利用N-甲基-D-天門冬胺酸(N-methyl-D-aspartate, NMDA)受體調節劑來發展新型抗憂鬱藥物越來越受到大家的關注。L-4-氟苯甘氨酸(L-4-fluorophenylglycine, L-4FPG)為中性胺基酸轉運蛋白ASCT1和ASCT2的抑制劑，透過增加細胞外D-絲胺酸的含量來調節NMDA受體的功能。本研究旨在探討L-4FPG作為抗憂鬱藥物的潛力。首先，雄性ICR小鼠在類憂鬱行為測試30分鐘前接受L-4FPG給藥(0.3、1及3 mg/kg，腹腔注射)，給予L-4FPG(1和3 mg/kg)的小鼠在陌生環境抑制攝食試驗以及強迫游泳試驗中表現出類抗憂鬱劑的行為，而L-4FPG的急性類抗憂鬱劑的效果，可以被雷帕霉素靶蛋白的抑制劑雷帕霉素(20 mg/kg，口服給藥)所逆轉。接下來，在社交失敗壓力(social defeat stress, SDS)的憂鬱動物模型中測試L-4FPG的影響，雄性C57BL/6J小鼠在10天的SDS之後給予L-4FPG (3 mg/kg，腹腔注射，每天給藥)持續14天，可以緩解在明暗箱試驗、尾部懸吊試驗、強迫游泳試驗以及噴灑糖水試驗中的類焦慮及類憂鬱行為。最後本研究也評估了L-4FPG的預防效果，雄性C57BL/6J小鼠在每天SDS的30分鐘前給予L-4FPG (0.3及3 mg/kg，腹腔注射)持續14天，結果顯示，同時給予3 mg/kg 劑量的L-4FPG減少了C57BL/6J小鼠在SDS期間，受到具有攻擊性ICR小鼠的攻擊時產生的防禦行為，也防止了SDS所誘發的社交迴避、類焦慮及類憂鬱行為。本研究結果顯示，調節ASCT轉運蛋白，對於預防及治療憂鬱症，可能是一具有潛力的策略。

There has been increased interest in using N-methyl-D-aspartate (NMDA) receptor modulators in the development of novel antidepressant medication. L-4-fluorophenylglycine (L-4FPG), an inhibitor of neutral amino acid transporter ASCT1 and ASCT2, regulates NMDA receptor function via enhancing extracellular levels of D-serine. The present study aimed to explore the potential of L-4FPG as an antidepressant. At first, male ICR mice received L-4FPG (0.3, 1, and 3 mg/kg, i.p.) 30 minutes prior to the depression-like behavioral tests. Mice treated with L-4PFG (1 and 3 mg/kg) showed antidepressant-like behaviors in novelty suppressed feeding test and forced swimming test. The acute antidepressant-like effects of L-4FPG could be reversed by rapamycin (20 mg/kg, p.o.), an mTOR inhibitor. Next, the effects of L-4FPG were tested in social defeat stress (SDS) model of depression. Male C57BL/6J mice were injected with L-4FPG (3 mg/kg, i.p. daily) for 14 days after 10-day SDS. L-4FPG treatment after SDS could reduce the anxiety- and depressive-like behaviors in the light-dark box test, tail suspension test, forced swimming test, and splash test. Last, the preventive effects of L-4FPG were assessed. Male C57BL/6J mice were injected with L-4PFG (0.3 and 3 mg/kg, i.p) 30 minutes prior to each SDS session daily for 14 days. The results showed that co-treatment of L-4FPG at the dose of 3 mg/kg decreased the defensive behavior in C57BL/6J mice under attack by aggressive ICR mice during SDS and also prevented the social avoidance, anxiety- and depressive-like behaviors induced by SDS. These findings suggest that the modulation of ASCT transporter might be a potential strategy for the prevention and treatment of depressive disorder.

摘要---------------------------------------------------------ii
Abstract-----------------------------------------------------iv
Contents-----------------------------------------------------vi
Table contents-----------------------------------------------viii
Figure contents----------------------------------------------x
Abbreviation list--------------------------------------------xii
Introduction-------------------------------------------------1
1.Depression------------------------------------------------1
2.Social defeat stress (SDS)--------------------------------6
3.L-4-fluorophenylglycine (L-4FPG)--------------------------9
Hypothesis---------------------------------------------------11
Aims---------------------------------------------------------13
Materials and Methods----------------------------------------15
1.Animals---------------------------------------------------15
2.Drugs-----------------------------------------------------15
3.Social defeat stress model--------------------------------16
4.Behavioral tests------------------------------------------17
5.mRNA expression assays------------------------------------21
6.Statistical analyses--------------------------------------23
Experimental designs-----------------------------------------25
Results------------------------------------------------------29
1.Effects of acute L-4FPG treatment on anxiety- and depression-like behaviors.----------------------------------------------29
2.Effects of rapamycin on the antidepressant-like effects of acute L-4FPG treatment.--------------------------------------30
3.Effects of L-4FPG post-treatment on behavioral changes after repeated social defeat stress.-------------------------------31
4.Effects of L-4FPG co-treatment on behavioral changes induced by repeated social defeat stress.-------------------------------36
5.Effects of L-4FPG additional treatment after repeated social defeat stress on the mRNA levels of IL6, TNFα, Iba-1, ASCT1, ASCT2, NR2A, and NR2B.---------------------------------------41
Discussion---------------------------------------------------43
1.Effects of acute treatment of L-4FPG on the depression-like and anxiety-like behavioral tests.-------------------------------43
2.Rapamycin blocked the acute antidepressant-like effects of L-4FPG.--------------------------------------------------------44
3.Repeated social defeat stress produced anxiety-like and depression-like behaviors.-----------------------------------44
4.Social defeat stress did not significantly affect the recognition and memory ability in NLRT and NORT.-------------46
5.The depression-like behavior induced by social defeat stress is a long-lasting effect.---------------------------------------46
6.Post-treatment of L-4FPG reduced anxiety-like and depression-like behavior after social defeat stress.--------------------46
7.The decline of beneficial effects of L-4FPG posttreatment on depression-like behavior.------------------------------------47
8.Co-treatment of L-4FPG (3 mg/kg) decreased higher defensive responses and prevented social avoidance, anxiety-like, and depression-like behaviors induced by SDS.--------------------47
9.Social defeat stress changed mRNA levels on Iba-1, NR2B, and ASCT2 in the hippocampus, but L-4FPG treatment did not reverse the changes.-----------------------------------------------------48
10.Other mechanisms of L-4FPG-------------------------------50
11.The safety of L-4FPG-------------------------------------51
Conclusion---------------------------------------------------53
References---------------------------------------------------55
Tables-------------------------------------------------------69
Figures------------------------------------------------------75

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