Abstract
Our previous study showed that hypidone hydrochloride (YL-0919), a partial serotonin 1A (5-HT1A) receptor agonist and 5-HT reuptake inhibitor, exerts a significant antidepressant effect in various animal models. The aim of the present study was to further investigate the underlying mechanisms and whether it could act as a fast-onset antidepressant. In the current study, depressive-like behavior was induced in rats by a chronic unpredictable stress (CUS) model and assessed with the Sucrose Preference Test (SPT). Treatment with YL-0919 (2.5 mg/kg, i.g.), but not with fluoxetine (Flx; 10 mg/kg, i.g.), caused a fast improvement in the SPT scores. In CUS-exposed rats, YL-0919 treatment for 5 days decreased the immobility time in a forced swimming test (FST), and a 10-day treatment decreased the latency to feed in a Novelty-Suppressed Feeding Test (NSFT). In addition to the behavioral tests, the effects of YL-0919 on synaptic protein expression were also evaluated. Western blotting showed that YL-0919 significantly enhanced the expression levels of synaptic proteins such as synapsin I, postsynaptic density protein 95 (PSD95), phosphorylated mammalian targeting of rapamycin (pmTOR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. To determine how the mTOR signaling is involved in the fast-onset antidepressant-like effects of YL-0919, the mTOR-specific inhibitor rapamycin was administered intracerebroventricularly (i.c.v.) together with the YL-0919 treatment. The observed changes in behavioral tests and protein expression could be reversed by rapamycin treatment. This suggests that the fast-onset antidepressant effects of YL-0919 were partially caused by changes in synaptogenesis mediated by activation of mTOR pathways. Our data suggest that YL-0919 may be a powerful/effective antidepressant with fast-onset.
Highlights
Major depressive disorder is a serious neuropsychiatric condition that affects a large number of people worldwide (Kessler et al, 2003)
The data obtained in the current study demonstrate that YL-0919, which is a partial 5-HT1A receptor agonist and a selective serotonin reuptake inhibitor (SSRI), induces an antidepressant effect in rats after 3 days of treatment, which is significantly faster than conventional SSRIs such as Flx, and significantly influences synaptogenesis as observed by the expression of synaptic proteins such as synapsin I and PSD95
These antidepressant effects of YL-0919 treatment could be reversed by the mTOR-specific inhibitor rapamycin, which could block the upregulation of synaptic proteins caused by YL-0919
Summary
Major depressive disorder is a serious neuropsychiatric condition that affects a large number of people worldwide (Kessler et al, 2003). The antidepressants currently available in clinical settings mainly target noradrenaline/serotonin (NE/5-HT) transporters; these agents usually exhibit a time lag of weeks in their effects and show initial response rates of only around 33%. Chronic treatments must be a long-lasting course and the antidepressant treatment commonly needs several weeks to months to create an effect (Penn and Tracy, 2012). Novel agents that can induce the fast onset of robust antidepressant responses are needed to alleviate the challenges of the treatment of depression. As an NMDA receptor antagonist, a single intravenous administration of ketamine, induced a rapid and long-lasting antidepressant effect within 2 h, that lasted almost 1 week in clinical trials (Berman et al, 2000; Zarate et al, 2006). The side-effects of addiction and the potential of drug abuse associated with ketamine, have severely restricted its clinical use (Liston et al, 2006; Liebrenz et al, 2007)
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