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）：该建议的目的是评估涉及异常核酸核（ACB）功能的精神分裂症和其他精神疾病的潜在新靶标：ACB-lecatization Amy1受体。该受体结合降钙素肽家族的成员，包括淀粉蛋白，鲑鱼降钙素和降钙素基因相关肽（CGRP）。尽管ACB在该受体中最浓度的浓度中拥有大脑中的证据，但ACB - 位置化的链淀粉受体代表了独特的受体亚型的证据，并且ACB中ACB中的淀粉蛋白在ACB中的发现会产生有效的行为效应，从而回想起功能性多巴胺抑制剂，并且没有研究探索Acb amyyl aCB amyyl aCB amyyl aCB amyyl aCB amyls nip的影响。缺陷。鉴于ACB内的催眠药被人们普遍认为会导致精神分裂症的症状，但是可以选择性地影响ACB中的多巴胺传播而不会同时改变其他部位的DA信号和/或引起有效的副作用，因此，这是一个令人惊讶的遗漏。 ACB定位的AMY1受体代表了一个有吸引力的靶标，该靶标通过为精神分裂症制定这种特异性的药物疗法。本提案旨在通过评估不足的预硫代抑制（PPI）的动物模型来探索这一假设，即在大鼠中刺激和拮抗ACB AMY1受体的作用。 PPI是当弱的prestimulus紧接在惊人的刺激之前发生的惊吓反应的正常减少，并且是对核心信息过滤缺陷的操作度量，这些缺陷在精神分裂症，Tourette's综合征，强迫症和其他某些精神疾病中所见。 PPI是评估抗精神病药疗效的最精心验证的临床前范式之一，因为使动物中PPI缺陷的药物成功地治疗了临床PPI缺陷。目前的研究将确定ACB AMY1受体的刺激是否改善了基线或缺乏PPI（由苯丙胺或苯丙胺等精神病药物诱导）和/或/或该受体激动剂是否增强了PPI范式中临床处方的抗精神病药的功效。最后，我们将探索与甲基蛋白相关基因的家族是否受隔离饲养的调节，这是大鼠的发育操作，已知在成年期会产生类似精神分裂症的PPI缺陷。在最后一项研究的过程中，我们还将确定与氨基蛋白相关的基因本身是否受到发育调节。