Daily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback in rats
Daily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback in rats
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DOI：
10.1016/j.brainres.2007.05.080
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发表时间：
2007-09-05
期刊：
影响因子：
2.9
通讯作者：
Ziegler, Dana R.
中科院分区：
文献类型：
--
作者：
Mantsch, John R.;Cullinan, William E.;Ziegler, Dana R.
可卡因成瘾似乎与药物引起的应激源反应失调有关，这可能有助于进一步使用可卡因。本研究观察了在长时间(1.0 mg/kg/次输注，6h×14天)条件下，每日摄入可卡因(SA)的大鼠应激源诱导的下丘脑-垂体-肾上腺(HPA)轴激活的变化。在SA测试后24天，与生理盐水自我给药对照组相比，可卡因自我给药大鼠的基础血浆皮质酮(CORT)水平降低，但束缚诱导的反应比基线有所增加。这种增强的皮质醇反应可能归因于糖皮质激素受体(GR)介导的HPA功能反馈调节受损，因为可卡因自我给药大鼠对地塞米松(0.01 mg/kg，i.p.)的敏感性也较低。抑制血浆皮质醇水平。用免疫印迹法检测可卡因给药大鼠下丘脑背内侧(包括室旁核)GR蛋白的表达显著减少，而在垂体、下丘脑腹内侧部、背侧海马体、腹侧下丘脑、内侧前额叶皮质和杏仁核无明显变化。令人惊讶的是，用原位杂交法在PVN的单个时间点(90分钟)测量的基础促肾上腺皮质激素释放激素(CRH)mRNA或束缚后CRH mRNA的增加在两组之间没有差异。研究结果表明，可卡因的使用会导致个体对可能导致成瘾过程的压力源的反应发生持续变化。(C)2007 Elsevier B.V.保留所有权利。
Cocaine addiction appears to be associated with a drug-induced dysregulation of stressor responsiveness that may contribute to further cocaine use. The present study examined alterations in stressor-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in rats provided daily access to cocaine for self-administration (SA) under long-access conditions (1.0 mg/kg/infusion; 6 h x 14 days). Cocaine self-administering rats displayed reduced basal plasma corticosterone (CORT) levels but showed an augmented restraint-induced percent increase response from baseline compared to saline self-administering controls when measured 24 days after SA testing. This augmented CORT response may have been attributable to impaired glucocorticoid receptor (GR)-mediated feedback regulation of HPA function, since cocaine self-administering rats were also less susceptible to dexamethasone (0.01 mg/kg, i.p.) suppression of plasma CORT levels. GR protein expression measured using Western blot analysis was significantly reduced in the dorsomedial hypothalamus (including the paraventricular nucleus [PVN]) but not in the pituitary gland, ventromedial hypothalamus, dorsal hippocampus, ventral subiculum, medial prefrontal cortex or amygdala in cocaine self-administering rats. Surprisingly, basal corticotropin-releasing hormone (CRH) mRNA or post-restraint increases in CRH mRNA measured at a single (90 min) time-point in the PVN using in situ hybridization did not differ between groups. The findings suggest that cocaine use produces persistent changes in individual responsiveness to stressors that may contribute to the addiction process. (c) 2007 Elsevier B.V. All rights reserved.