Organic Cation Transporters as Targets for Novel Antidepressant Drugs

有机阳离子转运蛋白作为新型抗抑郁药物的靶标

• 批准号: 8262100
• 负责人: LYNETTE C DAWS
• 金额: $ 53.03万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262100
• 关键词: 1-Methyl-4-phenylpyridinium; Accounting; Acute; Address; Affinity; Antidepressive Agents; Behavioral; Behavioral Assay; Biogenic Amine Neurotransmitters; Biogenic Amines; Brain; Brain region; Cations; Cell Line; Cell membrane; Chronic; Corpus striatum structure; Data; Development; Disease; Dopamine; Event; Extracellular Fluid; Fluvoxamine; Foundations; Future; Genetic; Genotype; Goals; Hippocampus (Brain); Knowledge; Link; Literature; Major Depressive Disorder; Mediating; Mediator of activation protein; Mental Depression; Mus; Neurotransmitters; Norepinephrine; Organic Cation Transporter; Patients; Pharmaceutical Preparations; Preparation; Property; Public Health; Relative (related person); Reporting; Resistance; Role; Serotonin; Site; Speed; Therapeutic; Therapeutic Effect; Treatment Efficacy; Wild Type Mouse; analog; base; dopamine transporter; drug development; drug discovery; extracellular; improved; in vitro Assay; in vivo; inhibitor/antagonist; insight; monoamine; neurochemistry; neurotransmitter uptake; novel; patient population; research study; response; reuptake; uptake

DESCRIPTION (provided by applicant): Depression and related disorders are a major public health problem, compounded by the fact that at least half of patients are not effectively treated by currently available medications. Among the most commonly prescribed is the class of selective serotonin (5-HT) reuptake inhibitors (SSRIs), which act to inhibit 5-HT transporter (SERT) mediated 5-HT uptake. The increase in extracellular 5-HT that follows is thought to be critical for initiation of the cascade of downstream events needed for therapeutic effects. Although SERT is the major player regulating high-affinity 5-HT uptake, there is emerging evidence for an important role of organic cation transporter-3 (OCT3) and possibly the plasma membrane monoamine transporter (PMAT) in taking up 5-HT in brain. This raises the possibility that lack of therapeutic response following SERT blockade could be due to significant 5-HT uptake by OCT3 (and/or PMAT). Our studies using decynium-22 (D-22), a blocker of both OCT3 and PMAT, lend support to this idea. For example, D-22 augments the effect of an SSRI, fluvoxamine, to inhibit 5-HT uptake and to produce antidepressant-like effects in wildtype mice. Moreover, D-22 produces these effects also when given alone in mice that lack, or have reduced SERT expression. Thus, the antidepressant-like effect of D-22 appears to be most pronounced when SERT is either pharmacologically or genetically inactivated. We also found that OCT3 expression (but not PMAT) is increased in mice with a constitutive reduction of SERT, suggesting a compensatory role for OCT3. One important aspect of the proposed studies will be to examine the possibility that this also occurs after chronic treatment with SSRIs, which is known to reduce SERT expression. In addition to 5-HT, OCT3 (and PMAT) can transport norepinephrine (NE) and dopamine (DA), neurotransmitters also linked to the therapeutic action of current antidepressants. Taken together, the goals of the proposed studies are to (1) validate OCT3 (and/or PMAT) as the site where D-22 produces its antidepressant-like effect; (2) determine the relative importance of inhibition of 5-HT, NE and DA uptake in producing the antidepressant-like effect of D-22, and (3) examine the therapeutic potential of D-22 by studying its effect on biogenic amine uptake and antidepressant-like activity after its chronic administration. The results of these studies will help to establish OCT3 (and/or PMAT) as a novel target for the discovery of drugs with improved therapeutic potential, as well as provide a mechanism that can, at least in part, account for poor therapeutic response to current antidepressant drugs. PUBLIC HEALTH RELEVANCE: Although reports vary, it is estimated that major depression is unsuccessfully treated in more than half the patient population, underlining the urgent need to identify new targets for antidepressant medications. OCT3 is emerging as one such target. By validating this target, the experiments proposed here will lay the foundation for the discovery of novel antidepressants with marked therapeutic potential, especially in treatment resistant patients.

描述(由申请人提供)：抑郁症和相关疾病是一个主要的公共卫生问题，而且至少有一半的患者没有得到有效的现有药物治疗。其中最常用的处方是选择性5-羟色胺(5-HT)再摄取抑制剂(SSRI)，它可以抑制5-羟色胺转运体(SERT)介导的5-羟色胺摄取。随之而来的细胞外5-羟色胺的增加被认为是启动治疗效果所需的一系列下游事件的关键。虽然SERT是调节高亲和力5-羟色胺摄取的主要因素，但越来越多的证据表明，有机阳离子转运体3(Oct3)可能是质膜单胺转运体(PmAt)在脑内摄取5-羟色胺的重要作用。这增加了一种可能性，即SERT阻断后缺乏治疗反应可能是由于10月3日(和/或pmAt)大量摄取5-羟色胺。我们使用Oct3和PMAt的阻断剂Decynium-22(D-22)的研究支持这一观点。例如，D-22增强了SSRI，氟伏沙明的作用，以抑制5-羟色胺的摄取，并在野生型小鼠中产生抗抑郁药物样的效果。此外，D-22单独给药时，在缺乏或减少SERT表达的小鼠身上也会产生这些效果。因此，当SERT药物失活或基因失活时，D-22的抗抑郁药样作用似乎最为明显。我们还发现，在SERT结构性降低的小鼠中，Oct3的表达增加(但不是pmAt)，这表明Oct3具有代偿作用。拟议研究的一个重要方面将是检查在使用SSRIs进行慢性治疗后是否也会发生这种情况，众所周知，SSRI可以减少SERT的表达。除了5-羟色胺，Oct3(和pmAt)还可以运输去甲肾上腺素(NE)和多巴胺(DA)，这两种神经递质也与当前抗抑郁药物的治疗作用有关。综上所述，这些研究的目标是：(1)验证Oct3(和/或pmAt)是D-22产生抗抑郁药样作用的部位；(2)确定抑制5-羟色胺、去甲肾上腺素和多巴胺摄取在产生D-22抗抑郁药样作用中的相对重要性；以及(3)通过研究D-22长期给药后对生物胺摄取和抗抑郁药样活性的影响来检验D-22的治疗潜力。这些研究的结果将有助于将Oct3(和/或pmAt)确立为发现具有改善治疗潜力的药物的新靶点，并至少提供了一种机制，至少可以部分解释对现有抗抑郁药物的不良治疗反应。 与公共卫生相关：尽管报告各不相同，但据估计，在超过一半的患者中，重度抑郁症没有得到成功的治疗，这突显了迫切需要为抗抑郁药物确定新的靶点。10月3日正在成为这样的目标之一。通过验证这一目标，本文提出的实验将为发现具有显著治疗潜力的新型抗抑郁药物奠定基础，特别是在治疗耐药患者中。