Neurochemical and behavioral effects of hypidone hydrochloride (YL‐0919): A novel combined selective serotonin reuptake inhibitor and partial 5‐HT1A agonist

The purpose of the present study was to investigate the pharmacology of hypidone hydrochloride (YL-0919), a novel selective serotonin reuptake inhibitor (SSRI) and 5-hydroxytryptamine (5-HT)1A receptor agonist with high affinity for serotonin transporter (SERT) and 5-HT1A receptors. YL-0919 promoted [35S]GTPγS binding at 85% of the magnitude of the full 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), suggesting that YL-0919 is a high-efficacy partial agonist of 5-HT1A receptors. Compared with fluoxetine, YL-0919 produced a larger maximal increase in extracellular 5-HT in the ventral hippocampus of freely moving rats after acute treatment, but no significant changes were observed in the levels of noradrenaline or dopamine. In behavioral tests, acute YL-0919 treatment potentiated 5-hydroxytryptophan (5-HTP)-induced head twitches but showed no effect on high-dose apomorphine-induced hypothermia. In the novelty-suppressed feeding test (NSF), both subchronic (7 days) and chronic (14 days) treatment with YL-0919 decreased the latency to feed. In the learned helplessness paradigm, YL-0919 (1.25-5 mg/kg) significantly decreased the escape latencies and number of failures. In addition, YL-0919 exerted an anxiolytic effect in the Vogel-type conflict and elevated plus-maze tests in rats. Furthermore, rats treated with YL-0919 for 7 days and 21 days, and fluoxetine for 21 days, showed enhanced long-term potentiation (LTP). Finally, we also found that YL-0919 did not result in a marked inhibition of sexual function at doses close to those producing antidepressant-like effects. These data suggest that YL-0919 is likely a fast-onset potent antidepressant with few side effects. This article is protected by copyright. All rights reserved.