Cited by 509Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionNeuroscience and Neuropharmacology Research

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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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Pliakas, Andrea M., Carlson, Richard R., Neve, Rachael L., Konradi, Christine, Nestler, Eric J., Carlezon, William A.·2001·The Journal of Neuroscience

DOI 10.1523/jneurosci.21-18-07397.2001PMC PMC4205577

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Abstract

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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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)
ORCID: Neve, Rachael L.
Konradi, Christine
Nestler, Eric J.
Carlezon, William A.
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
DOI: 10.1523/jneurosci.21-18-07397.2001
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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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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