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-depressi...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.展开更多
基金supported by National Natural Science Foundation of China(No.82104278)Leading Technology Foundation Research Project of Jiangsu Province(No.BK20192005,China)+4 种基金National Key Project of Science and Technology for Innovation Drugs of China(No.2017ZX09301013)CAMS Innovation Fund for Medical Sciences(CIFMS,No.2021-I2M-5-011,China)Sanming Project of Medicine in Shenzhen(No.SZSM201801060,China)Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMKF202203,China)National Innovation and Entrepreneurship Training Program for Undergraduate,China Pharmaceutical University(Nos.2023103161381 and 2023103161287,China)。
文摘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.
