5-HT6 receptor agonist and memory-enhancing properties of hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI. (August 2018)

• Record Type: Journal Article
• Authors: Chen, Xiao-fei; Jin, Zeng-liang; Gong, Ying; Zhao, Nan; Wang, Xiao-yun; Ran, Yu-hua; Zhang, You-zhi; Zhang, Li-ming; Li, Yun-Feng
• Is Part Of: Neuropharmacology. Volume 138(2018)
• Page Start: 1
• Page End: 9
• Publication Date: 2018-08
• Subjects: YL-0919 -- Cognition -- 5-HT6 receptor -- Antidepressant -- Memory; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.05.027
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Most current antidepressants are lacking a pro-cognition effect or even impair cognition as a side effect, and there are few effective psychopharmacological options that improve cognitive dysfunction in depression. Our previous studies revealed that hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI, has antidepressant- and anxiolytic-like effects. Here, further studies found that YL-0919, but not vilazodone (a 5-HT1A receptor partial agonist and SSRI), exerted a significant memory-enhancing effect in the Morris water maze, object recognition test and step-down passive avoidance task. Because the 5-HT6 receptor has emerged as an interesting drug target to improve cognition, we investigated the target profile of YL-0919 using radioligand binding assays, [ 35 S]-GTPγS binding and cAMP stimulation assays. YL-0919 was found to act as a highly effective, full agonist of 5-HT6 receptors. Finally, we observed that the memory-enhancing activities of YL-0919 were completely reversed after co-administration of SB271046 (a selective 5-HT6 receptor antagonist) at a dose that does not alter cognition. In summary, the findings of the current study suggest that YL-0919 has clear memory-enhancing effects, which might be at least partially mediated by 5-HT6 receptor activation. Highlights: YL-0919 was found to act as a highly effective, full agonist of 5-HT6 receptors. YL-0919 has clear memory-enhancing effects on behaviours. Direct activation of 5-HT6 receptors partially mediates the memory-enhancing actions of YL-0919.