Abstract：
The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly prescribed to treat major depressive disorder and is found at high concentrations in the aquatic environment. Concerns have been raised related to the health of aquatic organisms in response to this nontargeted pharmaceutical exposure. For instance, we previously demonstrated that exposure to venlafaxine perturbs neurodevelopment, leading to behavioural alterations in zebrafish (Danio rerio). We also observed disruption in serotonin expression in the pineal and raphe, regions critical in regulating circadian rhythms, leading us to hypothesize that zygotic exposure to venlafaxine disrupts the circadian locomotor rhythm in larval zebrafish. To test this, we microinjected zebrafish embryos with venlafaxine (1 or 10 ng) and recorded the locomotor activity in 5-day-old larvae over a 24-h period. Venlafaxine deposition reduced larval locomotor activity during the light phase, but not during the dark phase of the diurnal cycle. The melatonin levels were higher in the dark compared to during the light photoperiod and this was not affected by embryonic venlafaxine deposition. Venlafaxine exposure also did not affect the transcript abundance of clock genes, including clock1a, bmal2, cry1a and per2, which showed a clear day/night rhythmicity. A notable finding was that exposure to luzindole, a melatonin receptor antagonist, decreased the locomotor activity in the control group in light, whereas the activity was higher in larvae raised from the venlafaxine-deposited embryos. Overall, zygotic exposure to venlafaxine disrupts the locomotor activity of larval zebrafish fish during the day, demonstrating the capacity of antidepressants to disrupt the circadian rhythms in behaviour. Our results suggest that disruption in melatonin signalling may be playing a role in the venlafaxine impact on circadian behaviour, but further investigation is required to elucidate the possible mechanisms in larval zebrafish.
摘要：
抗抑郁药文拉法辛,选择性5-羟色胺和去甲肾上腺素再摄取抑制剂，通常用于治疗重度抑郁症，并且在水生环境中发现高浓度。由于这种非靶向药物暴露，人们对水生生物的健康感到担忧。例如,我们以前证明暴露于文拉法辛会扰乱神经发育，导致斑马鱼（Daniorerio）的行为改变。我们还观察到松果体和松果体中5-羟色胺表达的破坏，调节昼夜节律的关键区域，引导我们假设合子暴露于文拉法辛会破坏幼体斑马鱼的昼夜节律运动节奏。为了测试这个，我们用文拉法辛（1或10ng）显微注射斑马鱼胚胎，并记录了24小时内5天大幼虫的运动活动。文拉法辛沉积降低了光照期幼虫的运动活动，但不是在昼夜周期的黑暗阶段。与光照周期相比，黑暗中的褪黑激素水平更高，这不受胚胎文拉法辛沉积的影响。文拉法辛暴露也不影响时钟基因的转录丰度，包括clock1a,bmal2，cry1a和per2，显示出清晰的昼夜节律。一个值得注意的发现是暴露于luzindole,褪黑激素受体拮抗剂，在光照下，对照组的运动活动减少，而从文拉法辛沉积的胚胎中培养的幼虫的活性更高。总的来说,合子接触文拉法辛会破坏白天斑马鱼幼虫的运动活动，证明抗抑郁药破坏行为昼夜节律的能力。我们的结果表明，褪黑激素信号的中断可能在文拉法辛对昼夜节律行为的影响中起作用。但是需要进一步的研究来阐明幼体斑马鱼的可能机制。
