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

基本信息

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
项目类别：
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

项目摘要

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（申请人提供）：抑郁症是一个重大的公共卫生问题，大多数患者没有得到有效治疗，这一问题在儿童和青少年中进一步加剧，目前只有两种抗抑郁药物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其增加细胞外 5-HT 水平的能力引起的下游事件触发的。然而，我们使用成年小鼠进行的研究表明 SSRIs 具有抑制 5-HT 的能力。 HT 的摄取因 5-HT 的非 SERT 癸酎 22 (D22) 敏感转运蛋白的存在而受到极大限制，因此，通过防止细胞外 5-HT 上升至治疗有用的水平，非 SERT 转运蛋白可以抑制 HT 的吸收。为 SSRIs 的有限治疗效果提供了机制基础。然而，对于青少年大脑中 SERT 的表达或功能知之甚少，并且对 SERT 的表达和活性一无所知。 OCT 和 PMAT 在这些年轻人中的表达和功能毫不奇怪，对于青少年、青少年和成人大脑中 SERT、OCT 和 PMAT 与抗抑郁反应之间的关系一无所知。通过 (1) 提供幼年、青少年和成年小鼠 SERT 表达和功能的系统概况，并关键性地确定 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 在儿童期和青春期比成年期的 5-HT 摄取中发挥更重要的作用。可能是抗抑郁药物的有用靶标，特别是在这一年轻人群中，考虑到与成年期功能障碍之间的密切联系，本文提出的研究将为儿童期和青春期大脑摄取 5-HT 的调节机制提供新的见解。 5-HT信号传导和许多精神疾病，其中抑郁症最为突出，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我们对这些疾病的病因学基础的理解，重要的是，将指导改进治疗的开发。