Neuropharmacology Unit, Division of Pharmacology, Central Drug Research Institute, Lucknow, 226001, India.
Stress. 2010 Jul;13(4):355-64. doi: 10.3109/10253891003667862.
Stress plays a key role in the induction of various clinical disorders by altering monoaminergic response and antioxidant defenses. In the present study, alterations in the concentrations of dopamine (DA), serotonin (5-HT) and their metabolites, and simultaneous changes in the antioxidant defense system and lipid peroxidation in different brain regions (frontal cortex, striatum, and hippocampus) were investigated immediately and 24 h after exposure to chronic unpredictable stress (CUS). CUS involved subjecting Sprague-Dawley rats to two different types of stressors varying from mild to severe intensity every day in an unpredictable manner, over a period of 7 days. CUS significantly decreased DA and 5-HT concentrations, with increased DA turnover ratios in the selected brain regions. In the frontal cortex and striatum, DA metabolite concentrations were increased; however, in the hippocampus they remained unaltered. Further, a decrease of 5-hydroxyindoleacetic acid content was observed in the frontal cortex and striatum, with no significant alteration in the hippocampus. CUS also reduced the activities of superoxide dismutase and catalase, with increased lipid peroxidation and decreased glutathione levels in the selected brain regions. Glutathione peroxidase activity was increased in the frontal cortex and hippocampus only. The pattern of CUS-induced monoamine and oxidative changes immediately after the last stressor and 24 h later were similar when compared with the control group, indicating that the observed changes were due to the chronic exposure to the various stressors and were not merely acute effects of the last stressor. The altered redox state in the striatum and frontal cortex might be related to the perturbed DA and/or 5HT levels, while the hippocampus seems to be less influenced by CUS in terms of monoamine metabolite changes. These results suggest that the perturbed monoamine levels could interact with the oxidative load during CUS. Hence, the current study has implications for pharmacological interventions targeting both central monoamines and cellular antioxidants as a potential stress management strategy for protecting against central stress-induced disorders.
应激通过改变单胺能反应和抗氧化防御作用在诱发各种临床疾病中起着关键作用。在本研究中，我们研究了慢性不可预测应激（CUS）暴露后即刻和 24 小时，不同脑区（前额皮质、纹状体和海马）中多巴胺（DA）、5-羟色胺（5-HT）及其代谢物浓度的变化，以及抗氧化防御系统和脂质过氧化的同时变化。CUS 涉及每天以不可预测的方式将 Sprague-Dawley 大鼠暴露于两种不同类型的应激源，应激源的强度从轻到重不等，持续 7 天。CUS 显著降低了所选脑区中 DA 和 5-HT 的浓度，并增加了 DA 的周转率比值。在前额皮质和纹状体中，DA 代谢物浓度增加；然而，在海马体中它们保持不变。进一步观察到，前额皮质和纹状体中的 5-羟吲哚乙酸含量减少，而海马体中没有明显变化。CUS 还降低了超氧化物歧化酶和过氧化氢酶的活性，导致所选脑区的脂质过氧化和谷胱甘肽水平降低。只有在额皮质和海马体中，谷胱甘肽过氧化物酶的活性增加。与对照组相比，最后一次应激后即刻和 24 小时后 CUS 诱导的单胺和氧化变化的模式相似，表明观察到的变化是由于慢性暴露于各种应激源引起的，而不仅仅是最后一次应激源的急性影响。纹状体和前额皮质中氧化还原状态的改变可能与 DA 和/或 5HT 水平的紊乱有关，而海马体似乎在单胺代谢物变化方面较少受到 CUS 的影响。这些结果表明，在 CUS 期间，紊乱的单胺水平可能与氧化负荷相互作用。因此，本研究对靶向中枢单胺和细胞抗氧化剂的药理学干预具有重要意义，作为一种潜在的应激管理策略，可用于预防中枢应激引起的疾病。
