Neurochemical and behavioural effects of hypidone hydrochloride (YL-0919): a novel combined selective 5-HT reuptake inhibitor and partial 5-HT 1A agonist

• Published in: British journal of pharmacology Vol. 174; no. 9; pp. 769 - 780
• Main Authors: Zhang, Li-Ming, Wang, Xiao-Yun, Zhao, Nan, Wang, Yu-Lu, Hu, Xiao-Xu, Ran, Yu-Hua, Liu, Yan-Qin, Zhang, You-Zhi, Yang, Ri-Fang, Li, Yun-Feng
• Format: Journal Article
• Language: English
• Published: England 01.05.2017
• Subjects: Animals; Anti-Anxiety Agents - metabolism; Anti-Anxiety Agents - pharmacology; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Avoidance Learning - drug effects; Avoidance Learning - physiology; Dose-Response Relationship, Drug; Drug Partial Agonism; Female; Hippocampus - drug effects; Hippocampus - metabolism; Male; Mice; Mice, Inbred ICR; Microdialysis - methods; Piperidines - metabolism; Piperidines - pharmacology; Pyridones - metabolism; Pyridones - pharmacology; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT1A - metabolism; Serotonin 5-HT1 Receptor Agonists - metabolism; Serotonin 5-HT1 Receptor Agonists - pharmacology; Serotonin Uptake Inhibitors - metabolism; Serotonin Uptake Inhibitors - pharmacology; Sexual Behavior, Animal - drug effects; Sexual Behavior, Animal - physiology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13675

Our previous studies revealed that hypidone hydrochloride (YL-0919), which acts as a selective 5-HT (serotonin) reuptake inhibitor (SSRI) and displays partial 5-HT receptor agonist properties, exerts a significant antidepressant effect in various animal models. The aim of present research was to further investigate the pharmacology of YL-0919. We first investigated the target profile of YL-0919 using [ S]-GTPγS binding and microdialysis. To determine whether the 5-HT or noradrenergic systems are involved in the antidepressant-like effect of YL-0919, the 5-hydroxytryptophan (5-HTP)-induced head-twitch test and antagonism with a high dose of apomorphine were performed. Using the learned helplessness paradigm, the novelty suppressed feeding test, the Vogel-type conflict and elevated plus-maze test, we further verified the antidepressant-like and anxiolytic-like effects of YL-0919. The effects of YL-0919 on hippocampal long-term potentiation (LTP) and sexual behaviour were also evaluated. Data from the present study demonstrated that YL-0919 displays partial 5-HT receptor agonist properties, producing a greater impact on extracellular 5-HT levels than a conventional SSRI (fluoxetine), as well as significant antidepressant and anxiolytic effects. Furthermore, YL-0919 treatment rapidly influenced the synaptic plasticity (enhancing LTP) of rats. Finally, at doses close to those producing antidepressant-like effects, YL-0919 did not result in a marked inhibition of sexual function. These data suggest that YL-0919 is probably a fast-onset potent antidepressant with few side effects.