Department of Physiology, Faculty of Medicine, Iran University of Medical Science, Tehran, Iran.
Department of Physiology, Faculty of Medicine, Iran University of Medical Science, Tehran, Iran; Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Science, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, Iran University of Medical Science, Tehran, Iran.
J Chem Neuroanat. 2020 Apr;105:101768. doi: 10.1016/j.jchemneu.2020.101768. Epub 2020 Feb 13.
Anhedonia or inability to experience pleasure is the sign of various neuropsychiatric conditions. Current treatment options do not provide adequate control of anhedonia. The present study was conducted to evaluate the protective effects of valproic acid (VPA) as a nonspecific histone deacetylase (HDAC) inhibitor to reverse the effects of stress on induction of anhedonia and explore possible mechanisms. To induce anhedonia, a rat model of chronic unpredictable mild stress (CUMS) was established. Animals were assigned into no stress, stress (6 weeks of CUMS) and two treatment groups. VPA treatment was carried out for 4 continuous weeks (200 mg/kg/day). Behavioral assessments were performed using sucrose consumption (SCT) and new object recognition (NOR) tests. The expression of genes was evaluated using qRT-PCR. The cell density was determined using Nissl staining. Rats with CUMS showed depressive-like behaviors and impaired memory performance compared with the non-stressed group (p < 0.01). Moreover, they had significantly higher levels of HDAC3 and MC4R expression in the nucleus accumbens (NAc) compared to the non-stressed group (p < 0.01). The NAc cell density was significantly higher in the non-stressed rats (p < 0.05). Corticosterone plasma level was increased in the CUMS compared to the non-stressed group (p < 0.05). In the CUMS + VPA subgroup, the corticosterone (CORT) plasma level was lower compared with the CUMS + Saline and/or the CUMS groups (p < 0.05). These findings suggest that VPA can improve anhedonia and stress. Although the protective effect of VPA might link to decreasing HDAC3 and MC4R genes expression in NAc.
快感缺失或无法体验愉悦是各种神经精神疾病的标志。目前的治疗选择并不能提供对快感缺失的充分控制。本研究旨在评估丙戊酸（VPA）作为一种非特异性组蛋白去乙酰化酶（HDAC）抑制剂的保护作用，以逆转应激对快感缺失诱导的影响，并探讨可能的机制。为了诱导快感缺失，建立了慢性不可预测轻度应激（CUMS）大鼠模型。动物被分为无应激、应激（6 周 CUMS）和两个治疗组。VPA 治疗持续 4 周（200mg/kg/天）。使用蔗糖消耗（SCT）和新物体识别（NOR）测试进行行为评估。使用 qRT-PCR 评估基因表达。使用尼氏染色法测定细胞密度。与非应激组相比，CUMS 大鼠表现出类似抑郁的行为和记忆功能受损（p<0.01）。此外，与非应激组相比，它们的伏隔核（NAc）中 HDAC3 和 MC4R 表达水平显著升高（p<0.01）。非应激大鼠的 NAc 细胞密度明显更高（p<0.05）。与非应激组相比，CUMS 组的皮质酮（CORT）血浆水平升高（p<0.05）。与 CUMS+生理盐水和/或 CUMS 组相比，CUMS+VPA 亚组的 CORT 血浆水平较低（p<0.05）。这些发现表明 VPA 可以改善快感缺失和应激。尽管 VPA 的保护作用可能与 NAc 中 HDAC3 和 MC4R 基因表达的降低有关。
