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（适用提供）：抑郁症是大多数患者没有有效治疗的主要公共卫生问题。目前仅批准两种抗抑郁药的儿童和青少年，此问题进一步加剧了。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，并通过通过羟色胺转运蛋白从细胞外液中阻断5-HT的高亲和力摄取来起作用。 （Sert）。 SSRI的理论效用被认为是由下游事件触发的，这些事件是由于它们增加了5-HT细胞外水平的能力而发生的。然而，我们使用成年小鼠的研究表明，SSRI抑制5-HT摄取的能力受到5-HT的非官能，Decynium-22（D22）敏感转运蛋白的存在的限制。通过防止细胞外5-HT上升到治疗有用的水平，非SERT转运蛋白为有限的SSRI治疗效率提供了机械基础。 D22抑制有机CATIO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，但在青少年和青春期的大脑中，它们对血清素能神经传递的影响可能更大，尤其是当它们的表达和活性比SERT大于SERT时。然而，关于SERT在少年和青少年大脑中的表达或功能知之甚少，对这些年轻时代的OCT和PMAT的表达和功能一无所知。毫不奇怪，少年，青少年和成人大脑以及抗抑郁反应的SERT，OCT和PMAT之间的关系一无所知。拟议的研究的目标是通过（1）通过（1）为少年，青少年和成年小鼠提供系统的表达和功能，并重要地确定OCT和PMAT的表达和功能如何与SERT的表达和功能范围，以及（2）确定这些抗抑郁药对这些抗抑郁药的反应对这些抗抑郁剂的反应，以确定对这些变速箱的变形者的差异，并在少年中差异化。我们的初步数据支持以下假设：OCT和/或PMAT在儿童期和青少年时期比成年时在5-HT摄取中起着更突出的作用，并且可能是抗抑郁药的有用靶标，尤其是在这份年轻人口中。与成年相比，这里提出的研究将提供有关在儿童期和青少年期间在大脑中摄取5-HT吸收机制的新见解。鉴于5-HT信号传导中功能障碍与许多精神疾病之间的牢固联系，与成人相比，抑郁症是显着的，阐明儿童和青少年5-HT吸收的机制将进一步了解我们对这些疾病的病因学基础的理解，并且重要的是，将指导改善治疗的发展。