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

垂体腺苷酸环化酶激活多肽（垂体腺苷酸环化酶激活多肽，PACAP）是一种作为神经递质或神经调节剂发挥多种活性的神经肽。我们最近开发的缺乏编码神经肽PACAP （Adcyap1^<-/->）的Adcyap1基因的小鼠具有显著的表型，包括行为异常，暗示PACAP调节精神运动功能。本研究旨在探讨pacap介导的脑功能控制机制，以更好地了解神经心理功能障碍的病理生理机制，并寻找新的药物靶点来治疗相关疾病。结果表明：1)Adcyap1^<-/->小鼠表现出明显的新事物诱导的过度运动和强烈的跳跃行为，对环境的适应程度最低。精神兴奋剂安非他明可减轻过度运动。2)这种矛盾的抗多动作用被选择性5-HT_<1A>受体拮抗剂WAY-阻断，而安非他明在接受5-HT_<1A>受体拮抗剂的野生型小鼠中产生镇静作用。4) Adcyap1^<-/->小鼠5-HT_<1A>激动剂诱导的低温明显降低。5)经安非他明处理的Adcyap1^<-/->小鼠前额叶皮层c- fos阳性神经元增加，提示前额叶神经元抑制作用增强。6) Adcyap1^<-/->小鼠在强迫游泳试验中表现出抑郁样行为水平升高，非典型抗精神病药物利培酮可减轻这种行为。包括安非他明在内的精神兴奋剂在患有多动障碍（如注意缺陷多动障碍（ADHD））的人身上起着抗多动药物的作用，已知在增强注意力相关过程方面有效；然而，潜在的机制在很大程度上仍然未知。本研究提示5-HT_<1A>受体介导的5-羟色胺能机制在安非他明的抗多动作用中起重要作用。最后，Adcyap1^<-/->小鼠可能提供精神疾病的动物模型，具有表型相似性和理论基础。它们还可能为预测人类疾病的未知方面（如遗传学、神经生物学或新的治疗方法）提供有用的模型。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