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

腺苷酸环化酶激活多肽（PACAP）是一种具有多种神经递质或神经调质活性的神经肽。我们最近开发的小鼠缺乏编码神经肽PACAP（Adcyap 1 ^<-/->）的Adcyap 1基因，具有显著的表型，包括行为异常，暗示PACAP在精神功能的调节中。本研究旨在研究PACAP介导的脑功能控制机制，旨在更好地了解神经心理功能障碍的病理生理学基础，并确定治疗相关疾病的新药物靶点。结果总结如下：1）Adcyap 1 ^<-/->小鼠表现出明显的新奇诱导的过度运动和强烈的跳跃行为，对环境的适应性最小。精神兴奋剂苯丙胺可减少运动过度。2）这种反常的抗运动过度作用可被选择性5-HT_2受体拮抗剂WAY-<1A> 关于我们 100635.3）相比之下，安非他明在接受5-HT_激动剂的野生型小鼠中产生了镇静作用。4）Adcyap 1 ^&lt;-/-&gt;小鼠中5-HT_激动剂诱导的体温降低显著降低。5）安非他明处理的Adcyap 1 ^&lt;-/-&gt;小鼠的前额叶皮质中c-Fos阳性神经元增加，表明前额叶神经元的抑制控制增加。6）Adcyap 1 ^&lt;-/-&gt;小鼠在强迫游泳试验中显示出抑郁样行为水平增加，<1A>包括安非他明在内的精神兴奋剂在患有多动症（如注意力缺陷多动障碍（ADHD））的人类中用作抗多动症剂，并且已知其在增强注意力相关过程中有效;<1A>然而，其基本机制在很大程度上仍不清楚。本研究提示，5-HT_2受体介导的肾上腺素能机制是苯丙胺抗运动亢进作用的关键。<1A>最后，Adcyap 1 ^&lt;-/-&gt;小鼠可能提供精神疾病的动物模型，具有表型相似性和希望的理论依据。它们还可以为预测人类疾病的未知方面提供有用的模型，例如遗传学，神经生物学或新治疗方法。少

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