Ascorbate deficiency decreases dopamine release in gulo–/– and APP/PSEN1 mice,Journal of Neurochemistry

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Ascorbate deficiency decreases dopamine release in gulo–/– and APP/PSEN1 mice
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-08-14 , DOI: 10.1111/jnc.15151
David C Consoli ₁ , Lillian J Brady ₂ , Aaron B Bowman ₃ , Erin S Calipari ₂ , Fiona E Harrison ₁

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Dopamine (DA) has important roles in learning, memory, and motivational processes and is highly susceptible to oxidation. In addition to dementia, Alzheimer's disease (AD) patients frequently exhibit decreased motivation, anhedonia, and sleep disorders, suggesting deficits in dopaminergic neurotransmission. Vitamin C (ascorbate, ASC) is a critical antioxidant in the brain and is often depleted in AD patients as a result of disease‐related oxidative stress and dietary deficiencies. To probe the effects of ASC deficiency and AD pathology on the DAergic system, gulo^–/– mice, which like humans depend on dietary ASC to maintain adequate tissue levels, were crossed with APP/PSEN1 mice and provided sufficient or depleted ASC supplementation from weaning until 12 months of age. Ex vivo fast‐scan cyclic voltammetry showed that chronic ASC depletion and APP/PSEN1 genotype both independently decreased dopamine release in the nucleus accumbens, a hub for motivational behavior and reward, while DA clearance was similar across all groups. In striatal tissue containing nucleus accumbens, low ASC treatment led to decreased levels of DA and its metabolites 3,4‐dihydroxyohenyl‐acetic acid (DOPAC), 3‐methoxytyramine (3‐MT), and homovanillic acid (HVA). Decreased enzyme activity observed through lower pTH/TH ratio was driven by a cumulative effect of ASC depletion and APP/PSEN1 genotype. Together the data show that deficits in dopaminergic neurotransmission resulting from age and disease status are magnified in conditions of low ASC which decrease DA availability during synaptic transmission. Such deficits may contribute to the non‐cognitive behavioral changes observed in AD including decreased motivation, anhedonia, and sleep disorders.

中文翻译：

抗坏血酸缺乏会减少 gulo–/– 和 APP/PSEN1 小鼠的多巴胺释放

多巴胺 (DA) 在学习、记忆和动机过程中发挥重要作用，并且极易被氧化。除了痴呆症之外，阿尔茨海默病 (AD) 患者还经常表现出动机下降、快感缺乏和睡眠障碍，这表明多巴胺能神经传递存在缺陷。维生素 C（抗坏血酸，ASC）是大脑中一种重要的抗氧化剂，由于疾病相关的氧化应激和饮食缺乏，AD 患者经常会缺乏维生素 C。为了探讨 ASC 缺陷和 AD 病理学对 DAergic 系统的影响，将 gulo ^–/–小鼠（与人类一样依赖饮食 ASC 来维持足够的组织水平）与 APP/PSEN1 小鼠杂交，并在断奶时提供充足或耗尽的 ASC 补充直到 12 个月大。离体快速扫描循环伏安法显示，慢性 ASC 耗竭和 APP/PSEN1 基因型均独立减少伏核（动机行为和奖励的枢纽）中多巴胺的释放，而所有组的 DA 清除率相似。在含有伏隔核的纹状体组织中，低 ASC 治疗导致 DA 及其代谢物 3,4-二羟基苯乙酸 (DOPAC)、3-甲氧基酪胺 (3-MT) 和高香草酸 (HVA) 水平降低。通过降低 pTH/TH 比率观察到的酶活性降低是由 ASC 消耗和 APP/PSEN1 基因型的累积效应驱动的。这些数据共同表明，年龄和疾病状态导致的多巴胺能神经传递缺陷在低 ASC 的情况下会被放大，从而降低突触传递过程中 DA 的可用性。这种缺陷可能导致 AD 中观察到的非认知行为变化，包括动机下降、快感缺乏和睡眠障碍。

更新日期：2020-08-14

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