D-serine has attracted increasing attention for its possible role in depression. L-4-Fluorophenylglycine (L-4FPG), an inhibitor of the neutral amino acid transporter ASCT1/2, has been shown to regulate extracellular D-serine levels. The present study aimed to explore the potential antidepressant effects of L-4FPG. First, the acute effects of L-4FPG on the forced swimming test, elevated plus maze test, and novelty-suppressed feeding test were examined. L-4FPG showed antidepressant-like effects, which could be reversed by rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist. The phosphorylation levels of mTOR and GluR1 in the hippocampus were also increased after L-4FPG treatment. Next, the therapeutic effects of L-4FPG were examined in a chronic social defeat stress (CSDS) model of depression. L-4FPG ameliorated depression-like behaviors in mice subjected to CSDS. Furthermore, treatment with L-4FPG prior to each social defeat stress session not only decreased defensive behaviors but also prevented CSDS-induced social avoidance and anxiety-like and depression-like behaviors. These findings suggest that L-4FPG may be useful not only in alleviating depression but also in protecting against chronic stress-related psychiatric disorders.

D-丝氨酸因其在抑郁症中的可能作用而受到越来越多的关注。L-4-氟苯基甘氨酸 (L-4FPG) 是一种中性氨基酸转运蛋白 ASCT1/2 的抑制剂，已被证明可调节细胞外D-丝氨酸水平。本研究旨在探讨 L-4FPG 的潜在抗抑郁作用。首先，研究了 L-4FPG 对强迫游泳试验、高架十字迷宫试验和抑制新奇喂养试验的急性影响。L-4FPG 显示出抗抑郁样作用，可以被雷帕霉素（一种哺乳动物的雷帕霉素靶蛋白 (mTOR) 抑制剂）和 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)（一种 α-氨基-3）逆转-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体拮抗剂。在 L-4FPG 处理后，海马中 mTOR 和 GluR1 的磷酸化水平也增加了。接下来，在抑郁症的慢性社交失败压力 (CSDS) 模型中检查了 L-4FPG 的治疗效果。L-4FPG 改善了 CSDS 小鼠的抑郁样行为。此外，在每次社交失败压力会议之前用 L-4FPG 治疗不仅减少了防御行为，而且还防止了 CSDS 引起的社交回避和焦虑样和抑郁样行为。这些发现表明，L-4FPG 不仅可用于缓解抑郁症，还可用于预防慢性压力相关的精神疾病。