Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice

Yoko Hagino; Shinya Kasai; Masayo Fujita; Susumu Setogawa; Hiroshi Yamaura; Dai Yanagihara; Makoto Hashimoto; Kazuto Kobayashi; Herbert Y. Meltzer; Kazutaka Ikeda

doi:10.1038/npp.2014.295

Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice

Yoko Hagino, Shinya Kasai, Masayo Fujita, Susumu Setogawa, Hiroshi Yamaura, Dai Yanagihara, Makoto Hashimoto, Kazuto Kobayashi, Herbert Y. Meltzer, Kazutaka Ikeda^*

^*Corresponding author for this work

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.

Original language	English (US)
Pages (from-to)	1141-1150
Number of pages	10
Journal	Neuropsychopharmacology
Volume	40
DOIs	https://doi.org/10.1038/npp.2014.295
State	Published - 2015

Funding

We acknowledge Drs Minoru Saitoe and Tomoyuki Furuyashiki for critically reading the manuscript, Mr Michael Arends for assistance with editing the manuscript, and Ms Satomi Soma, Ms Junko Wakamatsu, Ms Yurie Nakamoto, and Ms Etsuko Kamegaya for assistance with breeding the DD mice. This work was supported by grants from the Ministry of Health, Labour and Welfare of Japan (H22-Iyaku-015 and H25-Iyaku-020), JSPS KAKENHI Grants 24659549, 24659490, and 24650205, MEXT KAKEN-HI Grant 25116532, the Smoking Research Foundation, the Naito Foundation, and the Astellas Foundation for Research on Metabolic Disorders. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

ASJC Scopus subject areas

Psychiatry and Mental health
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/npp.2014.295

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@article{10c019e20b6647cba884b49e06044f18,

title = "Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice",

abstract = "Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.",

author = "Yoko Hagino and Shinya Kasai and Masayo Fujita and Susumu Setogawa and Hiroshi Yamaura and Dai Yanagihara and Makoto Hashimoto and Kazuto Kobayashi and Meltzer, {Herbert Y.} and Kazutaka Ikeda",

note = "Funding Information: We acknowledge Drs Minoru Saitoe and Tomoyuki Furuyashiki for critically reading the manuscript, Mr Michael Arends for assistance with editing the manuscript, and Ms Satomi Soma, Ms Junko Wakamatsu, Ms Yurie Nakamoto, and Ms Etsuko Kamegaya for assistance with breeding the DD mice. This work was supported by grants from the Ministry of Health, Labour and Welfare of Japan (H22-Iyaku-015 and H25-Iyaku-020), JSPS KAKENHI Grants 24659549, 24659490, and 24650205, MEXT KAKEN-HI Grant 25116532, the Smoking Research Foundation, the Naito Foundation, and the Astellas Foundation for Research on Metabolic Disorders. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2015 American College of Neuropsychopharmacology. All rights reserved.",

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doi = "10.1038/npp.2014.295",

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AU - Hagino, Yoko

AU - Kasai, Shinya

AU - Fujita, Masayo

AU - Setogawa, Susumu

AU - Yamaura, Hiroshi

AU - Yanagihara, Dai

AU - Hashimoto, Makoto

AU - Kobayashi, Kazuto

AU - Meltzer, Herbert Y.

AU - Ikeda, Kazutaka

N1 - Funding Information: We acknowledge Drs Minoru Saitoe and Tomoyuki Furuyashiki for critically reading the manuscript, Mr Michael Arends for assistance with editing the manuscript, and Ms Satomi Soma, Ms Junko Wakamatsu, Ms Yurie Nakamoto, and Ms Etsuko Kamegaya for assistance with breeding the DD mice. This work was supported by grants from the Ministry of Health, Labour and Welfare of Japan (H22-Iyaku-015 and H25-Iyaku-020), JSPS KAKENHI Grants 24659549, 24659490, and 24650205, MEXT KAKEN-HI Grant 25116532, the Smoking Research Foundation, the Naito Foundation, and the Astellas Foundation for Research on Metabolic Disorders. The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2015 American College of Neuropsychopharmacology. All rights reserved.

PY - 2015

Y1 - 2015

N2 - Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.

AB - Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.

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Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice

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