Laboratory of Biology of Addictive Diseases, The Rockefeller University, New York, NY, 10065, USA.
Stress. 2010 Nov;13(6):481-90. doi: 10.3109/10253891003786415. Epub 2010 Jul 28.
There is evidence that increased release of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) contributes to stress responsivity during cocaine withdrawal (WD). Recent studies suggest that tissue plasminogen activator (tPA) in the CeA is a downstream effector protein for CRF after acute "binge" cocaine administration. The purpose of this study was to determine if tPA modulates cocaine WD-induced stress responsivity. Wild-type (WT) and tPA-deficient (tPA - / - ) mice were subjected to chronic (14 days) "binge" cocaine (45 mg/kg per day) or its acute (1 day) WD. Extracellular tPA activity, CRF mRNA levels, and plasma corticosterone (CORT) levels were measured in tPA - / - and WT mice. Extracellular tPA activity was reduced by 50% in the CeA and medial amygdala of WT mice after chronic cocaine and returned to basal levels after acute WD. Unlike WT mice, tPA - / - mice did not display elevated amygdalar CRF mRNA levels during cocaine WD. In comparison to WT mice, tPA - / - mice showed a blunted plasma CORT response during acute WD. These results demonstrate that tPA activity in the amygdala (Amy) is altered by chronic cocaine exposure, and further suggest an involvement of tPA in modulating amygdalar CRF stress responsive system and hypothalamic-pituitary-adrenal axis in response to acute cocaine WD.
有证据表明，杏仁中央核（CeA）中促肾上腺皮质释放因子（CRF）的释放增加有助于可卡因戒断（WD）期间的应激反应。最近的研究表明，CeA 中的组织纤溶酶原激活物（tPA）是急性“狂欢”可卡因给药后 CRF 的下游效应蛋白。本研究旨在确定 tPA 是否调节可卡因 WD 诱导的应激反应。野生型（WT）和 tPA 缺陷型（tPA-/-）小鼠接受慢性（14 天）“狂欢”可卡因（45mg/kg/天）或其急性（1 天）WD。在 tPA-/-和 WT 小鼠中测量 tPA-/-和 WT 小鼠的细胞外 tPA 活性、CRF mRNA 水平和血浆皮质酮（CORT）水平。慢性可卡因处理后，WT 小鼠 CeA 和内侧杏仁核中的细胞外 tPA 活性降低了 50%，并在急性 WD 后恢复到基础水平。与 WT 小鼠不同，tPA-/-小鼠在可卡因 WD 期间没有表现出杏仁核 CRF mRNA 水平升高。与 WT 小鼠相比，tPA-/-小鼠在急性 WD 期间表现出血浆 CORT 反应迟钝。这些结果表明，杏仁核中的 tPA 活性被慢性可卡因暴露改变，并进一步表明 tPA 参与调节杏仁核 CRF 应激反应系统和下丘脑-垂体-肾上腺轴对急性可卡因 WD 的反应。
