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Knockdown of Piccolo in the Nucleus Accumbens Suppresses Methamphetamine-Induced Hyperlocomotion and Conditioned Place Preference in Mice

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Abstract

Methamphetamine (METH), the most widely distributed psychostimulant, aberrantly activates the reward system in the brain to induce addictive behaviors. The presynaptic protein “Piccolo”, encoded by Pclo, was identified as a METH-responsive protein with enhanced expression in the nucleus accumbens (NAc) in mice. Although the physiological and pathological significance of Piccolo has been identified in dopaminergic signaling, its role in METH-induced behavioral abnormalities and the underlying mechanisms remain unclear. To clarify such functions, mice with Piccolo knockdown in the NAc (NAc-miPiccolo mice) by local injection of an adeno-associated virus vector carrying miRNA targeting Pclo were generated and investigated. NAc-miPiccolo mice exhibited suppressed hyperlocomotion, sensitization, and conditioned place preference behavior induced by systemic administration of METH. The excessive release of dopamine in the NAc was reduced in NAc-miPiccolo mice at baseline and in response to METH. These results suggest that Piccolo in the NAc is involved in METH-induced behavioral alterations and is a candidate therapeutic target for the treatment of drug addiction.

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Data Availability

The data presented in this manuscript are available from the corresponding authors on reasonable request.

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Acknowledgements

We thank Naomi Takino and Mika Ito for their technical assistance in producing the AAV vectors.

Funding

This research was supported by a Grant-in-Aid for Scientific Research (KAKENHI) (B) [JSPS KAKENHI Grant Number, 26293213, JP21H02632] (SM, AN), Kobayashi Foundation (AN), AdAMS (Ac210045, AN), Smoking Research Foundation Grant for Biomedical Research and Foundation (AN), JST SPRING, Grant Number JPMJSP2145 (YK). The funders had no role in the study design, data collection or analysis, decision to publish, or manuscript preparation.

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Authors and Affiliations

  1. Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Yuka Kusui, Naotaka Izuo, Kyosuke Uno, Bin Ge & Atsumi Nitta

  2. Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Japan

    Kyosuke Uno

  3. Division of Neurological Gene Therapy, Center for Open Innovation, Jichi Medical University, Shimotsuke, Japan

    Shin-ichi Muramatsu

  4. Center for Gene & Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Shin-ichi Muramatsu

  5. Department of Pharmaceutical Therapy and Neuropharmacology, School of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Atsumi Nitta

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  1. Yuka Kusui
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  2. Naotaka Izuo
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Contributions

Y. K., K.U., B.G. and A.N. were responsible for study concept and design. Y.K. and K.U. contributed to the acquisition of data for behavioral experiments, in vivo microdialysis, and neurotransmitter content. S.M. designed and produced the AAV vectors. Y.K. and N.I. analyzed the data and interpreted the findings. Y.K. and N.I. drafted the manuscript. A.N. critically revised the manuscript for intellectual content. All the authors reviewed the content and approved the final version for publication.

Corresponding author

Correspondence to Atsumi Nitta.

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Competing interest

SM has equity in the Gene Therapy Research Institution, Co., Ltd., which commercializes the use of AAV vectors for gene therapy applications. To the extent that the work in this manuscript increases the value of these commercial holdings, SM has conflicts of interest. The other authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

All animal experiments followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Animal experimental protocols were approved by the Animal Care and Use Committee of the University of Toyama (Approval number: A2018PHA-13) and conducted in accordance with Institutional Animal Experiment Handling Rules of the University of Toyama. All procedures related to genetic modification followed the Guideline for Recombinant DNA Experiments from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and were approved by the Gene Recombination Experiment Safety Committee of the University of Toyama (Approval number: G2015PHA-14).

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Kusui, Y., Izuo, N., Uno, K. et al. Knockdown of Piccolo in the Nucleus Accumbens Suppresses Methamphetamine-Induced Hyperlocomotion and Conditioned Place Preference in Mice. Neurochem Res 47, 2856–2864 (2022). https://doi.org/10.1007/s11064-022-03680-3

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