A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Nucleus Accumbens Neuron Subtypes in Cocaine Action
Open accessAbstract
Background Molecules critically involved in cocaine behavioral plasticity are known to regulate and interact with peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In addition, the PGC-1α promoter has binding sites for early growth response 3 (Egr3), which plays a dynamic role in cocaine action in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D 1 (D1-MSN) versus D 2 (D2-MSN). However, the role of PGC-1α in NAc in cocaine action is unknown.Methods PGC-1α messenger RNA and protein were examined in NAc after repeated cocaine exposure. Binding of Egr3 to and histone methylation at the PGC-1α promoter was examined in NAc using chromatin immunoprecipitation after repeated cocaine. PGC-1α ribosome-associated messenger RNA in MSN subtypes was assessed after repeated cocaine using D1-Cre-RiboTag and D2-Cre-RiboTag lines. Finally, PGC-1α was expressed in NAc D1-MSNs versus D2-MSNs using a Cre-inducible adeno-associated virus and Cre lines during cocaine conditioned place preference and cocaine-induced locomotion.Results Repeated cocaine increased PGC-1α levels and increased Egr3 binding and H3K4me3 at the PGC-1α promoter in NAc. Increased PGC-1α occurred in D1-MSNs, while D2-MSNs showed reduced levels. Viral-mediated expression of PGC-1α in D1-MSNs enhanced behavioral responses to cocaine, while expression in D2-MSNs blunted these behaviors.Conclusions We demonstrate a novel role for PGC-1α in NAc in cocaine action. PGC-1α is enhanced in NAc D1-MSNs, specifically after cocaine exposure. These data are consistent with increased active methylation and Egr3 binding at the PGC-1α promoter. Finally, we demonstrate a bidirectional role for PGC-1α in mediating behavioral plasticity to cocaine through D1-MSNs versus D2-MSNs.
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PGC1α is regulated by both CREB and Egr3.
“For example, the mitochondrial biogenesis regulator PPAR-γ coactivator 1-α (PGC1α) is regulated by both CREB [128] and Egr3 [129].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [129]
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- Authors
- Chandra, R., Engeln, M., Francis, T. C., Konkalmatt, P., Patel, D., & Lobo, M. K.
- Affiliations
- University of Maryland, Baltimore (US)
- George Washington University (US)
- Corresponding author
- Lobo, Mary Kay
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 81
- Issue
- 7
- Pages
- 564-572
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5346327
- OpenAlex
- W2543609654
- Cited by
- 35
- References
- 46
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 11 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 1
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (R01DA038613)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- PGC-1α, nucleus accumbens, medium spiny neurons, cocaine, dopamine D1 receptor, dopamine D2 receptor, EGR3, H3K4me3, histone methylation, cocaine conditioned place preference, behavioral plasticity, gene expression regulation
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Cocaine, Histones, Male, Methylation, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Nucleus Accumbens, Promoter Regions, Genetic, RNA, Messenger, Receptors, Dopamine D1, Receptors, Dopamine D2, Mice, Early Growth Response Protein 3
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