Chronic stress in rats has been shown to impair learning and memory, and precipitate several affective disorders like depression and anxiety. The mechanisms involved in these stress-induced disorders and the possible reversal are poorly understood, thus limiting the number of drugs available for their treatment. Our earlier studies suggest cholinergic dysfunction as the underlying cause in the behavioral deficits following stress. Muscarinic cholinergic agonist, oxotremorine is demonstrated to have a beneficial effect in reversing brain injury-induced behavioral dysfunction. In this study, we have evaluated the effect of oxotremorine treatment on chronic restraint stress-induced cognitive deficits. Rats were subjected to restraint stress (6 h/day) for 21 days followed by oxotremorine treatment for 10 days. Spatial learning and memory was assessed in a partially baited eight-arm radial maze task. Stressed rats exhibited impairment in performance, with decreased percentage of correct choices and an increase in the number of reference memory errors (RMEs). Oxotremorine treatment (0.1 or 0.2 mg/kg, i.p.) to stressed rats resulted in a significant increase in the percent correct choices and a decrease in the number of RMEs compared with stress as well as the stress+vehicle-treated groups. In the retention test, oxotremorine treated rats committed less RMEs compared with the stress group. Chronic restraint stress decreased acetylcholinesterase (AChE) activity in the hippocampus, frontal cortex and septum, which was reversed by both the doses of oxotremorine. Further, oxotremorine treatment also restored the norepinephrine levels in the hippocampus and frontal cortex. Thus, this study demonstrates the potential of cholinergic muscarinic agonists and the involvement of both cholinergic and noradrenergic systems in the reversal of stress-induced learning and memory deficits.

译文

大鼠的慢性压力已被证明会损害学习和记忆,并引发几种情感障碍,如抑郁和焦虑。对这些应激引起的疾病的机制和可能的逆转知之甚少,因此限制了可用于治疗的药物数量。我们早期的研究表明,胆碱能功能障碍是压力后行为缺陷的根本原因。毒蕈碱胆碱能激动剂氧代吗啡被证明在逆转脑损伤引起的行为功能障碍方面具有有益作用。在这项研究中,我们评估了氧代吗啡治疗对慢性束缚应激引起的认知缺陷的影响。对大鼠进行约束应激 (6 h/天) 21天,然后进行氧代雷丁治疗10天。在部分诱饵的八臂径向迷宫任务中评估了空间学习和记忆。应激大鼠的表现受损,正确选择的百分比降低,参考记忆错误 (rme) 的数量增加。与应激以及应激 + 媒介物处理组相比,对应激大鼠进行氧代雷丁处理 (0.1或0.2 mg/kg,i.p.) 导致正确选择百分比显着增加,rme数量减少。在保留试验中,与应激组相比,氧代雷莫林处理的大鼠产生的RMEs较少。慢性束缚应激降低了海马,额叶皮层和隔膜中的乙酰胆碱酯酶 (AChE) 活性,这两种剂量的氧代雷莫林都可以逆转。此外,氧代吗啡治疗还恢复了海马和额叶皮层中的去甲肾上腺素水平。因此,这项研究证明了胆碱能毒蕈碱激动剂的潜力,以及胆碱能和去甲肾上腺素能系统参与逆转应激诱导的学习和记忆缺陷。

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