Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant-like effects of ketamine

被引:0
作者
Yin, Yong-Yu [1 ]
Yan, Jiao-Zhao [2 ]
Wei, Qian-Qian [3 ]
Sun, Si-Rui [4 ]
Ding, Yu-Qiang [5 ]
Zhang, Li-Ming [1 ]
Li, Yun-Feng [1 ,2 ]
机构
[1] Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, Beijing Key Lab Neuropsychopharmacol, Beijing, Peoples R China
[2] Beijing Inst Basic Med Sci, Beijing, Peoples R China
[3] Nantong Univ, Sch Med, Nantong, Peoples R China
[4] Capital Med Univ, Beijing Ditan Hosp, Beijing, Peoples R China
[5] Fudan Univ, Dept Lab Anim Sci, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
5-HT; AMPA; antidepressant; ketamine; sustained; D-ASPARTATE ANTAGONIST; NEUROTROPHIC FACTOR; MODEL; 5-HT; RELEASE; SYSTEM; CORTEX; NEUROPLASTICITY; PHARMACOLOGY; EXPRESSION;
D O I
10.1111/bph.17324
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background and Purpose The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear. Experimental approach The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain. Key Results 60 min after injection, ketamine (10 mg.kg(-1), i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg.kg(-1), i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naive or CRS-treated mice. Conclusion and Implications This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.
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收藏
页码:4874 / 4889
页数:16
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