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，而且至少一半的患者无法通过目前可用的药物得到有效治疗，这一事实使情况变得更加复杂。最常用的处方是选择性血清素 (5-HT) 再摄取抑制剂 (SSRI)，其作用是抑制 5-HT 转运蛋白 (SERT) 介导的 5-HT 摄取。随后细胞外 5-HT 的增加被认为对于启动治疗效果所需的一系列下游事件至关重要。尽管 SERT 是调节高亲和力 5-HT 摄取的主要参与者，但有新的证据表明有机阳离子转运蛋白 3 (OCT3) 以及可能的质膜单胺转运蛋白 (PMAT) 在大脑摄取 5-HT 方面发挥着重要作用。这提出了一种可能性，即 SERT 阻断后缺乏治疗反应可能是由于 OCT3（和/或 PMAT）显着摄取 5-HT 所致。我们使用 Decynium-22 (D-22)（OCT3 和 PMAT 的阻断剂）进行的研究支持了这一想法。例如，D-22 增强了 SSRI 氟伏沙明的作用，抑制 5-HT 摄取并在野生型小鼠中产生抗抑郁样作用。此外，D-22 在 SERT 表达缺失或减少的小鼠中单独给药时也会产生这些作用。因此，当 SERT 被药理学或基因失活时，D-22 的抗抑郁样作用似乎最为明显。我们还发现，SERT 持续减少的小鼠中 OCT3 表达（但不是 PMAT）增加，表明 OCT3 具有补偿作用。拟议研究的一个重要方面将是检验这种情况在长期使用 SSRIs 治疗后是否也发生的可能性，众所周知，SSRIs 会减少 SERT 的表达。除了 5-HT 之外，OCT3（和 PMAT）还可以转运去甲肾上腺素 (NE) 和多巴胺 (DA)，这些神经递质也与当前抗抑郁药的治疗作用有关。总而言之，拟议研究的目标是 (1) 验证 OCT3（和/或 PMAT）是 D-22 产生抗抑郁样作用的位点； (2) 确定抑制 5-HT、NE 和 DA 摄取在产生 D-22 抗抑郁样作用中的相对重要性，以及 (3) 通过研究 D-22 对生物胺摄取的影响来检查 D-22 的治疗潜力以及长期给药后的抗抑郁样活性。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标，并提供一种机制，至少可以部分解释治疗反应不佳的原因。目前的抗抑郁药物。 公共健康相关性：尽管报告有所不同，但据估计，超过一半的患者群体的重度抑郁症没有得到成功治疗，这凸显了迫切需要确定抗抑郁药物的新靶点。 OCT3 正在成为这样的目标之一。通过验证这一目标，这里提出的实验将为发现具有显着治疗潜力的新型抗抑郁药奠定基础，特别是对于治疗耐药的患者。