Li-Ming Zhang1, Xiao-Yun Wang1,2, Nan Zhao1, Yu-Lu Wang1,3, Xiao-Xu Hu1, Yu-Hua Ran1, Yan-Qin Liu1, You-Zhi Zhang1, Ri-Fang Yang4, Yun-Feng Li1. 1. Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China. 2. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 3. College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China. 4. Department of Medicinal Chemistry, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Abstract
BACKGROUND AND PURPOSE: Our previous studies revealed that hypidone hydrochloride (YL-0919), which acts as a selective 5-HT (serotonin) reuptake inhibitor (SSRI) and displays partial 5-HT1A 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. EXPERIMENTAL APPROACH: We first investigated the target profile of YL-0919 using [35 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. KEY RESULTS: Data from the present study demonstrated that YL-0919 displays partial 5-HT1A 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. CONCLUSIONS AND IMPLICATIONS: These data suggest that YL-0919 is probably a fast-onset potent antidepressant with few side effects.
BACKGROUND AND PURPOSE: Our previous studies revealed that hypidone hydrochloride (YL-0919), which acts as a selective 5-HT (serotonin) reuptake inhibitor (SSRI) and displays partial 5-HT1A 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. EXPERIMENTAL APPROACH: We first investigated the target profile of YL-0919 using [35 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. KEY RESULTS: Data from the present study demonstrated that YL-0919 displays partial 5-HT1A 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. CONCLUSIONS AND IMPLICATIONS: These data suggest that YL-0919 is probably a fast-onset potent antidepressant with few side effects.