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NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward

Molecular Psychiatry volume 24, pages 1668–1684 (2019)Cite this article

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Abstract

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.

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Acknowledgements

We thank Mark Brown and Mariah Hildebrand for animal care and genotyping. We also thank Eric Nestler, Deveroux Ferguson, and Rachel Neve for the mCREB and SIRT1 viruses, and Gary Thomas for the SIRT1 partial constructs. We thank Joe Takahashi for the ClockΔ19 mice and CLOCK expression constructs. This work was funded by DA039865, DA037636, MH106460, MH082876, DA023988, DA042886, NS058339, NARSAD, and IMHRO to CAM, and DA038564, DA041872, and NARSAD to RWL.

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Authors and Affiliations

  1. Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, 15219, USA

    Ryan W. Logan, Puja K. Parekh, Gabrielle N. Kaplan, Darius D. Becker-Krail, Wilbur P. Williams III, Micah A. Shelton, Xiyu Zhu, Hui Zhang, Spencer Waplinger, Ethan Fitzgerald, Jeffrey Oliver-Smith, Poornima Sundarvelu, John F. Enwright III, Yanhua H. Huang & Colleen A. McClung

  2. Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Ryan W. Logan, Puja K. Parekh, Gabrielle N. Kaplan, Darius D. Becker-Krail, Xiyu Zhu, Yanhua H. Huang & Colleen A. McClung

  3. Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, ME, 04609, USA

    Ryan W. Logan & Colleen A. McClung

  4. Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Shintaro Yamaguchi & Jun Yoshino

  5. School of Medicine, Peking Union Medical College, Tsinghua University, Beijing, China

    Hui Zhang

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Logan, R.W., Parekh, P.K., Kaplan, G.N. et al. NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward. Mol Psychiatry 24, 1668–1684 (2019). https://doi.org/10.1038/s41380-018-0061-1

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  • DOI: https://doi.org/10.1038/s41380-018-0061-1

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