Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence
Open accessAbstract
Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior.
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This is the first study to show transcriptional changes in glia that occur after long-term activation of astrocytes with the Gq-DREADD in an in vivo model.
“To the best of our knowledge, this is the first study to show transcriptional changes in glia that occur after long-term activation of astrocytes with the Gq-DREADD in an in vivo model.”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Bull et al., 2014
The section “Stimulating NAcore Astrocytes Decreased the Motivation to Self-Administer Ethanol after 3 Weeks Abstinence” reports Gq-DREADD activation in rat astrocytes and a behavioral effect. The cited paper does not report transcriptional changes after long-term activation or establish a first study to show them. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNone of these previous studies looked at the effect of long-term Gq-DREADD-mediated activation on the transcriptome of astrocytes or other neighboring brain cells.
“However, none of these studies looked at the effect of long-term Gq-DREADD-mediated activation on the transcriptome of astrocytes or other neighboring brain cells.”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Bull et al., 2014
The sections on stimulating NAcore astrocytes report calcium responses, reward-related behavior, and ethanol self-administration after Gq-DREADD activation, not transcriptomic effects. The Discussion says downstream mechanisms remain unknown. This supports the characterization of this study, but the paper does not establish that none of the other previous studies examined transcriptomes after long-term activation. (LLM, conf=0.76)
Experimental — accuracy not yet measuredPrevious studies have expressed the Gq-DREADD specifically in astrocytes using the GFAP promotor and showed an increase in intracellular Ca2+ after activation with CNO.
“Previous studies have expressed the Gq-DREADD specifically in astrocytes using the GFAP promotor and showed an increase in intracellular Ca 2+ after activation with CNO (Agulhon et al., 2013;Bull et al., 2014;Scofield et al., 2015).”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Bull et al., 2014
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Cites
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“Previous studies have expressed the Gq-DREADD specifically in astrocytes using the GFAP promotor and showed an increase in intracellular Ca2+ after activation with CNO (Agulhon et al., 2013; Bull et al., 2014; Scofield et al., 2015).”
Background
- Authors
- Bull, C., Freitas, K. C., Zou, S., Poland, R. S., Syed, W. A., Urban, D. J., Minter, S. C., Shelton, K. L., Hauser, K. F., Negus, S. S., Knapp, P. E., & Bowers, M. S.
- Affiliations
- Virginia Commonwealth University (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Bowers, M Scott
- Venue
- Neuropsychopharmacology
- Published
- 2014-06-06
- Volume
- 39
- Issue
- 12
- Pages
- 2835-2845
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4200494
- OpenAlex
- W2008969164
- Cited by
- 145
- References
- 2
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 19 · 2020: 13 · 2019: 13 · 2018: 13 · 2017: 15 · 2016: 16 · 2015: 9 · 2014: 1
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (UL1TR000058)
- National Institute on Alcohol Abuse and Alcoholism (P30AA019372, L30 AA015858)
- National Institute on Drug Abuse (K02DA027374, R01DA026946)
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Advancing Translational Sciences
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Keywords
- astrocytes, nucleus accumbens core, ethanol self-administration, alcohol abstinence, motivation, drug-seeking behavior, gap junction hemichannels, glial fibrillary acidic protein, DREADD, intracellular calcium, reward, brain stimulation
- MeSH terms
- Alcohol Drinking, Ethanol, Animals, Astrocytes, Calcium, Central Nervous System Depressants, Cytosol, Glial Fibrillary Acidic Protein, Male, Motivation, Nucleus Accumbens, Reward, Self Administration, Rats, Sprague-Dawley, Rats, Wistar, Gap Junctions, Drug-Seeking Behavior
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