AMY-1 receptors: Novel targets for antipsychotic development

AMY-1 受体：抗精神病药物开发的新靶点

• 批准号: 8291252
• 负责人: VAISHALI P BAKSHI
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291252
• 关键词: Acute; Address; Adult; Adverse effects; Affect; Affective; Affinity; Agonist; Amphetamines; Animal Model; Animals; Antipsychotic Agents; Attention; Behavioral; Behavioral Mechanisms; Binding; Biological Assay; Brain; Brain Part; Brain region; Calcitonin; Calcitonin Gene-Related Peptide; Calcitonin Receptor; Characteristics; Chronic Disease; Clinical; Corpus striatum structure; Delusions; Development; Diabetes Mellitus; Disease; Dopamine; Dopamine Antagonists; Dose; Drug Delivery Systems; Exploratory/Developmental Grant; Family; Functional disorder; Future; Gene Family; Gene Targeting; Generations; Genes; Genetic Transcription; Gilles de la Tourette syndrome; Goals; Hallucinations; Hallucinogens; In Situ Hybridization; Infusion procedures; Insulin Resistance; Investigation; Ligands; Measures; Medial; Mental disorders; Motor; Motor Activity; Nucleus Accumbens; Obsessive-Compulsive Disorder; Pathologic Processes; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phencyclidine; Population; Pre-Clinical Model; Property; Proteins; Psychotic Disorders; Rattus; Receptor Gene; Regulation; Research; Role; Salmon; Satiation; Schizophrenia; Signal Transduction; Site; Stimulus; Symptoms; Techniques; Testing; Therapeutic Effect; Time; Translations; Weight Gain; Weight-Loss Drugs; Western Blotting; Work; adrenomedullin; amylin receptor; atypical antipsychotic; base; drug development; energy balance; improved; information processing; islet amyloid polypeptide; member; novel; pre-clinical; prepulse inhibition; receptor; receptor binding; research study; response; success; transmission process

DESCRIPTION (provided by applicant): The goal of this proposal is to evaluate a potential new target for the treatment of schizophrenia and other psychiatric disorders that involve aberrant nucleus accumbens (Acb) function: the Acb-localized AMY1 receptor. This receptor binds members of the calcitonin family of peptides, including amylin, salmon calcitonin, and calcitonin gene-related peptide (CGRP). Despite the fact that the Acb possesses among the densest concentrations of this receptor in the brain, the evidence that the Acb-localized amylin receptor represents a unique receptor subtype, and the finding that amylin in the Acb produces potent behavioral effects reminiscent of functional dopamine antagonism, there has been no research exploring the effects of Acb amylin receptor manipulations on schizophrenia-like information-processing deficits. This is a surprising omission given that that hyperdopaminergia within Acb is widely thought to contribute to the symptomatology of schizophrenia, but antipsychotic drugs that can selectively influence dopamine transmission in Acb without concomitantly altering DA signaling in other sites and/or causing potent side-effects are not available. The Acb-localized AMY1 receptor represents an attractive target with which to enact such an anatomically specific pharmacotherapy for schizophrenia. The present proposal seeks to explore this hypothesis by evaluating in animal models of deficient prepulse inhibition (PPI) the effects of stimulating and antagonizing the Acb AMY1 receptor in rats. PPI is the normal diminution of the startle response that occurs when a weak prestimulus immediately precedes the startling stimulus, and is an operational measure of core information-filtering deficits that are seen in schizophrenia, Tourette's Syndrome, Obsessive-compulsive disorder, and certain other mental illnesses. PPI is among the most well-validated preclinical paradigms with which to assess antipsychotic efficacy, as drugs that normalize PPI deficits in animals successfully treat clinical PPI deficits. The present studies will determine if stimulation of Acb AMY1 receptors improves baseline or deficient PPI (induced by psychotomimetic drugs such as amphetamine or phencyclidine), and/or if agonists for this receptor augment the efficacy of clinically prescribed antipsychotic medications in the PPI paradigm. Finally, we will explore whether the family of amylin-related genes is regulated by isolation rearing, a developmental manipulation in rats that is known to produce schizophrenia-like PPI deficits in adulthood. In the course of this last study, we will also determine whether amylin-related genes themselves are developmentally regulated.

描述（由申请人提供）：该提案的目的是评估治疗精神分裂症和其他涉及异常伏核（Acb）功能的精神疾病的潜在新靶点：Acb 定位的 AMY1 受体。该受体结合降钙素肽家族的成员，包括胰淀素、鲑鱼降钙素和降钙素基因相关肽 (CGRP)。尽管 Acb 拥有大脑中该受体浓度最高的事实，但有证据表明 Acb 定位的胰淀素受体代表了一种独特的受体亚型，并且发现 Acb 中的胰岛淀粉样多肽产生了令人想起功能性多巴胺拮抗作用的有效行为效应，目前还没有研究探索 Acb 胰淀素受体操作对精神分裂症样信息处理缺陷的影响。这是一个令人惊讶的遗漏，因为人们普遍认为 Acb 内的多巴胺能亢进会导致精神分裂症的症状，但可以选择性影响 Acb 中多巴胺传递而不同时改变其他位点的 DA 信号传导和/或引起有效副作用的抗精神病药物是无法使用。 Acb 定位的 AMY1 受体代表了一个有吸引力的靶标，可以利用它来针对精神分裂症制定这种解剖学特异性的药物疗法。本提案旨在通过在前脉冲抑制（PPI）缺陷的动物模型中评估刺激和拮抗大鼠 Acb AMY1 受体的效果来探索这一假设。 PPI 是惊吓反应的正常减弱，当在惊吓刺激之前立即出现微弱的预刺激时，会发生惊吓反应，并且是精神分裂症、抽动秽语综合征、强迫症和某些其他精神疾病中所见的核心信息过滤缺陷的操作测量。疾病。 PPI 是评估抗精神病药疗效的最经过充分验证的临床前范式之一，因为使动物 PPI 缺陷正常化的药物可以成功治疗临床 PPI 缺陷。目前的研究将确定Acb AMY1受体的刺激是否可以改善基线或缺陷的PPI（由安非他明或苯环己哌啶等拟精神病药物引起），和/或该受体的激动剂是否可以增强PPI范式中临床处方抗精神病药物的疗效。最后，我们将探讨胰淀素相关基因家族是否受到隔离饲养的调节，隔离饲养是一种大鼠发育操作，已知会在成年期产生类似精神分裂症的 PPI 缺陷。在最后一项研究过程中，我们还将确定胰淀素相关基因本身是否受到发育调节。