Epub – Molecular Psychiatry: NAD+ Cellular Redox and SIRT1 Regulate the Diurnal Rhythms of Tyrosine Hydroxylase and Conditioned Cocaine Reward

May 4, 2018

Logan RW, Parekh PK, Kaplan GN, Becker-Krail DD, Williams WP 3rd, Yamaguchi S, Yoshino J, Shelton MA, Zhu X, Zhang H, Waplinger S, Fitzgerald E, Oliver-Smith J, Sundarvelu P, Enwright JF 3rd, Huang YH, McClung CA.

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.

Logan RW, Parekh PK, Kaplan GN, Becker-Krail DD, Williams WP 3rd, Yamaguchi S, Yoshino J, Shelton MA, Zhu X, Zhang H, Waplinger S, Fitzgerald E, Oliver-Smith J, Sundarvelu P, Enwright JF 3rd, Huang YH, McClung CA. NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward. Mol Psychiatry. 2018 May 4. doi: 10.1038/s41380-018-0061-1. [Epub ahead of print] PubMed PMID: 29728703.
https://www.ncbi.nlm.nih.gov/pubmed/29728703

 

Translational Neuroscience Program

Understanding the Brain
to Improve Mental Health

 

 

 

 

© 2020 University of Pittsburgh

            a

Assistant Director
slovsl@upmc.edu

            a

University of Pittsburgh
3811 O'Hara Street, BST W1651
Pittsburgh, PA 15213

            a

University of Pittsburgh
Department of Psychiatry

W1651 Biomedical Science Tower
203 Lothrop Street
Pittsburgh, PA 15213

Bridgeside Point II, Suite 223
450 Technology Drive
Pittsburgh, PA 15219

a

412-624-3894