1995 Fiscal Year Final Research Report Summary
Development of behavioral tolerance and reverse tolerance during withdrawal periods after chronic psychostimulant treatment
| Project/Area Number |
06670964
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Psychiatric science
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| Research Institution | Yamaguchi University |
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Principal Investigator |
USHIJIMA Itsuko Department of Neuropsychiatry, Assistant Professor, 医学部, 助手 (30168679)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Michio Department of Neuropsychiatry, Professor, 医学部, 教授 (00034942)
MIZUKI Yasushi Department of Neuropsychiatry, Associate Professor, 医学部, 助教授 (00080721)
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| Project Period (FY) |
1994 – 1995
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| Keywords | Cocaine / Methamphetamine / Chronic treatment / Withdrawal period / SCH23390 catalepsy / Haloperidol-catalepsy / Pertussis toxin / Gi-protein ADP-ribosylation |
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| Research Abstract |
Chronic treatment with the indirect dopamine agonists cocaine and methamphetamine, caused supersinsitivity of D_1 receptors (decrease of SCH23390 catalepsy) and subsensitivity of D_2 receptors (increase of haloperidol catalepsy) during the early withdrawal period in mice. This decrease in cataleptic response to SCH23390 after exposure to cocaine could be interpreted as development of supersensitivity of dopamine D_1 receptors, which corresponds to the development of sensitization to cocaine. The increase in haloperidol catalepsy after exposure to cocaine may represent a state of subsensitivity of dopamine D_2 receptors, which corresponds with the development of tolerance to cocaine. This would indicate that the D_1 receptor may be mainly involved in psychostimulant-induced sensitization, which in man is manifested as psychostimulant-induced psychosis and schizophrenia-like symptoms. The chronic cocaine pretreatment caused sub-sensitivity of D_1 receptors (an increase in SCH-23390 catal
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epsy) after a longer period of withdrawal. It was apparent that the longer the period and the higher the dose of pretreatment with cocaine, the less were the alterations in initial responses and the greater were the alterations in subsequent responses to the dopamine D_1 receptor antagonists. Coadministration of either SCH23390 or haloperidol prevented the development of D_1 receptor supersinsitivity and D_2 receptor subsensitivity induced during early with- drawal periods. However, the subsensitive effect of dopamine D_1 receptors during long-term withdrawal period was rather aggravated by coadministration of SCH-23390 or haloperidol, suggesting that dopamine D_1 or D_2 receptor antagonist is not effective as an antipsychotic drug in the withdrawal periods. Furthermore, the decreasing effect of chronic cocaine on SCH23390 catalepsy was inhibited by a single pretreatment with pertussis toxin which catalyze ADP-ribosylation of G_i-proteins, whereas the increasing effect of that on haloperidol catalepsy was enhanced. These results suggest that there may be an interrelationship between D_2 receptor subsensitivity, but not D_1 receptor supersensitivity and, during early withdrawal periods and Gi-protein ADP-ribosylation. Less
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