Bray Brenna, Scholl Jamie L, Tu Wenyu, Watt Michael J, Renner Kenneth J, Forster Gina L
Division of Basic Biomedical Sciences, Center for Brain and Behavior Research, University of South Dakota, 414 East Clark St, Vermillion, SD, United States.
Department of Biology, Center for Brain and Behavior Research, University of South Dakota, 414 East Clark St, Vermillion, SD, United States.
Brain Res. 2016 Aug 1;1644:278-87. doi: 10.1016/j.brainres.2016.05.030. Epub 2016 May 18.
Amphetamine withdrawal is associated with heightened anxiety-like behavior, which is directly driven by blunted stress-induced glucocorticoid receptor-dependent serotonin release in the ventral hippocampus. This suggests that glucocorticoid availability in the ventral hippocampus during stress may be reduced during amphetamine withdrawal. Therefore, we tested whether amphetamine withdrawal alters either peripheral or hippocampal corticosterone stress responses. Adult male rats received amphetamine (2.5mg/kg, ip) or saline for 14 days followed by 2 weeks of withdrawal. Contrary to our prediction, microdialysis samples from freely-moving rats revealed that restraint stress-induced corticosterone levels in the ventral hippocampus are enhanced by amphetamine withdrawal relative to controls. In separate groups of rats, plasma corticosterone levels increased immediately after 20min of restraint and decreased to below stress-naïve levels after 1h, indicating negative feedback regulation of corticosterone following stress. However, plasma corticosterone responses were similar in amphetamine-withdrawn and control rats. Neither amphetamine nor stress exposure significantly altered protein expression or enzyme activity of the steroidogenic enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD1) or hexose-6-phosphate dehydrogenase (H6PD) in the ventral hippocampus. Our findings demonstrate for the first time that amphetamine withdrawal potentiates stress-induced corticosterone in the ventral hippocampus, which may contribute to increased behavioral stress sensitivity previously observed during amphetamine withdrawal. However, this is not mediated by either changes in plasma corticosterone or hippocampal steroidogenic enzymes. Establishing enhanced ventral hippocampal corticosterone as a direct cause of greater stress sensitivity may identify the glucocorticoid system as a novel target for treating behavioral symptoms of amphetamine withdrawal.
苯丙胺戒断与焦虑样行为增强有关，这是由腹侧海马中应激诱导的糖皮质激素受体依赖性5-羟色胺释放减弱直接驱动的。这表明在苯丙胺戒断期间，应激时腹侧海马中的糖皮质激素可用性可能会降低。因此，我们测试了苯丙胺戒断是否会改变外周或海马的皮质酮应激反应。成年雄性大鼠接受苯丙胺（2.5mg/kg，腹腔注射）或生理盐水，持续14天，随后戒断2周。与我们的预测相反，来自自由活动大鼠的微透析样本显示，相对于对照组，苯丙胺戒断增强了束缚应激诱导的腹侧海马中的皮质酮水平。在单独的几组大鼠中，束缚20分钟后血浆皮质酮水平立即升高，1小时后降至低于未经历应激的水平，表明应激后皮质酮的负反馈调节。然而，苯丙胺戒断大鼠和对照大鼠的血浆皮质酮反应相似。苯丙胺和应激暴露均未显著改变腹侧海马中类固醇生成酶11β-羟基类固醇脱氢酶（11β-HSD1）或己糖-6-磷酸脱氢酶（H6PD）的蛋白表达或酶活性。我们的研究结果首次证明，苯丙胺戒断会增强应激诱导的腹侧海马中的皮质酮，这可能导致先前在苯丙胺戒断期间观察到的行为应激敏感性增加。然而，这不是由血浆皮质酮或海马类固醇生成酶的变化介导的。将腹侧海马中增强的皮质酮确立为更高应激敏感性的直接原因，可能会将糖皮质激素系统确定为治疗苯丙胺戒断行为症状的新靶点。
