| Project/Area Number |
05454308
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Psychiatric science
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| Research Institution | Hokkaido University |
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Principal Investigator |
KOYAMA Tsukasa Hokkaido Univ.medicine, Professor, 医学部, 教授 (10113557)
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| Co-Investigator(Kenkyū-buntansha) |
KUSUMI Ichiro Hokkaido Univ.Medicine, Instructor, 医学部, 助手 (30250426)
OHMORI Tetsuro Hokkaido Univ.Medical Hospital, Instructor, 医学部・附属病院, 助手 (00221135)
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| Project Period (FY) |
1993 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1994: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1993: ¥4,900,000 (Direct Cost: ¥4,900,000)
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| Keywords | Atypical antipsychotic drug / Clozapine / Serotonin-Dopamine antagonist / Schizophrenia / Negative Symptoms / Prefrontal Cortex / Extrapyramidal side effects / 非定型抗精神病薬 / 前頭葉皮質ドーパミン / clozapine / ドーパミンD_4受容体 / 恐怖条件付け / Dopamine / Noradrenaline / Transporter / Atypical Antipsychotics / Conditioned Fear |
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| Research Abstract |
A series of experiments was conducted to clarify the mode of action mechanisms of atypical antipsychotic drugs (APDs)
(1) A certain group of atypical APD was characterized by high occupancy of serotonin (5-HT) _<2A> receptor with lower or minimal occupancy of dopamine D_2 receptor in vivo.
(2) The treatment of clozapine or ziprasidone induced the significantly greater increases in dopamine release in the prefrontal cortex, when compared to the treatment of other APDs.
(3) Only clozapine and ziprasidone inhibited the reuptake of noradrenaline in the synaptosomes from the prefrontal cortex. The preferential dopaminergic activation in the prefrontal cortex might be related the inhibition of crossed reuptake of dopamine at the noradrenaline transporter by clozapine or ziprasidone.
(4) Chronic treatment with various typical APDs increased the number of striatal D_2 receptors, while no increase was observed with the atypical APDs. Coadministration of 5-HT_<2A> antagonist with haloperidol attenuated the D_2 receptor up-regulation.
(5) The atypical APDs dose-dependently inhibited the acquisition of conditioned fearinduced freezing. the ED_<50>s for this effect significantly correlated with the Ki values for D_4 receptors.
These results provide evidence for the hypothesis that the preferential dopaminergic activation in the prefrontal cortez and the antagonism of 5-HT_<2A> or D_4 receptors by the atypical APDs might account for one or more of the clinical advantage of the etypical APDs.
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