Abstract：
Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalently co-occurring, important risk factors for a broad array of neuropsychiatric diseases. To date, how these two contrastive concomitant pairs increase the risk of neuropsychiatric states, notably exacerbating PTSD-related symptoms, remains unknown. Moreover, pharmacological interventions with agents that could reverse PTSD-AUD comorbidity, however, remained limited. Hence, we investigated the neuroprotective actions of naringin in mice comorbidly exposed to PTSD followed by repeated ethanol (EtOH)-induced AUD. Following a 7-day single-prolong-stress (SPS)-induced PTSD in mice, binge/heavy drinking, notably related to AUD was induced in the PTSD mice with every-other-day ethanol (2 g/kg, p.o.) administration, followed by daily treatments with naringin (25 and 50 mg/kg) or fluoxetine (10 mg/kg), from days 8-21. PTSD-AUD-related behavioral changes, alcohol preference, hypothalamic-pituitary-adrenal (HPA)-axis dysfunction-induced neurochemical alterations, oxidative/nitrergic stress, and inflammation were examined in the prefrontal-cortex, striatum, and hippocampus. PTSD-AUD mice showed aggravated anxiety, spatial-cognitive, social impairments and EtOH intake, which were abated by naringin, similar to fluoxetine. Our assays on the HPA-axis showed exacerbated increased corticosterone release and adrenal hypertrophy, accompanied by marked dopamine and serotonin increase, with depleted glutamic acid decarboxylase enzyme in the three brain regions, which naringin, however, reversed, respectively. PTSD-AUD mice also showed increased TNF-α, IL-6, malondialdehyde and nitrite levels, with decreased antioxidant elements in the prefrontal-cortex, striatum, and hippocampus compared to SPS-EtOH-mice; mainly exacerbating catalase and glutathione decrease in the hippocampus relative SPS-mice. These findings suggest that AUD exacerbates PTSD pathologies in different brain regions, notably comprising neurochemical dysregulations, oxidative/nitrergic and cytokine-mediated inflammation, with HPA dysfunction, which were, however, revocable by naringin.
摘要：
创伤后应激障碍（PTSD）和酒精使用障碍（AUD）普遍并存，一系列神经精神疾病的重要危险因素。迄今为止,这两个对比的伴随对如何增加神经精神状态的风险，特别是加重PTSD相关症状，仍然未知。此外，药物干预可以逆转PTSD-AUD合并症的药物，然而,仍然有限。因此，我们研究了柚皮苷对共同暴露于PTSD，然后反复乙醇（EtOH）诱导的AUD的小鼠的神经保护作用。在小鼠中进行7天单次延长应激（SPS）诱导的PTSD后，暴饮暴食/酗酒，在PTSD小鼠中，每隔一天使用乙醇（2g/kg，p.o.)管理，然后每天用柚皮苷（25和50mg/kg）或氟西汀（10mg/kg）治疗，第8-21天PTSD-AUD相关行为变化，酒精偏好,下丘脑-垂体-肾上腺（HPA）-轴功能障碍诱导的神经化学改变，氧化/硝化应激，在前额叶皮层检查炎症，纹状体,和海马体。PTSD-AUD小鼠表现出严重的焦虑，空间认知，社会损害和EtOH摄入量，因为柚皮苷而减弱了，与氟西汀相似。我们对HPA轴的分析显示皮质酮释放和肾上腺肥大加剧，伴随着多巴胺和血清素的显著增加，三个脑区的谷氨酸脱羧酶耗尽，其中柚林，然而,反转,分别。PTSD-AUD小鼠也显示增加的TNF-α，IL-6、丙二醛和亚硝酸盐水平，前额叶皮层的抗氧化元素减少，纹状体,和海马与SPS-EtOH-小鼠相比；相对于SPS-小鼠，海马中主要加剧过氧化氢酶和谷胱甘肽的减少。这些发现表明，AUD加剧了不同脑区的PTSD病理，特别是包括神经化学失调，氧化/硝基和细胞因子介导的炎症，HPA功能障碍，是，然而,可通过柚皮苷撤销。
