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，这一事实使至少一半的患者没有被当前可用的药物有效治疗。最常见的规定是选择性5-羟色胺（5-HT）再摄取抑制剂（SSRIS）类，这些抑制剂可抑制5-HT转运蛋白（SERT）介导的5-HT摄取。据认为，以下细胞外5-HT的增加对于启动治疗作用所需的下游事件的级联至关重要。尽管SERT是调节高亲和力5-HT吸收的主要参与者，但有新兴的证据表明有机阳离子转运蛋白3（OCT3）以及可能是质膜单胺转运蛋白转运蛋白（PMAT）在大脑中增加5-HT中的重要作用。这增加了SERT封锁后缺乏治疗反应的可能性可能是由于OCT3（和/或PMAT）的5-HT摄取。我们使用Decynium-22（D-22）（Oct3和PMAT的阻滞剂）的研究为这一想法提供了支持。例如，D-22增强了SSRI氟氟众胺的影响，抑制5-HT摄取并在野生型小鼠中产生抗抑郁样作用。此外，当在缺乏或降低SERT表达的小鼠中单独给出时，D-22也会产生这些效果。因此，当SERT在药理学或遗传上灭活时，D-22的抗抑郁样作用似乎最为明显。我们还发现，在SERT构成降低的小鼠中，OCT3表达（而不是PMAT）增加，这表明OCT3具有补偿性作用。拟议的研究的一个重要方面将是检查这种可能性在慢性SSRI治疗后也发生的可能性，众所周知，这可以降低SERT表达。除5-HT外，OCT3（和PMAT）还可以运输去甲肾上腺素（NE）和多巴胺（DA），神经递质还与当前抗抑郁药的治疗作用有关。综上所述，拟议的研究的目标是（1）验证OCT3（和/或PMAT）作为D-22产生其抗抑郁药样效应的部位； （2）确定抑制5-HT，NE和DA摄取在产生D-22的抗抑郁样作用中的相对重要性，以及（3）通过研究其对生物胺摄取的作用和抗抑郁药在长期给药后检查D-22的治疗潜力。这些研究的结果将有助于建立OCT3（和/或PMAT），作为发现具有改善治疗潜力的药物的新目标，并且提供了一种机制，至少可以部分地说明对当前抗抑郁药的治疗反应不佳。 公共卫生相关性：尽管有报道有所不同，但据估计，在一半以上的患者人群中，重大抑郁症未能成功治疗，这强调了迫切需要确定抗抑郁药的新目标。 Oct3正在成为这样一个目标。通过验证该目标，此处提出的实验将为发现具有明显治疗潜力的新型抗抑郁药奠定基础，尤其是在耐药患者中。