AMY-1 receptors: Novel targets for antipsychotic development

描述（由申请人提供）：本提案的目的是评估治疗涉及异常伏隔核（Acb）功能的精神分裂症和其他精神疾病的潜在新靶点：Acb定位的AMY1受体。该受体结合降钙素家族的多肽成员，包括amylin，鲑鱼降钙素和降钙素基因相关肽（CGRP）。尽管Acb是大脑中这种受体浓度最高的区域之一，有证据表明Acb定位的amylin受体代表了一种独特的受体亚型，并且发现Acb中的amylin产生强大的行为效应，使人想起功能性多巴胺拮抗剂，但尚未有研究探索Acb amylin受体操纵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Acb内的高多巴胺能被广泛认为有助于精神分裂症的症状学，但抗精神病药物可以选择性地影响Acb中多巴胺的传递，而不会同时改变其他部位的DA信号和/或引起强烈的副作用。acb定位的AMY1受体代表了一个有吸引力的目标，与之制定这种解剖特异性的精神分裂症药物治疗。本研究旨在通过在脉冲前抑制（PPI）缺陷的动物模型中评估刺激和拮抗大鼠Acb AMY1受体的作用来探索这一假设。PPI是受惊反应的正常减弱，发生在微弱的前刺激紧接在令人震惊的刺激之前，是一种核心信息过滤缺陷的可操作测量方法，见于精神分裂症、图雷特综合症、强迫症和某些其他精神疾病。PPI是评估抗精神病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PPI基线或不足（由拟精神药物如安非他明或苯环利定诱导），和/或该受体的激动剂是否增加了PPI范例中临床处方抗精神病药物的疗效。最后，我们将探讨胰淀粉酶相关基因家族是否受到隔离饲养的调控，隔离饲养是一种已知会在成年期产生精神分裂症样PPI缺陷的大鼠发育操作。在最后一项研究中，我们还将确定胰淀素相关基因本身是否受发育调节。

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.