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

 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治疗。这个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被批准用于他们。两者都属于选择性5-羟色胺（5-HT）再摄取抑制剂（SSRI）类抗抑郁药，通过阻断5-羟色胺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，这些事件是响应于它们增加细胞外5-HT水平的能力而发生的。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5-HT的非SERT、脱环素-22（D22）敏感转运蛋白的存在的极大限制。因此，通过阻止细胞外5-HT升高到治疗有用的水平，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体（OCT）和质膜单胺转运体（PMAT）的活性。OCT和PMAT在成人大脑中表达，但它们对多巴胺能神经传递的影响可能在青少年和青少年大脑中更大，特别是如果它们的表达和活性不成比例地大于SERT。然而，对SERT在青少年大脑中的表达和功能知之甚少，对OCT和PMAT在这些年轻年龄段的表达和功能也一无所知。毫不奇怪，对青少年、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。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、青少年和成年小鼠中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的表达和功能变化，以及（2）确定对这些转运蛋白阻断剂的抗抑郁样反应在幼年、青少年和成年小鼠中的差异。我们的初步数据支持这一假设，OCT和/或PMAT发挥更突出的作用，5-HT摄取在儿童和青少年比在成年期，并可能是有用的抗抑郁药物的目标，特别是在这个年轻的人群。与成年期相比，儿童期和青春期脑内5- HT摄取的调节机制将得到新的认识。鉴于5-HT信号传导功能障碍与许多精神疾病之间的密切联系，其中抑郁症是突出的，阐明儿童和青少年与成人相比控制5-HT摄取的机制将进一步加深我们对这些疾病的病因学基础的理解，重要的是，将指导改进治疗方法的发展。

 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.