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Amphetamine-induced behavior requires CaMKII-dependent dopamine transporter phosphorylation

Molecular Psychiatry volume 19, pages 279–281 (2014)Cite this article

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The dopamine (DA) transporter (DAT), which mediates the inactivation of released DA through its reuptake, is a primary molecular target for psychostimulants.1, 2 Cocaine and methylphenidate (MPH) exert their psychostimulant properties by blocking DA reuptake, leading to the elevation of extracellular DA.2 In contrast, amphetamine (AMPH) acts as a substrate for DAT and subsequently induces non-exocytotic DAT-mediated release of DA (DA efflux).2 Here we use a Drosophila behavioral assay to delineate the signaling mechanisms that modulate DAT-mediated AMPH-induced behavior in vivo. Understanding these mechanisms is critical to understanding how the actions of AMPH might be blocked therapeutically, while simultaneously preserving DA transport.

Multiple lines of evidence suggest that kinase activity can modulate DAT function and, more specifically, AMPH action on DAT. Both calcium/calmodulin kinase II alpha (CaMKII) and protein kinase C (PKC) can phosphorylate an N-terminal DAT peptide in vitro3 and inhibiting the activity of either kinase attenuates AMPH-induced DA efflux in rodent striatial slices.3, 4 Data from CaMKII and PKC knockout mice suggest a role for these kinases in regulating AMPH action in vivo.5, 6 However, it is difficult to ascertain from these studies using global knockout strategies whether the observed effects on AMPH-induced DA efflux are mediated directly through alterations in DAT phosphorylation or whether they arise indirectly through phosphorylation of other targets or through circuit effects.

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Authors and Affiliations

  1. Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, NY, USA

    A B Pizzo, C S Karam, Y Zhang, C L Ma & J A Javitch

  2. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA

    A B Pizzo, C S Karam, Y Zhang & J A Javitch

  3. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA

    A B Pizzo, C S Karam, Y Zhang & J A Javitch

  4. Barnard College, New York, NY, USA

    C L Ma

  5. Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, USA

    B D McCabe

  6. Department of Neuroscience, Columbia University College of Physicians and Surgeons, New York, NY, USA

    B D McCabe

  7. Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY, USA

    J A Javitch

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  1. A B Pizzo
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  2. C S Karam
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Correspondence to J A Javitch.

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Pizzo, A., Karam, C., Zhang, Y. et al. Amphetamine-induced behavior requires CaMKII-dependent dopamine transporter phosphorylation. Mol Psychiatry 19, 279–281 (2014). https://doi.org/10.1038/mp.2013.29

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