Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, MC7756, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
Cells. 2022 Aug 8;11(15):2454. doi: 10.3390/cells11152454.
Selective serotonin reuptake inhibitors (SSRIs) are less efficacious in treating depression in children than in adults. SSRIs block serotonin uptake via the high-affinity, low-capacity serotonin transporter. However, the low-affinity, high-capacity organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) are emerging as important players in serotonin uptake. We hypothesized that OCT3 and/or PMAT are functionally upregulated in juveniles, thereby buffering SSRIs' ability to enhance serotonergic neurotransmission. Unlike in adult mice, we found the OCT/PMAT blocker, decynium-22, to have standalone antidepressant-like effects in juveniles. Using in vivo high-speed chronoamperometry, we found that juveniles clear serotonin from the CA3 region of the hippocampus ~2-fold faster than adult mice. Cell density did not differ between ages, suggesting that faster serotonin clearance in juveniles is unrelated to faster diffusion through the extracellular matrix. Western blot and immunohistochemistry showed that juvenile mice have modestly greater expression of PMAT than adults, whereas OCT3 expression in the CA3 region of the hippocampus was similar between ages. Together, these data suggest that faster serotonin clearance and antidepressant-like effects of decynium-22 in juvenile mice may be due to functionally upregulated PMAT. Faster serotonin clearance via PMAT in juveniles may contribute to reduced therapeutic efficacy of SSRIs in children relative to adults.
选择性 5-羟色胺再摄取抑制剂（SSRIs）在治疗儿童抑郁症方面的疗效不如成人。SSRIs 通过高亲和力、低容量的 5-羟色胺转运体来阻断 5-羟色胺的摄取。然而，低亲和力、高容量的有机阳离子转运体 3（OCT3）和质膜单胺转运体（PMAT）正成为 5-羟色胺摄取的重要参与者。我们假设 OCT3 和/或 PMAT 在青少年中功能上调，从而缓冲 SSRIs 增强 5-羟色胺能神经传递的能力。与成年小鼠不同，我们发现 OCT/PMAT 阻断剂 decynium-22 在青少年中具有独立的抗抑郁样作用。通过体内高速 chronoamperometry，我们发现青少年从海马 CA3 区清除 5-羟色胺的速度比成年小鼠快 2 倍左右。细胞密度在不同年龄之间没有差异，这表明青少年中 5-羟色胺清除速度更快与细胞外基质中更快的扩散无关。Western blot 和免疫组织化学显示，青少年小鼠的 PMAT 表达比成年小鼠略高，而海马 CA3 区的 OCT3 表达在不同年龄之间相似。这些数据表明，青少年中 5-羟色胺清除速度更快和 decynium-22 的抗抑郁样作用可能是由于 PMAT 的功能上调。通过 PMAT 更快地清除 5-羟色胺可能导致 SSRIs 在儿童中的治疗效果相对成人降低。
