| Project/Area Number |
13672283
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
HASHIMOTO Hitoshi Osaka Univ, Grad Sch of Pharmaceutical Sci, Associate Professor, 薬学研究科, 助教授 (30240849)
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| Co-Investigator(Kenkyū-buntansha) |
BABA Akemichi Osaka Univ, Grad Sch of Pharmaceutical Sci, Professor, 薬学研究科, 教授 (70107100)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | PACAP / mutant mice / psychomotor behavior / prepulse inhibition / schizophrenia / neuronal plasticity / learning and memory / behavioral pharmacology / 遺伝子欠損マウス / アンフェタミン / LTP / 記憶 / 好奇心 / 探索行動 / 不安 / セロトニン / SSRI |
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| Research Abstract |
To investigate the physiological roles of endogenous PACAP in higher-order brain/psychological processes, behavioral and electrophysiological analyses were carried out in PACAP gene knockout (PACAP-l-) mice which was recently generated in this laboratory, and the following results were obtained:
1. PACAP-l- mice displayed markedly increased locomotor activity and explosive jumping behavior. These aberrant behaviors were ameliorated by the antipsychotic drug haloperidol and selective serotonin reuptake inhibitor (SSRI).
2. Increased exploratory-related and reduced anxiety-related behavior in PACAP-l- mice was demonstrated by zone monitoring in the open field, on the elevated plus maze, and by the emergence and novel object tests.
3. PACAP-l- mice exhibited normal prepulse inhibition (PPI) of the acoustic startle response at 4 weeks of age; however, they suffer impairment of PPI after 6 weeks of age.
4. This reduced PPI was ameliorated by the psychostimulant, but unaffected by haloperidol.
5. In PACAP-l- mice, the induction of long-term potentiation (LTP) of hippocampal synaptic strength was reduced. In addition, PACAP heterozygous mutant mice and PACAP (PAC1) receptor exon 2-targeted mice showed a moderate defect in LTP, suggesting a gene-dosage effect for the PACAP gene.
6. The behavioral study revealed impaired memory retention of PACAP-l- mice in several behavioral paradigms.
In conclusion, the present study proposes a role of PACAP-ergic neurons in regulating psychomotor behaviors and suggests that the phenotype of PACAP-l- mice in part resembles those in human psychiatric disorders. The present study also provides an insight into the role of PACAP in higher brain functions.
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