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的治疗。这一问题在儿童和青少年中进一步加剧，他们目前只批准了两种抗抑郁药物。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5-羟色胺转运体阻止细胞外液中5-羟色胺的高亲和力摄取 (插入)。SSRIs的治疗作用被认为是由下游事件触发的，这些下游事件发生在它们增加细胞外5-羟色胺水平的能力上。然而，我们使用成年小鼠的研究表明，SSRI抑制5-羟色胺摄取的能力受到非SERT，D22(D22)敏感的5-羟色胺转运体的存在的极大限制。因此，通过阻止细胞外5-羟色胺升高到治疗有用的水平，非SERT转运体为SSRIs有限的治疗效果提供了机制基础。D22抑制有机钙转运体(OCTs)和质膜单胺转运体(PMAT)的活性。OCTs和pmAt在成人脑中表达，但它们对青少年脑中5-羟色胺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，对SERT在青少年脑中的表达或功能知之甚少，对OCTs和pmAt在这些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、OCTs和PMAt与抗抑郁反应之间的关系一无所知。建议研究的目的是通过(1)提供SERT在幼年、青少年和成年小鼠中的表达和功能的系统概况，以及重要的是，确定OCTs和pmAt的表达和功能如何随SERT的表达和功能的变化，以及(2)确定这些转运体的阻滞剂对这些转运体阻滞剂的抗抑郁样反应在幼年、青少年和成年小鼠中的差异，以填补这些关键的知识空白。我们的初步数据支持这样的假设，即OCT和/或PMAT在儿童和青春期的5-羟色胺摄取中起着比成年期更显著的作用，可能是抗抑郁药物的有用靶点，特别是在这一年轻群体中。这里提出的研究将为儿童和青春期大脑中5-羟色胺摄取的调节机制提供新的见解，与成年相比。鉴于5-羟色胺信号转导功能障碍与许多精神疾病之间的密切联系，其中抑郁是突出的，阐明与成人相比控制儿童和青少年5-羟色胺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.