| Co-Investigator(Kenkyū-buntansha) |
YAMADA Michio Yamaguchi University School of Medicine, Professor, 医学部, 教授 (00034942)
AKIMOTO Takashi Yamaguchi University School of Medicine, Associate Professor, 医学部, 助教授 (80231827)
SUETSUGI Masatomo Yamaguchi University School of Medicine, Research Associate, 医学部, 助手 (40294631)
KAWANO Michihide Yamaguchi University Hospital, Assistant Professor, 医学部附属病院, 講師 (60284254)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
The role of Gi-proteins on cataleptic responses induced by SCH23390, a dopamine Di receptor antagonist, and haloperidol, a mainly dopamine D2 receptor antagonist, 20 days after chronic cocaine treatment in rats was examined by intraperitoneal or intracerebroventriculor injection (i.p. in mice and i.c.v. in rats) of pertussis toxin (PTh) or cholera toxin (CTX), which catalyzes adenosine diphosphate (ADP)-ribosylation of Gi-proteins and Gs-proteins, respectively. In rats pretreated chronically with cocaine, haloperidol (0.1 mg/kg i.p.) exerted an enhanced cataleptic response, but SCH23390 (0.1 mg/kg i.p.) produced an attenuated response at 1 day, which converted to a supernormal response, when it was administered 20 days after the last cocaine injection. The attenuated SCH23390 cataleptic response (Di receptor supersensitivity induced one day after chronic cocaine treatment), was reversed one day after PTX treatment, whereas the enhanced haloperidol catalepsy was further potentiated. The
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enhanced cataleptic responses induced by SCH23390 and haloperidol were further potentiated 20 days after PTX (0.1 IOTA g, i.c.v. in rats, and 1 IOTA i.v. in mice) and last cocaine treatment. Regarding ADP- ribosylation of Gs-protein, the enhancing effect of SCH23390 catalepsy was potentiated, but that of haloperidol catalepsy was not affected, by CTX (0.1 , IOTA g, i.c.v. in rats, and 10 IOTA g/kg i.v. in mice), which by itself was not affected. These' results suggest that the subsensitivity of postsynaptic D_1 and D_2 receptors (increased SCH23390 catalepsy) seen during long-term withdrawal periods from chronic cocaine treatment, may involve both CTX-sensitive Gs- and PTX-sensitive Gi-protein ADP-ribosylations, or Gi protein ADP-ribosylation. The enhanced SCH23390 catalepsy seen 20 days after chronic cocaine treatment was potentiated by a single administration of clozapine or risperidone, atypical neuroleptic, in dose dependent manner, but was antagonized in animals pretreated chronically with clozapine + cocaine. In contrast, the degree of enhanced SCH23390 catalepsy seen 20 days after pretreatment chronically with a combination of cocaine + risperidone was similar to that seen after chronic cocaine alone. Chronic cocaine treatment inhibited the immobility response in the forced swimming test' 1-7 days after the chronic cocaine alone, but activated 20 days later. Chronic treatment with clozapine + cocaine antagonized the enhanced immobility response seen 20 days after chronic cocaine alone. There is a relationship between the increased cataleptic responses induced by dopamine antagonists and the enhanced immobility in the forced swimming test 20 days after chronic cocaine treatment. Less
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