OCT Blockade to Restore Sociability in 5-HT Transporter Knock-Out Mice

OCT 阻断可恢复 5-HT 转运蛋白敲除小鼠的社交能力

基本信息

批准号：
8048331
负责人：
GEORGIANNA G. GOULD
金额：
$ 7.43万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8048331
关键词：
1-Methyl-4-phenylpyridinium Accounting Acute Adjuvant Adult Affect Affinity Aggressive behavior Anxiety Autistic Disorder BTBR Mouse Behavior Behavioral Biogenic Amines Blood Brain Characteristics Chronic Complex Data Dimensions Disease Dose Drug Delivery Systems Early treatment Education Employment Etiology Excision Exhibits Extracellular Fluid Fluoxetine Functional disorder Future Genes Genetic Polymorphism Goals High Pressure Liquid Chromatography Hippocampus (Brain)Human Impairment Individual Interpersonal Relations Intervention Investigation Iodides Knockout Mice Knowledge Link Measures Mediating Mental Depression Mental disorders Mood Disorders Motivation Mus National Institute of Mental Health Neurons Neurotoxins Neurotransmitters Organic Cation Transporter Patients Pharmaceutical Preparations Pharmacologic Substance Play Predisposition Prozac Regulation Relative (related person)Research Risperidone Rodent Role Saline Schizophrenia Selective Serotonin Reuptake Inhibitor Serotonin Social Behavior Social Interaction Symptoms Synaptosomes System Testing Therapeutic Therapeutic Intervention Treatment Efficacy Withdrawal addiction atypical antipsychotic autism spectrum disorder cyanine extracellular improved inattention inhibitor/antagonist interest intervention effect male monoamine neuromechanism neurotransmission novel patient population research study reuptake serotonin transporter social social communication impairment tool transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD), depression and schizophrenia are complex psychiatric conditions involving serotonin (5-HT) dysfunction with a range of symptoms which prominently include impaired social behavior. Drug interventions for these disorders, such as risperidone (Risperdal) and fluoxetine (Prozac), commonly enhance 5-HT neurotransmission or mimic its downstream effects, but these interventions often do not improve social behavior, particularly in patients with gene polymorphisms impairing 5-HT transporter (SERT) function. SERT tightly controls the strength and duration of 5-HT neurotransmission by high affinity uptake of 5-HT from extracellular fluid in brain, but a role for organic cation transporter 3 (OCT3) in 5-HT uptake is emerging as an important mechanism contributing to regulation of extracellular levels of 5-HT in brain. These new findings suggest OCT3 might be a novel target for therapeutic intervention to improve social behavior. Consistent with this idea, we found that acute OCT3 blockade increased social behavior in socially-impaired BTBR mice. The studies we propose here will build on these new findings using SERT knock-out (-/-) mice, which like BTBR mice, are less social than their wild-type (SERT +/+) counterpart. Importantly, SERT-/- mice have increased OCT3 expression and function relative to +/+ mice, making them a unique and useful tool for exploring the effects of OCT3 blockade on 5-HT neurotransmission and social behavior. We hypothesize that the OCT3 blocker, 1,12-diethyl-2,22-cyanine iodide (decynium-22 (D-22)), will improve social behavior in SERT-/- mice more effectively than risperidone, while fluoxetine, which blocks SERT, will have no effect in SERT -/- mice. We expect, however, that D-22 administered in combination with risperidone will produce the greatest increase in social behavior in SERT -/- mice. D-22's effects on SERT +/+ mice, which express both SERT and OCT3 and are highly sociable relative to other strains, will be of interest for use of OCT3 blockade to other ends in broader patient populations. Behavioral data will be correlated with D-22 inhibition of [3H] 5-HT uptake into synaptosomes prepared from hippocampus. Serotonin is a substrate for several biogenic amine transporters, so measuring its uptake in SERT -/- mice, along with selective blockade and control experiments to account for contributions from other transporters expressed in hippocampus, will provide important new information about the relative roles of SERT, OCT3 and other monoamine transporters in 5-HT uptake. Finally, to confirm that D- 22 is exerting its effects centrally, we will measure brain concentration of behaviorally active doses of D-22. Extremely little is known about the role of OCT3 in brain and even less about the effects of systemically administered D-22. Therefore, these fundamental experiments are an essential first step in establishing the potential of OCT3 as a novel target for therapeutic intervention in the treatment of social dysfunction prominent in many psychiatric disorders. PUBLIC HEALTH RELEVANCE: Dysfunction of the serotonin neurotransmitter system has been strongly implicated in the etiology of autism, schizophrenia and depression, and may also underlie impaired social interaction common to these disorders. The proposed studies examine a novel target for pharmaceutical intervention to regulate 5-HT neurotransmission and improve sociability, the organic cation transporter 3 (OCT3), which like the serotonin transporter (SERT, the target of Prozac), removes serotonin from extracellular fluid in the brain to stop neurotransmission. Blockade of OCT3 may prove to be a more uniformly useful mechanism to enhance 5-HT transmission, particularly in patients with SERT gene polymorphisms that make drugs like Prozac less effective.

描述（由申请人提供）：自闭症谱系障碍 (ASD)、抑郁症和精神分裂症是复杂的精神疾病，涉及血清素 (5-HT) 功能障碍，具有一系列症状，其中突出包括社交行为受损。针对这些疾病的药物干预，例如利培酮 (Risperdal) 和氟西汀 (Prozac)，通常会增强 5-HT 神经传递或模仿其下游效应，但这些干预措施通常不会改善社会行为，特别是对于基因多态性损害 5-HT 的患者转运蛋白（SERT）功能。 SERT 通过从大脑细胞外液中高亲和力摄取 5-HT 来严格控制 5-HT 神经传递的强度和持续时间，但有机阳离子转运蛋白 3 (OCT3) 在 5-HT 摄取中的作用正在成为促进 5-HT 摄取的重要机制。脑内 5-HT 细胞外水平的调节。这些新发现表明 OCT3 可能是改善社会行为的治疗干预的新靶点。与这个想法一致，我们发现急性 OCT3 阻断增加了社交障碍 BTBR 小鼠的社交行为。我们在此提出的研究将建立在使用 SERT 敲除 (-/-) 小鼠的这些新发现的基础上，这些小鼠与 BTBR 小鼠一样，比野生型 (SERT +/+) 小鼠的社交能力较差。重要的是，相对于 +/+ 小鼠，SERT-/- 小鼠的 OCT3 表达和功能有所增加，这使它们成为探索 OCT3 阻断对 5-HT 神经传递和社会行为影响的独特且有用的工具。我们假设 OCT3 阻断剂 1,12-二乙基-2,22-碘化氰 (decynium-22 (D-22)) 将比利培酮更有效地改善 SERT-/- 小鼠的社交行为，而氟西汀则可阻断SERT，对 SERT -/- 小鼠没有影响。然而，我们预计 D-22 与利培酮联合给药将最大程度地提高 SERT -/- 小鼠的社交行为。 D-22 对 SERT +/+ 小鼠的影响（SERT +/+ 小鼠同时表达 SERT 和 OCT3，并且相对于其他品系具有高度社交性），对于在更广泛的患者群体中使用 OCT3 阻断其他末端将引起兴趣。行为数据将与D-22对从海马制备的突触体摄取[3H]5-HT的抑制相关。血清素是几种生物胺转运蛋白的底物，因此测量其在 SERT -/- 小鼠中的摄取，以及选择性阻断和对照实验以解释海马中表达的其他转运蛋白的贡献，将提供有关 SERT 相对作用的重要新信息、OCT3 和其他单胺转运蛋白在 5-HT 摄取中的作用。最后，为了确认 D-22 集中发挥其作用，我们将测量行为活跃剂量的 D-22 的大脑浓度。人们对 OCT3 在大脑中的作用知之甚少，对全身注射 D-22 的作用更是知之甚少。因此，这些基础实验是确定 OCT3 作为治疗许多精神疾病中突出的社会功能障碍的新靶点的潜力的重要第一步。公共卫生相关性：血清素神经递质系统的功能障碍与自闭症、精神分裂症和抑郁症的病因密切相关，也可能是这些疾病常见的社交互动受损的基础。拟议的研究探讨了调节 5-HT 神经传递和改善社交能力的药物干预的新靶标，即有机阳离子转运蛋白 3 (OCT3)，它与血清素转运蛋白（SERT，百忧解的靶标）一样，可从细胞外液中去除血清素。大脑停止神经传递。阻断 OCT3 可能被证明是增强 5-HT 传输的更普遍有用的机制，特别是对于具有 SERT 基因多态性的患者，这些多态性使百忧解等药物的效果较差。