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

• 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
• 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

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涉及5-羟色胺（5-HT）功能障碍的复杂精神病疾病，以及一系列症状，包括社交行为受损。这些疾病的药物干预措施，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交行为，尤其是在基因多态性的患者中会损害5-HT的患者，从而损害了5-HT的5-HT转运者（Sert）迁移（Sert）的功能。 SERT紧紧控制了5-HT神经传递的强度和持续时间，从大脑中细胞外液中的5-HT摄取5-HT的摄取，但在5-HT摄取中有机阳离子转运蛋白3（OCT3）的作用是一种重要的机制，是一种重要的机制，有助于调节大脑5-HT的细胞外水平。这些新发现表明OCT3可能是改善社会行为的治疗干预的新颖目标。与这个想法一致，我们发现急性OCT3封锁增加了社交受损的BTBR小鼠的社会行为。我们在这里提出的研究将基于这些新发现，使用SERT敲除（ - / - ）小鼠（像BTBR小鼠一样），其社交效果少于它们的野生型（SERT +/ +）对应物。重要的是，SERT - / - 小鼠相对于 +/ +小鼠具有增加的OCT3表达和功能，使其成为探索Oct3阻断对5-HT神经传递和社会行为的影响的独特而有用的工具。我们假设OCT3阻断剂，1,12-二乙基-2,22-苯胺碘化物（Decynium-22（D-22））将比利培酮更有效地改善SERT - / - 小鼠的社会行为，而氟西汀（氟西汀）（阻止Sert）在Sert - / - / - 小鼠中不会产生影响。但是，我们预计，与利培酮结合使用的D-22将产生SERT - / - 小鼠社会行为的最大增长。 D-22对SERT +/ +小鼠的影响（表达SERT和OCT3）相对于其他菌株具有高度的交际，将对更广泛的患者人群中的其他目的进行使用。行为数据将与D-22抑制[3H] 5-HT摄取对从海马制备制备的突触体的抑制相关。 5-羟色胺是几种生物胺转运蛋白的底物，因此测量其在SERT - / - 小鼠中的吸收，以及选择性封锁和控制实验，以说明来自海马中表达的其他转运蛋白的贡献，它将提供有关Sert，Oct3，Oct3，Oct3和其他单体胺转运剂的相对作用的重要新信息。最后，为了确认d-22在集中发挥其作用，我们将测量具有行为活跃剂量D-22的大脑浓度。关于OCT3在大脑中的作用，对系统给予的D-22的影响的知之甚少。因此，这些基本实验是确立OCT3作为治疗治疗社会功能障碍在许多精神疾病中显着的治疗干预措施的新型目标的重要第一步。 公共卫生相关性：5-羟色胺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有关，也可能是这些疾病常见的社会互动受损的基础。拟议的研究研究了有机阳离子转运蛋白3（OCT3）的药物干预措施的新型药物干预措施，它像5-羟色胺转运蛋白（SERT，Prozac的靶标）一样，将5-羟色胺从大脑的细胞外液中删除，以阻止神经液体。 OCT3的封锁可能被证明是增强5-HT传播的更均匀有用的机制，尤其是在SERT基因多态性的患者中，使Prozac这样的药物效果降低。