可卡因自我给药及消退导致伏隔核核心区胶质纤维酸性蛋白表达降低及星形胶质细胞形态学特征改变。
Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core.
作者信息
Scofield Michael D, Li Hao, Siemsen Benjamin M, Healey Kati L, Tran Phuong K, Woronoff Nicholas, Boger Heather A, Kalivas Peter W, Reissner Kathryn J
机构信息
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
出版信息
Biol Psychiatry. 2016 Aug 1;80(3):207-15. doi: 10.1016/j.biopsych.2015.12.022. Epub 2015 Dec 31.
BACKGROUND
As a more detailed picture of nervous system function emerges, diversity of astrocyte function becomes more widely appreciated. While it has been shown that cocaine experience impairs astroglial glutamate uptake and release in the nucleus accumbens (NAc), few studies have explored effects of self-administration on the structure and physiology of astrocytes. We investigated the effects of extinction from daily cocaine self-administration on astrocyte characteristics including glial fibrillary acidic protein (GFAP) expression, surface area, volume, and colocalization with a synaptic marker.
METHODS
Cocaine or saline self-administration and extinction were paired with GFAP Westerns, immunohistochemistry, and fluorescent imaging of NAc core astrocytes (30 saline-administering and 36 cocaine-administering male Sprague Dawley rats were employed). Imaging was performed using a membrane-tagged lymphocyte protein tyrosine kinase-green fluorescent protein (Lck-GFP) driven by the GFAP promoter, coupled with synapsin I immunohistochemistry.
RESULTS
GFAP expression was significantly reduced in the NAc core following cocaine self-administration and extinction. Similarly, we observed an overall smaller surface area and volume of astrocytes, as well as reduced colocalization with synapsin I, in cocaine-administering animals. Cocaine-mediated reductions in synaptic contact were reversed by the β-lactam antibiotic ceftriaxone.
CONCLUSIONS
Multiple lines of investigation indicate that NAc core astrocytes exist in a hyporeactive state following cocaine self-administration and extinction. Decreased association with synaptic elements may be particularly meaningful, as cessation of chronic cocaine use is associated with changes in synaptic strength and resistance to the induction of synaptic plasticity. We hypothesize that the reduced synaptic colocalization of astrocytes represents an important maladaptive cellular response to cocaine and the mechanisms underlying relapse vulnerability.
背景
随着对神经系统功能的了解日益深入，星形胶质细胞功能的多样性也得到了更广泛的认识。虽然已有研究表明，接触可卡因会损害伏隔核（NAc）中星形胶质细胞对谷氨酸的摄取和释放，但很少有研究探讨自我给药对星形胶质细胞结构和生理学的影响。我们研究了从每日可卡因自我给药中戒断对星形胶质细胞特征的影响，包括胶质纤维酸性蛋白（GFAP）表达、表面积、体积以及与突触标记物的共定位。
方法
将可卡因或生理盐水自我给药及戒断与GFAP免疫印迹、免疫组织化学和伏隔核核心星形胶质细胞的荧光成像相结合（使用了30只给予生理盐水和36只给予可卡因的雄性Sprague Dawley大鼠）。成像采用由GFAP启动子驱动的膜标记淋巴细胞蛋白酪氨酸激酶-绿色荧光蛋白（Lck-GFP），并结合突触素I免疫组织化学。
结果
在可卡因自我给药及戒断后，伏隔核核心中的GFAP表达显著降低。同样，我们观察到给予可卡因的动物中星形胶质细胞的总体表面积和体积较小，以及与突触素I的共定位减少。β-内酰胺类抗生素头孢曲松可逆转可卡因介导的突触接触减少。
结论
多项研究表明，在可卡因自我给药及戒断后，伏隔核核心星形胶质细胞处于低反应状态。与突触元件的关联减少可能特别重要，因为长期使用可卡因的戒断与突触强度的变化以及对突触可塑性诱导的抵抗力有关。我们假设星形胶质细胞与突触的共定位减少代表了对可卡因的一种重要的适应不良细胞反应以及复发易感性的潜在机制。
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