Analysis of molecular mechanisms implicated in psychiatric disorders by using of Adcyap1-deficient mice

垂体腺苷环化酶激活多肽(PACAP)是一种具有多种神经递质或神经递质活性的神经肽。我们最近培育的缺乏编码神经肽PACAP的ADCYAP1基因的小鼠(ADCYAP1^&lt；-/-&gt；)具有明显的表型，包括行为异常，暗示PACAP参与精神运动功能的调节。本研究旨在探讨PACAP介导的脑功能调控机制，旨在更好地了解神经心理功能障碍的病理生理学机制，并寻找治疗相关疾病的新药物靶点。主要研究结果如下：1)ADCYAP1^&lt；-/-&gt；小鼠表现出明显的新奇多动和剧烈跳跃行为，对环境的适应程度最低。2)这种矛盾的抗多动作用可被选择性5-羟色胺受体拮抗剂Way-…所阻断100635.3以上)相反，安非他明在接受5-羟色胺激动剂的野生型小鼠中产生了镇静作用。4)5-羟色胺激动剂诱导的体温过低在安非他明治疗的小鼠中显著降低。5)安非他明治疗的小鼠前额叶皮质c-Fos阳性神经元增加，这表明前额神经元的抑制控制增强。在强迫游泳测试中，小鼠表现出更多的抑郁样行为，这种行为可以被非典型的抗精神病药物利培酮减弱。包括苯丙胺在内的精神刺激剂在患有注意缺陷多动障碍(ADHD)等多动症的人类中作为抗多动症药物，已知在增强注意力相关过程方面有效；然而，其潜在机制在很大程度上仍不清楚。目前的研究表明，5-羟色胺受体介导的5-羟色胺能机制在苯丙胺的抗多动作用中起着关键作用。最后，ADCYAP1^&lt；-/-&gt；小鼠可能为精神障碍提供一个动物模型，具有表型相似性，有望具有理论基础。它们也可能为预测人类疾病的未知方面提供有用的模型，如遗传学、神经生物学或新的治疗方法。

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide exerting multiple activities as a neurotransmitter or neuromodulator. Our recently developed mice lacking the Adcyap1 gene encoding the neuropeptide PACAP (Adcyap1^<-/->) have marked phenotypes including behavioral abnormalities, implicating PACAP in the regulation of psychomotor functions. The current study was conducted to investigate the PACAP-mediated mechanisms involved in the control of brain functions, aiming to better understand the pathophysiology underlying neuropsychological dysfunctions, and to identify novel drug targets to treat the relevant disorders. The summarized results are as follows :1) Adcyap1^<-/-> mice show a marked novelty-induced hyperlocomotion and intense jumping behavior with minimal habituation to the environment. The psychostimulant amphetamine decreased the hyperlocomotion.2) This paradoxical antihyperkinetic effect was blocked by the selective 5-HT_<1A> receptor antagonist WAY- … More 100635.3) By contrast, amphetamine produced a calming effect in wild-type mice that received a 5-HT_<1A> agonist.4) 5-HT_<1A> agonist-induced hypothermia was markedly reduced in Adcyap1^<-/-> mice.5) c-Fos-positive neurons were increased in the prefrontal cortex in amphetamine-treated Adcyap1^<-/-> mice, suggesting increased inhibitory control by prefrontal neurons.6) Adcyap1^<-/-> mice showed increased levels of depressive-like behavior in the forced swimming test, and this behavior was attenuated by the atypical antipsychotic risperidone.Psychostimulants including amphetamine act as antihyperkinetic agents in humans with hyperkinetic disorder such as attention-deficit hyperactivity disorder (ADHD) and are known to be effective in enhancing attention-related processes ; however, the underlying mechanisms remain largely unknown. The present study suggests that serotonergic mechanisms mediated via 5-HT_<1A> receptor are critically involved in 'the antihyperkinetic effect of amphetamine. Finally, Adcyap1^<-/-> mice may provide an animal model for psychiatric disorders, with a phenotypic similarity and hopefully theoretical rationale. They may also provide a useful model for predicting unknown aspects of human diseases such as their genetics, neurobiology, or new treatments. Less