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

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, is 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.

The intertwined roles of circadian rhythmsand neuronal metabolism fueling drug reward and addiction

“…These findings suggest circadian and metabolic coupling, where molecular clocks may directly regulate the expression and function of key metabolic cofactors and mitochondrial biogenesis in the brain. Furthermore, changes in cellular metabolism or redox state can feedback to modulate the function of circadian proteins [12,46–52]. Given the intimate connections between rhythms and metabolism in other highly metabolic tissues including liver and muscle [43,46,47,53,54], cellular and molecular clocks are plausible regulators of metabolism and energetics in the brain.…”

“…The recycling of NAD + requires several enzymes, including nicotinamide phosphoribosyltransferase (NAM T), the rate-limiting enzyme for the conversion of nicotinamide mononucleotide (NMN) to NAD + . In liver and brain, the CLOCK:BMAL1 complex drives the rhythmic transcription of Nampt and thus, the circadian bioavailability of NAD + [12,52]. NAD + and NADH availability also modulate the DNA binding activity of CLOCK and NPAS2, indicating these transcription factors are integral redox sensors [41,43,130].…”

“…Most, if not all, of these drugs change patterns of VTA-NAc neurotransmission and plasticity at molecular, cellular, circuit levels [3–6]. Emerging data also suggests cellular and molecular rhythms are important regulators of drug reward, and circadian genes [7–11] have been directly implicated as modulators of the DA reward circuitry [12–16]. Additionally, disturbances in circadian regulation of the DA system alter the rewarding properties of drugs of abuse, further increasing vulnerability to substance abuse and addiction [12,17–22].…”

“…Emerging data also suggests cellular and molecular rhythms are important regulators of drug reward, and circadian genes [7–11] have been directly implicated as modulators of the DA reward circuitry [12–16]. Additionally, disturbances in circadian regulation of the DA system alter the rewarding properties of drugs of abuse, further increasing vulnerability to substance abuse and addiction [12,17–22]. Ultimately, these drug-induced effects on the CNS circadian system are energy-demanding [12,23,24].…”

“…Additionally, disturbances in circadian regulation of the DA system alter the rewarding properties of drugs of abuse, further increasing vulnerability to substance abuse and addiction [12,17–22]. Ultimately, these drug-induced effects on the CNS circadian system are energy-demanding [12,23,24]. Yet, we know little about how neurons and other neural cell-types meet these bioenergetic demands in response to drugs of abuse.…”