Diurnal Rhythms of Tyrosine Hydroxylase Expression are Regulated by NAD Cellular Redox and SIRT1

Abstract

The regulation of dopamine levels is important in a variety of diseases including addiction. Here we find a novel role for the CLOCK protein as a transcriptional repressor at the TH promoter which is mediated by its interaction with the metabolic sensing protein, SIRT1. Moreover, we demonstrate that TH transcription is modulated by the redox state of neurons, and daily rhythms in cellular redox balance in the VTA, and that TH transcription, is largely disrupted following chronic cocaine administration. Furthermore, interactions between CLOCK/SIRT1 are important in the regulation of cocaine reward and dopaminergic activity with interesting differences depending upon whether dopaminergic activity is in a heightened state and if there is a functional circadian clock. 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.