Organic Cation Transporters as Targets for Novel Antidepressant Drugs

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，至少有一半的患者没有得到目前可用药物的有效治疗。其中最常用的处方是选择性5-羟色胺（5-HT）再摄取抑制剂（SSRIs），其作用是抑制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下游级联事件的关键。尽管SERT是调节高亲和力5-HT摄取的主要参与者，但越来越多的证据表明有机阳离子转运体-3 （OCT3）和质膜单胺转运体（PMAT）在脑内摄取5-HT中起重要作用。这增加了SERT阻断后缺乏治疗反应的可能性，这可能是由于OCT3（和/或PMAT）对5-羟色胺的显著摄取。我们使用OCT3和PMAT阻滞剂decynd -22 （D-22）进行的研究支持了这一观点。例如，D-22增强了SSRI氟伏沙明的作用，抑制5-羟色胺的摄取，并在野生型小鼠中产生类似抗抑郁药的作用。此外，在缺乏或SERT表达减少的小鼠中单独给予D-22也会产生这些效果。因此，当SERT在药理学上或基因上失活时，D-22的抗抑郁样作用似乎最为明显。我们还发现，在SERT组成性降低的小鼠中，OCT3表达（而不是PMAT）增加，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慢性SSRIs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-羟色胺外，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的治疗作用有关。综上所述，拟议研究的目标是：(1)验证OCT3（和/或PMAT）是D-22产生类似抗抑郁作用的位点；(2)确定抑制5-羟色胺、NE和DA摄取在D-22产生抗抑郁样作用中的相对重要性；(3)通过研究D-22在长期给药后对生物胺摄取和抗抑郁样活性的影响，来检验D-22的治疗潜力。这些研究的结果将有助于建立OCT3（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，至少在一定程度上解释当前抗抑郁药物治疗效果差的原因。

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.