Organic Cation Transporters as Targets for Novel Antidepressant Drugs

抑郁症和相关疾病是一个主要的公共卫生问题，由于至少有一半的患者无法通过目前可用的药物进行有效治疗而变得更加复杂。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），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的增加被认为是启动治疗效果所需的下游事件级联的关键。虽然SERT是调节高亲和力5-HT摄取的主要参与者，但有证据表明有机阳离子转运蛋白3（OCT 3）和质膜单胺转运蛋白（PMAT）在脑中摄取5-HT中起重要作用。这增加了SERT阻断后缺乏治疗反应可能是由于OCT 3（和/或PMAT）的显著5-HT摄取的可能性。我们的研究使用decyloxime-22（D-22），OCT 3和PMAT的阻断剂，支持这一想法。例如，D-22增强了SSRI（氟伏沙明）抑制5-HT摄取的作用，并在野生型小鼠中产生抗抑郁样作用。此外，D-22在缺乏SERT表达或SERT表达降低的小鼠中单独给药时也产生这些作用。因此，D-22的抗抑郁样作用似乎是最明显的，当SERT是无活性或遗传失活。我们还发现，在SERT组成性减少的小鼠中，OCT 3表达（但不是PMAT）增加，表明OCT 3的代偿作用。拟议研究的一个重要方面将是检查SSRIs长期治疗后也发生这种情况的可能性，已知SSRIs可降低SERT表达。除了5-HT，OCT 3（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OCT 3（和/或PMAT）作为D-22产生其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，和（3）通过研究D-22长期给药后对生物胺摄取和抗抑郁样活性的影响来检查D-22的治疗潜力。这些研究的结果将有助于将OCT 3（和/或PMAT）作为发现具有改善治疗潜力的药物的新靶点，并提供一种机制，至少部分地解释了对当前抗抑郁药物的不良治疗反应。 公共卫生相关性：虽然报告各不相同，但据估计，超过一半的患者未能成功治疗重度抑郁症，这突出表明迫切需要确定抗抑郁药物的新靶点。OCT 3就是这样一个目标。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奠定基础，特别是在治疗抵抗性患者中。

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.