Mantsch John R, Taves Sarah, Khan Tayyiba, Katz Eric S, Sajan Tanveer, Tang Lee C, Cullinan William E, Ziegler Dana R
Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201, USA.
Neurosci Lett. 2007 Mar 30;415(3):269-73. doi: 10.1016/j.neulet.2007.01.036. Epub 2007 Jan 21.
Stress responses during cocaine withdrawal likely contribute to drug relapse and may be intensified as a consequence of prior cocaine use. The present study examined changes in stressor-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis during acute withdrawal from chronic cocaine administration. Adult male Sprague-Dawley rats received daily administration of cocaine (30 mg/kg, i.p.) or saline for 14 days. Twenty-four hours after the last injection, rats in each group were sacrificed under stress-free conditions or following 30 min of immobilization. Plasma corticosterone (CORT) was measured in trunk-blood using radioimmunoassay, corticotropin-releasing hormone (CRH) mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus were measured using in situ hybridization and glucocorticoid receptor (GR) protein expression in the pituitary gland and dissected brain regions was measured using Western blot analysis. Basal CRH mRNA in the PVN was unaltered as a result of prior cocaine administration. However, a significant increase in CRH mRNA was observed 90 min following the termination of restraint in cocaine withdrawn, but not saline-treated, rats. Basal CORT was also unaffected by prior cocaine administration, but the CORT response measured immediately after restraint was significantly augmented in cocaine-withdrawn rats. Differences in GR protein expression in number of regions implicated in negative feedback regulation of HPA function, including the hypothalamus, were not observed. These findings indicate that the HPA response to stressors is intensified during early withdrawal from cocaine administration and may be independent of changes in GR-mediated negative feedback.
可卡因戒断期间的应激反应可能导致药物复发，并且可能由于先前使用可卡因而加剧。本研究考察了慢性给予可卡因后急性戒断期间应激源诱导的下丘脑-垂体-肾上腺（HPA）轴激活的变化。成年雄性Sprague-Dawley大鼠每天接受可卡因（30mg/kg，腹腔注射）或生理盐水注射，持续14天。最后一次注射后24小时，每组大鼠在无应激条件下或固定30分钟后处死。用放射免疫分析法测定躯干血中的血浆皮质酮（CORT），用原位杂交法测定下丘脑室旁核（PVN）中的促肾上腺皮质激素释放激素（CRH）mRNA水平，用蛋白质免疫印迹分析法测定垂体和解剖脑区中的糖皮质激素受体（GR）蛋白表达。先前给予可卡因并未改变PVN中的基础CRH mRNA。然而，在可卡因戒断但未用生理盐水处理的大鼠中，约束终止后90分钟观察到CRH mRNA显著增加。基础CORT也不受先前给予可卡因的影响，但在可卡因戒断的大鼠中，约束后立即测得的CORT反应显著增强。在涉及HPA功能负反馈调节的多个区域，包括下丘脑，未观察到GR蛋白表达的差异。这些发现表明，在从可卡因给药中早期戒断期间，HPA对应激源的反应增强，并且可能独立于GR介导的负反馈变化。
