Astrocyte-mediated mechanisms of cocaine seeking

项目摘要/摘要 复发的倾向是上瘾的一个显著特征。因此，了解细胞机制 复吸易感性是成瘾研究的一个重要焦点。一个重要的和 多种药物滥用后观察到的长期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，人们对药物自我给药的影响知之甚少。 超越GLT-1表达的星形胶质细胞，或星形胶质细胞如何参与药物寻找的机制。 在之前的K99/R00奖期间收集的结果表明，GLT-1的恢复表达对 多种化合物降低大鼠自体复吸行为指标的作用机制 成瘾的管理和恢复模式。初步数据还表明，下调监管 可卡因诱导的GLT-1伴随着胶质纤维酸性蛋白(GFAP)和a 伏隔核核心星形胶质细胞回缩。星形胶质细胞回缩的特征是减少 表面积、体积和突触接触减少。这一发现代表了一个迄今未被赏识的发现 可卡因使用对星形胶质细胞生物学的基本影响。因此，减少GLT-1的表达是一种 在长期使用可卡因后，星形胶质细胞生物学中发生的更大规模适应的组成部分。这些 这些发现导致了一种假说，即可卡因戒断后伏隔核星形胶质细胞的回缩 大鼠参与了促使可卡因寻求的突触适应。为了检验这一假设，具体的 这项建议的目标是：(1)确定在成瘾周期的什么时候形态对 诱导星形胶质细胞(2)确定星形胶质细胞收缩和突触之间的功能关系 被认为是寻求可卡因的基础的适应，以及(3)确定星形胶质细胞之间的关系 戒毒后的退缩和寻药。这些问题将通过合并RAT来解决 可卡因自我给药与寻找可卡因的行为措施，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 星形胶质细胞动力学中的可卡因依赖适应如何对细胞和 以精神刺激成瘾为特征的行为病理学。这些研究还将提供重要的 关于星形胶质细胞作为药物治疗靶点的翻译潜力的信息 精神错乱。

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 These findings have led to the hypothesis that astrocyte retraction in the nucleus accumbens of cocaine-withdrawn rats contributes to synaptic adaptations that drive cocaine seeking.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.