Cited by 58Neurotransmitter Receptor Influence on BehaviorStress Responses and CortisolNeuroscience and Neuropharmacology Research

Overexpression of DeltaFosB in nucleus accumbens mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment

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Zhang, Yafang, Crofton, Elizabeth J., Li, Dingge, Lobo, Mary Kay, Fan, Xiuzhen, Nestler, Eric J., Green, Thomas A.·2014·Frontiers in Behavioral Neuroscience

Abstract

Environmental enrichment produces protective addiction and depression phenotypes in rats. ΔFosB is a transcription factor that regulates reward in the brain and is induced by psychological stress as well as drugs of abuse. However, the role played by ΔFosB in the protective phenotypes of environmental enrichment has not been well studied. Here, we demonstrate that ΔFosB is differentially regulated in rats reared in an isolated condition (IC) compared to those in an enriched condition (EC) in response to restraint stress or cocaine. Chronic stress or chronic cocaine treatment each elevates ΔFosB protein levels in the nucleus accumbens (NAc) of IC rats, but not of EC rats due to an already elevated basal accumulation of ΔFosB seen under EC conditions. Viral-mediated overexpression of ΔFosB in the NAc shell of pair-housed rats (i.e., independent of environmental enrichment/isolation) increases operant responding for sucrose when motivated by hunger, but decreases responding in satiated animals. Moreover, ΔFosB overexpression decreases cocaine self-administration, enhances extinction of cocaine seeking, and decreases cocaine-induced reinstatement of intravenous cocaine self-administration; all behavioral findings consistent with the enrichment phenotype. In contrast, however, ΔFosB overexpression did not alter responses of pair-housed rats in several tests of anxiety- and depression-related behavior. Thus, ΔFosB in the NAc the shell mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment.

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  • Enhancing ΔFOSB could be a viable approach to treat drug addiction by making subthreshold, non-reinforcing doses of cocaine more reinforcing, potentially reducing the risks of overdose.

    “Given that the major clinical problem in addiction is that the user becomes tolerant to the effects of the drug over time, prior studies reported that enhancing ΔFOSB could be a viable approach to treat drug addiction by making subthreshold, non-reinforcing doses of cocaine more reinforcing, potentially reducing the risks of overdose51.”

    From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [51]

    The Results (page unavailable in our copy) say that differences in cocaine intake appeared only at higher doses, not at the low doses the claim says became more reinforcing. The Discussion reports that ΔFosB overexpression in these rats decreased cocaine intake and seeking; it contrasts this with earlier findings of increased sensitivity to low-dose cocaine reward in transgenic mice. The paper does not propose reduced overdose risk through the mechanism claimed. (LLM, conf=0.86)

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Authors
Zhang, Y., Crofton, E. J., Li, D., Lobo, M. K., Fan, X., Nestler, E. J., & Green, T. A.
Affiliations
  • The University of Texas Medical Branch at Galveston (US)
  • University of Maryland, Baltimore (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Green, Thomas A.
Venue
Frontiers in Behavioral Neuroscience
Published
2014-08-29
Volume
8
Pages
297-297
ISSN
1662-5153 (ISSN-L)
OpenAlex
W2008508054
Cited by
58
References
59
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 6 · 2015: 3 · 2014: 2
FWCI
2.29
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institute of Mental Health (P50MH096890, R01MH051399)
  • National Institute on Drug Abuse (R01DA029091, R37DA007359, T32DA007287)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
ΔFosB, environmental enrichment, isolation, nucleus accumbens shell, cocaine self-administration, cocaine reinstatement, restraint stress, depression subtypes, viral overexpression, anxiety

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