Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
J Pineal Res. 2024 Aug;76(5):e12984. doi: 10.1111/jpi.12984.
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.
抗抑郁药文拉法辛是一种选择性 5-羟色胺和去甲肾上腺素再摄取抑制剂，常用于治疗重度抑郁症，并且在水环境中浓度很高。由于这种非靶向药物暴露，水生生物的健康问题引起了人们的关注。例如，我们之前证明，暴露于文拉法辛会干扰神经发育，导致斑马鱼（Danio rerio）出现行为改变。我们还观察到松果腺和中缝核中 5-羟色胺表达的中断，这些区域对调节昼夜节律至关重要，这使我们假设胚胎暴露于文拉法辛会破坏幼鱼的昼夜节律运动节律。为了验证这一点，我们用文拉法辛（1 或 10ng）微注射斑马鱼胚胎，并在 24 小时内记录 5 天大的幼虫的运动活动。文拉法辛沉积减少了幼虫在光期的运动活动，但不影响昼夜节律的暗期。与光周期相比，黑暗中褪黑素水平更高，而胚胎中文拉法辛沉积不影响褪黑素水平。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，它们表现出明显的昼夜节律性。一个值得注意的发现是，褪黑素受体拮抗剂 luzindole 的暴露降低了对照组在光下的运动活动，而在胚胎中文拉法辛沉积的幼虫中，活动水平更高。总的来说，胚胎暴露于文拉法辛会破坏幼鱼的运动活动，这表明抗抑郁药有能力破坏行为的昼夜节律。我们的结果表明，褪黑素信号的中断可能在文拉法辛对昼夜行为的影响中起作用，但需要进一步的研究来阐明幼鱼中可能的机制。
