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

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

Molecular psychiatry (2018-05-08)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
β-Nicotinamide mononucleotide, ≥95% (HPLC)
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Anti-phospho-CREB (Ser133) Antibody, Upstate®, from rabbit
Sigma-Aldrich
Cocaine free base
Sigma-Aldrich
β-Nicotinamide adenine dinucleotide, pkg of 50 mg (per vial)
Supelco
SUPELCOSIL LC-18-T HPLC Column, 3 μm particle size, L × I.D. 15 cm × 4.6 mm
Sigma-Aldrich
Anti-CREB Antibody, Chemicon®, from mouse
Sigma-Aldrich
Anti-Sirt1(Sir2) Antibody, Upstate®, from rabbit