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Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization

Molecular Psychiatry volume 13, pages 451–463 (2008)Cite this article

Abstract

Dopamine transporter (DAT) internalization is a mechanism underlying the decreased dopamine reuptake caused by addictive drugs like methamphetamine (METH). We found that Piccolo, a presynaptic scaffolding protein, was overexpressed in the nucleus accumbens (NAc) of the mice repeatedly administrated with METH. Piccolo downexpression by antisense technique augmented METH-induced behavioral sensitization, conditioned reward and synaptic dopamine accumulation in NAc. Expression of Piccolo C2A domain attenuated METH-induced inhibition of dopamine uptake in PC12 cells expressing human DAT. Consistent with this, it slowed down the accelerated DAT internalization induced by METH, thus maintaining the presentation of plasmalemmal DAT. In immunostaining and structural modeling Piccolo C2A domain displays an unusual feature of sequestering membrane phosphatidylinositol 4,5-bisphosphate, which may underlie its role in modulating DAT internalization. Together, our results indicate that Piccolo upregulation induced by METH represents a homeostatic response in the NAc to excessive dopaminergic transmission. Piccolo C2A domain may act as a cytoskeletal regulator for plasmalemmal DAT internalization, which may underlie its contributions in behavioral plasticity.

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Acknowledgements

We are thankful to Dr Seino Susumu and Dr Shibasaki Takao (Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Japan) for the kind gifts of pCMV-HA-Piccolo-PDZ, pCMV-Myc-Piccolo-C2A and pGEX4T-GST-p13192. We thank Mrs Nobushi Hamada and Yoshiyuki Nakamura radioisotope Center Medical Branch, Nagoya University School of Medicine for technical support. This study was supported in part by a Grant-in-Aid for Science Research and Special Coordination Funds for Promoting Science and Technology, Target-Oriented Brain Science Research Program and 21st Century Center of Excellence Program ‘Integrated Molecular Medicine for Neuronal and Neoplastic Disorders’ and ‘Academic Frontier Project for Private Universities (2007–2011), from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by a Grant-in-Aid for Health Science Research on Regulatory Science of Pharmaceuticals and Medical Devices, and Comprehensive Research on Aging and Health from the Ministry of Health, Labor and Welfare of Japan; by a Smoking Research Foundation Grant for Biomedical Research and Takeda Science Foundation.

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Authors and Affiliations

  1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

    X Cen, A Nitta, D Ibi, Y Zhao, M Niwa, K Taguchi, M Hamada & T Nabeshima

  2. National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu, China

    X Cen & L Wang

  3. Department of Pharmacology, College of Pharmacy, Nihon University, Chiba, Japan

    D Ibi & Y Ito

  4. Equipment Center for Research and Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Y Ito

  5. Department of Chemical Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya, Japan

    T Nabeshima

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Correspondence to T Nabeshima.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Cen, X., Nitta, A., Ibi, D. et al. Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization. Mol Psychiatry 13, 451–463 (2008). https://doi.org/10.1038/sj.mp.4002132

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