AMY-1 receptors: Novel targets for antipsychotic development

描述（由申请人提供）：本提案的目的是评价治疗精神分裂症和其他涉及异常丘脑核（Acb）功能的精神疾病的潜在新靶点：Acb定位的AMY 1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）。尽管事实上，Acb拥有的这种受体在大脑中的dennessy浓度，证据表明，Acb本地化的胰淀素受体代表一个独特的受体亚型，并发现胰淀素在Acb产生强大的行为效应，让人想起功能性多巴胺拮抗作用，一直没有研究探讨的影响Acb胰淀素受体操纵精神分裂症样的信息处理缺陷。这是一个令人惊讶的遗漏，因为Acb内的多巴胺能亢进被广泛认为有助于精神分裂症的精神病学，但是可以选择性地影响Acb中的多巴胺传递而不伴随改变其他部位的DA信号传导和/或引起强效副作用的抗精神病药物是不可用的。Acb定位的AMY 1受体代表了一个有吸引力的目标，制定这样的解剖学特异性药物治疗精神分裂症。本提案旨在探讨这一假设，通过评估在动物模型中的缺陷前脉冲抑制（PPI）的刺激和拮抗大鼠的Acb AMY 1受体的影响。PPI是惊吓反应的正常减少，当一个微弱的前刺激紧接在惊吓刺激之前时发生，并且是在精神分裂症，图雷特综合征，强迫症和某些其他精神疾病中观察到的核心信息过滤缺陷的操作措施。PPI是评估抗精神病药物疗效的最有效的临床前范例之一，因为使动物PPI缺陷正常化的药物成功治疗了临床PPI缺陷。目前的研究将确定Acb AMY 1受体的刺激是否改善基线或PPI不足（由拟精神病药物如安非他明或苯环己哌啶诱导），和/或该受体的激动剂是否增加PPI范例中临床处方的抗精神病药物的疗效。最后，我们将探讨是否家族的淀粉样蛋白相关基因的监管隔离饲养，发育操纵大鼠，已知在成年期产生精神分裂症样PPI赤字。在最后一项研究中，我们还将确定淀粉样蛋白相关基因本身是否受到发育调控。 公共卫生相关性：拟议工作的直接翻译意义将是确定抗精神病药物开发的新靶点，用于治疗精神分裂症，影响全球1%的人口。精神分裂症是一种毁灭性的慢性疾病，其特征是幻觉、妄想、情感失调和思维障碍。目前的治疗方法，虽然有帮助，但并不完全有效，并产生严重的副作用，包括体重增加，胰岛素抵抗和糖尿病。由于AMY 1受体选择性定位于最可能导致许多精神分裂症症状的脑区之一，因此AMY 1受体代表了产生抗精神病作用的强有力的新的推定候选者。此外，由于AMY受体的刺激促进体重减轻，因此这种药物靶点有可能不含甚至逆转当前抗精神病药物最有问题的副作用之一（体重增加，胰岛素抵抗和糖尿病）。

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. PUBLIC HEALTH RELEVANCE: The direct translational implication of the proposed work would be the identification of a novel target for antipsychotic drug development, to use in the treatment of schizophrenia, which affects 1% of the population worldwide. Schizophrenia is a devastating chronic illness characterized by hallucinations, delusions, affective dysregulation, and thought disorder. Current treatments, albeit helpful, are not completely effective and produce serious side effects including weight gain, insulin resistance, and diabetes. By virtue of its selective localization in one of the brain regions most likely to underlie many schizophrenic symptoms the AMY1 receptor represents a powerful new putative candidate for producing antipsychotic effects. Moreover, because stimulation of AMY receptors promotes weight loss, this drug target has the potential be free of or even reverse one of the most problematic side-effects of current antipsychotics (weight gain, insulin resistance and diabetes).