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

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-HT_1A receptor partial agonist and SSRI, has antidepressant- and anxiolytic-like effects. Here, further studies found that YL-0919, but not vilazodone (a 5-HT_1A 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, [³⁵S]-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.

Keywords: 5-HT(6) receptor; Antidepressant; Cognition; Memory; YL-0919.