Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India.
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India.
Neurochem Int. 2020 Jan;132:104605. doi: 10.1016/j.neuint.2019.104605. Epub 2019 Nov 18.
Depression is highly comorbid with anxiety disorders and associated with profound cognitive impairment. Moreover, cognitive deficits associated with hippocampal dysfunction are central in depression and anxiety disorders. Furthermore, depression is accompanied by glutamatergic dysfunction which can further impair the functioning of the hippocampus. Recent studies have shown that N-acetyl cysteine (NAC), a glutamate modulator produces an antidepressant-like effect by normalization of the periterminal release of glutamate and/or antioxidant effects. However, the effects of repeated NAC treatment on depression-induced anxiety, cognitive deficits, and associated neurochemical and structural alterations are relatively unknown. Accordingly, we investigated whether chronic NAC treatment could reverse cognitive deficits, and associated hippocampal volume loss and monoaminergic alterations in the neonatal clomipramine (CLI) model of depression. We found that chronic NAC treatment produces antidepressive and antianhedonic-like effects. NAC treatment also reversed CLI-induced anxiety. Interestingly, repeated NAC treatment improved the performance of CLI rats in rewarded alternation task in T-maze. The antidepressive-like and procognitive effects of NAC was associated with normalization of volume loss in CA1, dentate gyrus (DG) and hilar subfields of the hippocampus. Furthermore, NAC restored CLI-induced decrease in levels of monoamines and normalized enhanced metabolism in the hippocampus. Taken together, chronic NAC treatment ameliorates depressive and anxiety-like behavior, spatial learning deficits, and reverses CLI-induced pathological alterations at structural and neurochemical levels in the hippocampus. Our findings might help in evolving NAC as a viable pharmacotherapy for reversal of cognitive deficits in depression and associated disorders.
抑郁症与焦虑症高度共病，并与严重的认知障碍有关。此外，海马功能障碍相关的认知缺陷是抑郁症和焦虑症的核心。此外，抑郁症伴随着谷氨酸能功能障碍，这会进一步损害海马体的功能。最近的研究表明，N-乙酰半胱氨酸（NAC）是一种谷氨酸调节剂，通过使谷氨酸的终末释放正常化和/或抗氧化作用产生抗抑郁样作用。然而，重复 NAC 治疗对抑郁引起的焦虑、认知缺陷以及相关的神经化学和结构改变的影响相对未知。因此，我们研究了慢性 NAC 治疗是否可以逆转认知缺陷以及与海马体积减少和单胺能改变相关的抑郁样氯米帕明（CLI）模型。我们发现，慢性 NAC 治疗产生抗抑郁和抗快感缺失样作用。NAC 治疗还逆转了 CLI 诱导的焦虑。有趣的是，重复的 NAC 治疗改善了 CLI 大鼠在 T 迷宫中的奖励交替任务中的表现。NAC 的抗抑郁样和促认知作用与 CA1、齿状回（DG）和海马体的海马旁回体积减少的正常化有关。此外，NAC 恢复了 CLI 诱导的单胺水平下降，并使海马体代谢增强正常化。总之，慢性 NAC 治疗可改善抑郁和焦虑样行为、空间学习缺陷，并逆转 CLI 诱导的海马体在结构和神经化学水平上的病理性改变。我们的发现可能有助于将 NAC 作为一种可行的药物治疗方法，用于逆转抑郁症和相关疾病中的认知缺陷。
