Neurochemical and behavioural effects of hypidone hydrochloride (YL-0919): a novel combined selective 5-HT reuptake inhibitor and partial 5-HT1A agonist

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-HT_1A 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-HT_1A 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.

Figure 1

(A) Effect of YL‐0919, vilazodone and 8‐OH‐DPAT on [³⁵S]‐GTPγS binding to rat hippocampal membranes. (B) Effect of WAY‐100635 on 8‐OH‐DPAT‐induced stimulation of [³⁵S]‐GTPγS binding to rat hippocampal membranes. (C) Effect of WAY‐100635, mianserin or tropisetron on YL‐0919‐induced stimulation of [³⁵S]‐GTPγS binding to rat hippocampal membranes. The results are expressed as the mean ± SEM. Values for the % of the respective basal binding were obtained from four experiments performed in duplicate. ^* P < 0.05 versus Vehicle, ^# P < 0.05 versus 8‐OH‐DPAT or YL‐0919 (Two‐way ANOVA followed by Dunnett's test).

Figure 2

Effect of YL‐0919 on extracellular 5‐HT, NA or dopamine (DA) levels in rat hippocampus. Rats were treated with YL‐0919 (1.25 or 2.5 mg·kg⁻¹, i.g.), FLX (10 mg·kg⁻¹, i.g.) or vehicle at t = 0. And then a rapid and validated HPLC‐MS method coupled with microdialysis was used to monitor the levels of monoamine levels after YL‐0919 treatment. Data are expressed as a percentage of basal 5‐HT (NA, DA) (n = 6–9 per group). ^* P < 0.05 compared with the Vehicle group.

Figure 3

Effect of YL‐0919 in several behavioural and pharmacological models. Pretreatment with YL‐0919 (1.25 and 2.5 mg·kg⁻¹, i.g.) potentiated the ability of 5‐HTP‐induced head‐twitch response in 5‐HTP‐induced head‐twitch test (A); single YL‐0919 administration had no effect on high dose of apomorphine (16 mg·kg⁻¹) induced hypothermia (B); subchronic (7 days) treatment with YL‐0919 decreased the latency to feed (C). A similar result was observed after chronic (14 days) treatment with YL‐0919 treatment (D); sub‐chronic treatment with YL‐0919 significantly decreased escape latencies (E) and number of failures to escape (F) in comparison with control mice. Data are presented as the means ± SEM (n = 8–10). ^* P < 0.05, compared with the Vehicle (Veh) control group (ANOVA followed by Dunnett's test); ^# P < 0.05, compared with LH(+)‐Veh group.

Figure 4

Effects of YL‐0919 on behavioural models of anxiety. YL‐0919 significantly increased the number of shocks in Vogel‐type conflict test in rats (A) and the percentage of both the time spent and the entries into the open arms in the elevated plus‐maze test (B and C). Data are presented as the means ± SEM (n = 10). ^* P < 0.05, compared with the vehicle (Veh) group.

Figure 5

Hippocampal LTP (PS amplitude or fEPSP slope) in rats was greatly enhanced by YL‐0919 treatment in adult freely behaving rats. LTP was induced 12 h after the termination of sub‐chronic (7 days) or chronic (21 days) treatment with saline, FLX (10 mg·kg⁻¹, i.g.) or YL‐0919 (0.625–2.5 mg·kg⁻¹, i.g.) respectively. Results were summarized from all animals (n = 5–6). Each value represents the mean ± SEM. ^* P < 0.05, compared with the Vehicle group.

Figure 6

Effects of repeated YL‐0919 treatments on the sexual behaviours. Data are expressed as means ± SEM. ^* P < 0.05, compared with vehicle (Veh).