Age-related differences in serotonin clearance: novel targets for antidepressants

血清素清除率与年龄相关的差异：抗抑郁药的新目标

• 批准号: 9062518
• 负责人: LYNETTE C DAWS
• 金额: $ 56.97万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062518
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adult; Affinity; Age; Antidepressive Agents; Binding; Biological Assay; Brain; Brain region; Cell membrane; Child; Childhood; Citalopram; Clinical; Data; Development; Disease; Effectiveness; Event; Extracellular Fluid; Fluvoxamine; Functional disorder; Genes; Goals; Health; Heterozygote; Hippocampus (Brain); In Vitro; Knockout Mice; Knowledge; Link; Measures; Mediating; Mental Depression; Mental disorders; Moods; Mus; Organic Cation Transporter; POU2F1 gene; POU2F2 gene; Patients; Play; Population; Preclinical Testing; Public Health; Regulation; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Transduction; Swimming; Tail Suspension; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Variant; Western Blotting; age related; base; clinical efficacy; extracellular; feeding; improved; in vivo; inhibitor/antagonist; insight; interest; monoamine; neurotransmission; novel; postnatal; prevent; radioligand; response; reuptake; serotonin transporter; uptake

 DESCRIPTION (provided by applicant): Depression is a major public health problem for which the majority of patients are not effectively treated. This problem is exacerbated further in children and adolescents for whom only two antidepressant drugs are currently approved. Both belong to the selective serotonin (5-HT) reuptake inhibitor (SSRI) class of antidepressant, and act by blocking high-affinity uptake of 5-HT from extracellular fluid via the serotonin transporter (SERT). The therapeutic utility of SSRIs is thought to be triggered by downstream events that occur in response to their ability to increase extracellular levels of 5-HT. However, our studies using adult mice show that the ability of SSRIs to inhibit 5-HT uptake is greatly limited by the presence of non-SERT, decynium-22 (D22) sensitive transporters for 5-HT. Thus, by preventing extracellular 5-HT rising to therapeutically useful levels, non-SERT transporters provide a mechanistic basis for limited therapeutic efficacy of SSRIs. D22 inhibits activity of organic catio transporters (OCTs) and the plasma membrane monoamine transporter (PMAT). OCTs and PMAT are expressed in adult brain, but their impact on serotonergic neurotransmission may be even greater in juvenile and adolescent brain, particularly if their expression and activity is disproportionately greater than SERT. However, little is known about expression or function of SERT in juvenile and adolescent brain, and nothing is known about the expression and function of OCTs and PMAT at these young ages. Not surprisingly, nothing is known about the relation among SERT, OCTs and PMAT in juvenile, adolescent, and adult brain and antidepressant response. The goals of the proposed studies are to fill these critical gaps in knowledge by (1) providing a systematic profile for SERT expression and function in juvenile, adolescent, and adult mice and importantly, determining how expression and function of OCTs and PMAT varies with that of SERT, and (2) determining how the antidepressant-like response to blockers of these transporters differs among juvenile, adolescent, and adult mice. Our preliminary data support the hypothesis that OCTs and/or PMAT play a more prominent role in 5-HT uptake during childhood and adolescence than in adulthood, and may be useful targets for antidepressant drugs, especially in this young population. Studies proposed here will afford new insight into mechanisms regulating 5- HT uptake in brain during childhood and adolescence, compared with adulthood. Given the strong link between dysfunction in 5-HT signaling and many psychiatric disorders, depression being prominent among them, elucidating mechanisms controlling 5-HT uptake in children and adolescents compared with adults will further our understanding of the etiological bases for these disorders and importantly, will guide the development of improved treatments.

 描述（由申请人提供）：抑郁症是一个主要的公共卫生问题，大多数患者没有得到有效的治疗。对于儿童和青少年来说，这个问题更加严重，目前只有两种抗抑郁药物获得批准。两者都属于选择性血清素 (5-HT) 再摄取抑制剂 (SSRI) 类抗抑郁药，通过阻断血清素转运蛋白从细胞外液中高亲和力摄取 5-HT 发挥作用。 （SERT）。 SSRIs 的治疗效用被认为是由下游事件触发的，这些下游事件是对其增加细胞外 5-HT 水平的能力做出反应而发生的。然而，我们使用成年小鼠的研究表明，SSRIs 抑制 5-HT 摄取的能力受到非 SERT、癸鎓 22 (D22) 敏感 5-HT 转运蛋白的存在的极大限制。因此，通过阻止细胞外 5-HT 上升至治疗有效水平，非 SERT 转运蛋白为 SSRI 的有限治疗功效提供了机制基础。 D22 抑制有机阳离子转运蛋白 (OCT) 和质膜单胺转运蛋白 (PMAT) 的活性。 OCT 和 PMAT 在成人大脑中表达，但它们对青少年大脑中血清素能神经传递的影响可能更大，特别是如果它们的表达和活性不成比例地大于 SERT。然而，人们对SERT在青少年大脑中的表达和功能知之甚少，对OCT和PMAT在这些年轻时期的表达和功能也一无所知。不足为奇的是，我们对 SERT、OC​​T 和 PMAT 在青少年、青少年和成人大脑与抗抑郁反应中的关系一无所知。拟议研究的目标是通过以下方式填补这些关键知识空白：(1) 提供幼年、青少年和成年小鼠 SERT 表达和功能的系统概况，重要的是，确定 OCT 和 PMAT 的表达和功能如何随 SERT 变化，以及 (2) 确定幼年、青少年和成年小鼠对这些转运蛋白阻滞剂的抗抑郁样反应有何不同。我们的初步数据支持这样的假设：OCT 和/或 PMAT 在儿童期和青春期的 5-HT 摄取中比成年期发挥更重要的作用，并且可能是抗抑郁药物的有用靶标，尤其是在这个年轻人群体中。本文提出的研究将为儿童期和青春期与成年期相比大脑中 5-HT 摄取的调节机制提供新的见解。鉴于 5-HT 信号传导功能障碍与许多精神疾病（其中抑郁症最为突出）之间存在密切联系，阐明与成人相比控制儿童和青少年 5-HT 摄取的机制将进一步了解这些疾病的病因学基础，重要的是，将指导改进治疗的开发。