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

X. Cen, A. Nitta, D. Ibi, Y. Zhao, M. Niwa, K. Taguchi, M. Hamada, Y. Ito, Y. Ito, L. Wang, T. Nabeshima

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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.

Original languageEnglish
Pages (from-to)451-463
Number of pages13
JournalMolecular Psychiatry
Volume13
Issue number4
DOIs
Publication statusPublished - 01-04-2008

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Cen, X., Nitta, A., Ibi, D., Zhao, Y., Niwa, M., Taguchi, K., Hamada, M., Ito, Y., Ito, Y., Wang, L., & Nabeshima, T. (2008). Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization. Molecular Psychiatry, 13(4), 451-463. https://doi.org/10.1038/sj.mp.4002132