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Altered Responsiveness to Cocaine and Increased Immobility in the Forced Swim Test Associated with Elevated cAMP Response Element-Binding Protein Expression in Nucleus Accumbens
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Drugs of abuse regulate the transcription factor cAMP response element-binding protein (CREB) in striatal regions, including the nucleus accumbens (NAc). To explore how regulation of CREB in the NAc affects behavior, we used herpes simplex virus (HSV) vectors to elevate CREB expression in this region or to overexpress a dominant-negative mutant CREB (mCREB) that blocks CREB function. Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine, indicating increased cocaine reward. Conversely, rats treated with HSV-CREB spent less time in cocaine-associated environments, indicating increased cocaine aversion. Studies in which drug-environment pairings were varied to coincide with either the early or late effects of cocaine suggest that CREB-associated place aversions reflect increased cocaine withdrawal. Because cocaine withdrawal can be accompanied by symptoms of depression, we examined how altered CREB function in the NAc affects behavior in the forced swim test (FST). Elevated CREB expression increased immobility in the FST, an effect that is opposite to that caused by standard antidepressants and is consistent with a link between CREB and dysphoria. Conversely, overexpression of mCREB decreased immobility, an effect similar to that caused by antidepressants. Moreover, the kappa opioid receptor antagonist nor-Binaltorphimine decreased immobility in HSV-CREB- and HSV-mCREB-treated rats, suggesting that CREB-mediated induction of dynorphin (an endogenous kappa receptor ligand) contributes to immobility behavior in the FST. Exposure to the FST itself dramatically increased CREB function in the NAc. These findings raise the possibility that CREB-mediated transcription within the NAc regulates dysphoric states.
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“The NAC shell is activated during stress in rats and mice, and this same activation in mice is blocked by CRF-R1 antagonist (Pliakas et al 2001; Kreibich et al 2009).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Pliakas et al 2001
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Metadata
- Authors
- Pliakas, A. M., Carlson, R. R., Neve, R. L., Konradi, C., Nestler, E. J., & Carlezon, W. A.
- Affiliations
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-09-15
- Volume
- 21
- Issue
- 18
- Pages
- 7397-7403
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4205577
- OpenAlex
- W1928329059
- Cited by
- 509
- References
- 42
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 4 · 2021: 9 · 2020: 12 · 2019: 13 · 2018: 12 · 2017: 20 · 2016: 21 · 2015: 22 · 2014: 23 · 2013: 28 · 2012: 33
- FWCI
- 7.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health
- National Institute on Drug Abuse (R01DA007134)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CREB, nucleus accumbens, cocaine reward, cocaine withdrawal, depression-like behavior, kappa opioid receptor, nor-binaltorphimine, dynorphin, dominant-negative CREB, place conditioning
- MeSH terms
- Animals, Cocaine, Conditioning, Psychological, Dynorphins, Genes, Dominant, Genetic Vectors, Male, Microinjections, Motor Activity, Narcotic Antagonists, Nucleus Accumbens, Reaction Time, Swimming, Gene Expression, Rats, Sprague-Dawley, Cyclic AMP Response Element-Binding Protein, Receptors, Opioid, kappa, Gene Transfer Techniques, Simplexvirus, Hypokinesia, Rats
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