AMY-1 receptors: Novel targets for antipsychotic development

描述(由申请人提供)：本提案的目标是评估一种潜在的新靶点，用于治疗精神分裂症和其他涉及伏隔核(ACB)功能异常的精神障碍：ACB定位的AMY1受体。这种受体结合降钙素家族的成员，包括胰淀素、鲑鱼降钙素和降钙素基因相关肽(CGRP)。尽管ACB在大脑中拥有这种受体最密集的浓度，有证据表明ACB定位的淀粉素受体代表着一种独特的受体亚型，而且发现ACB中的淀粉素产生了让人想起功能性多巴胺拮抗的强大行为效应，但还没有研究探索ACB淀粉素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，因为人们普遍认为ACB内的高多巴胺痛有助于精神分裂症的症状，但抗精神病药物可以选择性地影响ACB中的多巴胺传递，而不会同时改变其他部位的DA信号和/或引起潜在的副作用，因此还没有找到。ACB定位的AMY1受体代表了一个有吸引力的靶点，可以用来制定这样一种针对精神分裂症的解剖学特异性药物疗法。目前的建议试图通过在脉冲前抑制(PPI)缺乏的动物模型中评估刺激和拮抗ACB AMY1受体的效果来探索这一假说。PPI是当微弱的前刺激紧接在令人震惊的刺激之前时发生的惊吓反应的正常减弱，是对核心信息过滤缺陷的可操作性指标，这些缺陷见于精神分裂症、抽动症、强迫症和某些其他精神疾病。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地治疗了临床PPI缺陷。目前的研究将确定刺激ACB AMY1受体是否改善基线或缺乏PPI(由安非他明或苯环利定等拟精神药物诱导)，和/或该受体的激动剂是否增强临床处方的抗精神病药物在PPI范例中的疗效。最后，我们将探索胰淀素相关基因家族是否受到隔离饲养的调控，隔离饲养是一种在大鼠身上进行的发育操作，已知在成年后会产生类似精神分裂症的PPI缺陷。在这最后一项研究中，我们还将确定淀粉素相关基因本身是否受到发育调节。 与公共卫生相关：拟议工作的直接翻译含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，精神分裂症影响全球1%的人口。精神分裂症是一种以幻觉、妄想、情感调节失调和思维障碍为特征的破坏性慢性疾病。目前的治疗方法虽然有帮助，但并不完全有效，而且会产生严重的副作用，包括体重增加、胰岛素抵抗和糖尿病。由于AMY1受体选择性地定位于最有可能导致许多精神分裂症症状的大脑区域之一，它代表了产生抗精神病作用的一个强大的新的假定候选者。此外，由于刺激AMY受体促进减肥，这种药物靶点有可能摆脱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).