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

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

研究成果: Article査読

15 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1668-1684
ページ数17
ジャーナルMolecular Psychiatry
24
11
DOI
出版ステータスPublished - 2019 11 1

ASJC Scopus subject areas

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

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