Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy.

Yue Zhang; Jingwen Gao; Na LI; Peng XU; Shimeng QU; Jinqian Cheng; Mingrui Wang; Xueru LI; Yaheng Song; Fan Xiao; Xinyu Yang; Jihong Liu; Hao Hong; Ronghao MU; Xiaotian LI; Youmei Wang; Hui XU; Yuan Xie; Tianming Gao; Guangji Wang; Jiye AA

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Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy.

Author: Yue ZHANG ¹ ; Jingwen GAO ¹ ; Na LI ¹ ; Peng XU ² ; Shimeng QU ¹ ; Jinqian CHENG ¹ ; Mingrui WANG ³ ; Xueru LI ⁴ ; Yaheng SONG ¹ ; Fan XIAO ¹ ; Xinyu YANG ⁵ ; Jihong LIU ⁵ ; Hao HONG ⁶ ; Ronghao MU ⁶ ; Xiaotian LI ⁷ ; Youmei WANG ² ; Hui XU ¹ ; Yuan XIE ¹ ; Tianming GAO ⁵ ; Guangji WANG ¹ ; Jiye AA ¹
Author Information

1. Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing 210009, China.
2. Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center, Ministry of Public Security, Beijing 100193, China.
3. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
4. School of Foreign Languages, China Pharmaceutical University, Nanjing 211198, China.
5. Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
6. Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
7. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Publication Type:Journal Article
Keywords: Crocin; D1-MSN; D2-MSN; Depression; Ketamine; Nucleus accumbens; Rapid antidepressant; cAMP
From: Acta Pharmaceutica Sinica B 2024;14(2):667-681
CountryChina
Language:English
Abstract: Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.