2005 Fiscal Year Final Research Report Summary
Analysis of molecular mechanisms implicated in psychiatric disorders by using of Adcyap1-deficient mice
| Project/Area Number |
15390049
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
HASHIMOTO Hitoshi Osaka University, Grad Sch of Pharmaceutic Sci, Assoc Prof, 薬学研究科, 助教授 (30240849)
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| Co-Investigator(Kenkyū-buntansha) |
BABA Akemichi Osaka University, Grad Sch of Pharmaceutic Sci, Prof, 薬学研究科, 教授 (70107100)
SHINTANI Norihito Osaka University, Grad Sch of Pharmaceutic Sci, Res Assoc, 薬学研究科, 助手 (10335367)
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| Project Period (FY) |
2003 – 2005
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| Keywords | PACAP / gene-modified mice / psychomotor functions / prepulse inhibition / amphetamine / serotonin / serotonin 1A receptor / prefrontal cortex |
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| Research Abstract |
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-
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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
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