NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward
Open accessAbstract
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.
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SIRT1 binds to CLOCK at the promoter of the gene encoding tyrosine hydroxylase in dopaminergic neurons to control rhythms in TH expression and dopamine synthesis.
“SIRT1 binds to CLOCK at the promoter of the gene encoding tyrosine hydroxylase (TH) in dopaminergic neurons to control rhythms in TH expression and, ultimately, dopamine synthesis264”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [264]
Circadian genes in brain regions outside the SCN contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and disruption of these functions might contribute to brain disorders.
“circadian genes in other brain regions outside of this central pace-maker also contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and the disruption of these functions might contribute to brain disorders264,304–315”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [264]
In the mouse ventral tegmental area, circadian regulation of SIRT1-dependent metabolic signalling is mechanistically linked to dopaminergic neurotransmission, which is important for drug reward.
“This study demonstrates mechanistic links between circadian regulation of SIRT1-dependent metabolic signalling and dopaminergic neurotransmission in the mouse ventral tegmental area, which is important for drug reward.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [264]
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The Role of Clock in Ethanol-Related Behaviors
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Self-citationCocaine self-administration behaviors in ClockΔ19 mice
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The controversial links among calorie restriction, SIRT1, and resveratrol
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Association between Sirtuin 1 Gene rs10997870 Polymorphism and Suicide Behaviors in Bipolar Disorder
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Rhythms of life: circadian disruption and brain disorders across the lifespan
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Self-citationCircadian rhythms and mood disorders: Time to see the light
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Self-citationCircadian Rhythms of the Hypothalamus: From Function to Physiology
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Self-citationRegulation and function of extra‐SCN circadian oscillators in the brain
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Self-citationMood‐related central and peripheral clocks
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Cocaine-mediated circadian reprogramming in the striatum through dopamine D2R and PPARγ activation
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The intertwined roles of circadian rhythmsand neuronal metabolism fueling drug reward and addiction
Freyberg, Z., & Logan, R. W. (2018) · Current Opinion in Physiology · doi:10.1016/j.cophys.2018.08.004 · Cited by 31 · see citing works
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Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2
Logan, R. W., Ozburn, A. R., Arey, R. N., Ketchesin, K. D., Winquist, A., Crain, A., Tobe, B. T. D., Becker‐Krail, D. D., Jarpe, M. B., Xue, X., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00958-2 · Cited by 28 · see citing works
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Self-citationFighting Against the Clock: Circadian Disruption and Parkinson’s Disease
Chen, Y.-C., Wang, W., Lewis, S. J. G., & Wu, S. (2023) · Journal of Movement Disorders · doi:10.14802/jmd.23216 · Cited by 26 · see citing works
Circadian Rhythms in Mood Disorders
Scott, M. R., & McClung, C. A. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-81147-1_9 · Cited by 26 · see citing works
Self-citationPEDOT/CNT Flexible MEAs Reveal New Insights into the Clock Gene's Role in Dopamine Dynamics
Wu, B., Castagnola, E., McClung, C. A., & Cui, X. T. (2024) · Advanced Science · doi:10.1002/advs.202308212 · Cited by 22 · see citing works
Self-citationKim, H., Wei, J., Call, T., Ma, X., Quintus, N. T., Summers, A. J., Carotenuto, S., Johnson, R., Nguyen, A., Cui, Y., et al. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.03.017 · Cited by 22 · see citing works
Vaillancourt, K., Chen, G. G., Fiori, L. M., Maussion, G., Yerko, V., Théroux, J., Ernst, C., Labonté, B., Calipari, E. S., Nestler, E. J., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103169 · Cited by 21 · see citing works
Sobriety and Satiety: Is NAD+ the Answer?
Braidy, N., Villalva, M. D., & van Eeden, S. (2020) · Antioxidants · doi:10.3390/antiox9050425 · Cited by 17 · see citing works
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Self-citationNon-nutritive Sweetener Aspartame Disrupts Circadian Behavior and Causes Memory Impairment in Mice
Bai, H., Zuo, X., Zhao, C., Zhang, S., & Feng, X. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c05394 · Cited by 15 · see citing works
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Self-citationFrancis, T. C., & Porcu, A. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1188184 · Cited by 14 · see citing works
Are Owls and Larks Different When it Comes to Aggression? Genetics, Neurobiology, and Behavior
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Delayed circadian rhythms and substance abuse: dopamine transmission’s time has come
Hasler, B. P., & McClung, C. A. (2021) · Journal of Clinical Investigation · doi:10.1172/jci152832 · Cited by 10 · see citing works
Self-citationThe circadian neurobiology of reward
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Wang, X., Gardner, W., Yu, S., & Serchov, T. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03001-3 · Cited by 9 · see citing works
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Sirtuin 1 inhibitor EX527 suppresses morphine-induced behavioral sensitization
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Tuned by time: the role of circadian rhythms in metabolic energy sensing and chronotherapy
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Astrocytes in the Circadian System: A Promising Target for Mood Disorder Interventions
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Overview and prospect of the role and mechanism of SIRT1 in nerve injury repair
Xue, L., Chen, L., Du, R.-L., Lou, M.-M., Wang, W., Xiong, L.-L., Xiao, Q., Wang, T.-H., & Yu, C. (2021) · Integrate Medicine · doi:10.61958/imdt4412
- Authors
- Logan, R. W., Parekh, P. K., Kaplan, G. N., Becker-Krail, D. D., Williams, W. P., Yamaguchi, S., Yoshino, J., Shelton, M. A., Zhu, X., Zhang, H., Waplinger, S., Fitzgerald, E., Oliver-Smith, J., Sundarvelu, P., Enwright, J. F., Huang, Y. H., & McClung, C. A.
- Affiliations
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
- Corresponding author
- McClung, Colleen A.
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2018-05-04
- Volume
- 24
- Issue
- 11
- Pages
- 1668-1684
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC6215755
- OpenAlex
- W2802469003
- Cited by
- 48
- References
- 129
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 8 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 1 · 2018: 3
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (18K15399)
- National Institute of Mental Health (R01MH106460, R01MH082876)
- National Institute on Drug Abuse (R01DA023988, R33DA041872, R21DA041872, R21DA037636, R01DA039865, K02DA042886, K01DA038654)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104995, P30DK056341)
- National Institute of Neurological Disorders and Stroke (R21NS058339, T32NS086749)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- NAD+, SIRT1, tyrosine hydroxylase, diurnal cycle, circadian clock, clock proteins, cellular redox state, cocaine reward, ventral tegmental area, dopamine synthesis, addiction, circadian metabolism
- MeSH terms
- Animals, Brain, Circadian Rhythm, Cocaine, Conditioning, Psychological, Conditioning, Operant, Male, Mice, Inbred BALB C, NAD, Neurons, Nucleus Accumbens, Oxidation-Reduction, Reward, Tyrosine 3-Monooxygenase, Ventral Tegmental Area, Mice, Sirtuin 1, CLOCK Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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