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Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2
Open accessAbstract
Background Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood.Methods We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing.Results Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine.Conclusions Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.
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“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 [309]
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Metadata
- Authors
- Ozburn, A. R., Falcon, E., Twaddle, A., Nugent, A. L., Gillman, A. G., Spencer, S. M., Arey, R. N., Mukherjee, S., Lyons-Weiler, J., Self, D. W., & McClung, C. A.
- Affiliations
- University of Pittsburgh (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- McClung, Colleen A.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 77
- Issue
- 5
- Pages
- 425-433
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4315729
- OpenAlex
- W1998157722
- Cited by
- 110
- References
- 46
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 11 · 2021: 6 · 2020: 25 · 2019: 6 · 2018: 12 · 2017: 12 · 2016: 8 · 2015: 4
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression Young Investigator Award and National Institutes of Health (DA07290, RR024153, DA028085, MH082876, DA023988)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- NPAS2, cocaine reward, circadian rhythm, nucleus accumbens, clocks, transcriptional regulation, diurnal gene expression, addiction, transcription factor binding sites
- MeSH terms
- Animals, Circadian Rhythm, Cocaine, Conditioning, Psychological, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Nucleus Accumbens, Reward, Space Perception, Receptors, Dopamine D1, Dopamine Uptake Inhibitors, Receptors, Dopamine D3, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, CLOCK Proteins
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