title: 3'-Deoxyadenosine (Cordycepin) Produces a Rapid and Robust Antidepressant Effect via Enhancing Prefrontal AMPA Receptor Signaling Pathway.
abstract: BACKGROUND
  The development of rapid and safe antidepressants for the treatment of major depression is in urgent demand. Converging evidence suggests that glutamatergic signaling seems to play important roles in the pathophysiology of depression.
  
  
  METHODS
  We studied the antidepressant effects of 3(')-deoxyadenosine (3'-dA, Cordycepin) and the critical role of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor in male CD-1 mice via behavioral and biochemical experiments. After 3'-dA treatment, the phosphorylation and synaptic localization of the AMPA receptors GluR1 and GluR2 were determined in the prefrontal cortex (PFC) and hippocampus (HIP). The traditional antidepressant imipramine was applied as a positive control.
  
  
  RESULTS
  We found that an injection of 3'-dA led to a rapid and robust antidepressant effect, which was significantly faster and stronger than imipramine, after 45min in tail suspension and forced swim tests. This antidepressant effect remained after 5 days of treatment with 3'-dA. Unlike the psycho-stimulants, 3'-dA did not show a hyperactive effect in the open field test. After 45min or 5 days of treatment, 3'-dA enhanced GluR1 S845 phosphorylation in both the PFC and HIP. In addition, after 45min of treatment, 3'-dA significantly up-regulated GluR1 S845 phosphorylation and GluR1, but not GluR2 levels, at the synapses in the PFC. After 5 days of treatment, 3'-dA significantly enhanced GluR1 S845 phosphorylation and GluR1, but not GluR2, at the synapses in the PFC and HIP. Moreover, the AMPA-specific antagonist GYKI 52466 was able to block the rapid antidepressant effects of 3'-dA.
  
  
  CONCLUSIONS
  This study identified 3'-dA as a novel rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the prefrontal AMPA receptor signaling pathway.
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Bai
authors.initials: B
authors.lastname: Li
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Hou
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Ming
authors.initials: M
authors.lastname: Zhu
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Hongkun
authors.initials: H
authors.lastname: Bao
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Jun
authors.initials: J
authors.lastname: Nie
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Zhang
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Liping
authors.initials: L
authors.lastname: Shan
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Kai
authors.initials: K
authors.lastname: Du
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Hongju
authors.initials: H
authors.lastname: Yang
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Meizhang
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Bingrong
authors.initials: B
authors.lastname: Zheng
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Xu
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Chunjie
authors.initials: C
authors.lastname: Xiao
authors.affiliation: School of Medicine, Yunnan University, Kunming, Yunnan, China (Mr B Li, Bao, MS Hou, Nie, and Dr Zhu, Yang, Zheng, Xiao, and J Du); Beijing Gragen Biotechnology Co. Ltd., Beijing, China (Ms Zhang, Shan, and Yao); Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (Mr K Du); Department of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming, Yunnan, China (Dr M Li); Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (Dr Xu).
authors.forename: Jing
authors.initials: J
authors.lastname: Du
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D001569:Benzodiazepines; D003839:Deoxyadenosines; D018691:Excitatory Amino Acid Antagonists; D007099:Imipramine; D018091:Receptors, AMPA; C061950:GYKI 52466; C058120:cordycepin; C104722:glutamate receptor ionotropic, AMPA 2
keywords: 3’-deoxyadenosine; GluR1; animal behavior; rapid antidepressant; synapse