱性是成瘾研究的重要重点。一个重要的和 响应多种滥用药物而观察到的持久细胞适应性是星形胶质的下调 谷氨酸转运蛋白GLT-1。但是，关于药物自我给药的影响相对较少了解 超出GLT-1表达的星形胶质细胞，或星形胶质细胞如何有助于寻求药物的机制。 在先前的K99/R00奖励期间收集的结果表明，GLT-1的恢复表达对于 多种化合物的作用机理，以减少大鼠自我复发的行为度量 成瘾的管理和恢复模型。初步数据还表明 可卡因的GLT-1伴随着胶质原纤维酸性蛋白（GFAP）和A的表达降低 伏隔核中星形胶质细胞的缩回。星形胶质细胞回收的特征是减少 表面积，体积和突触接触减少。这一发现代表了迄今为止无关的 可卡因在星形胶质细胞生物学上使用的基本结果。因此，GLT-1表达降低是 慢性可卡因使用后发生的星形胶质细胞生物学中大规模适应的成分。这些 发现导致了以下假设：可卡因可卡因的伏隔核中的星形胶质细胞回收 大鼠有助于突触适应可卡因寻求可卡因。为了检验这一假设， 该提案的目标是：（1）确定在成瘾周期何时形态学对 诱导星形胶质细胞（2）以确定星形胶质细胞回收与突触之间的功能关系 被认为是寻求可卡因的基础的改编，（3）确定星形胶质细胞之间的关系 停止吸毒后的缩回和药物。这些问题将通过将老鼠结合来解决 可卡因自我管理，采用可卡因寻求可卡因的行为度量，高分辨率成像 荧光标记的星形胶质细胞和全细胞贴片钳电生理学。这些研究将提供 对可卡因依赖性适应星形胶质细胞动力学如何有助于细胞和细胞的新见解。 心理刺激成瘾的行为病理特征。这些研究也将提供重要 朝着星形胶质细胞作为药物使用的药物治疗靶标的转化潜力的信息 疾病。