Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect
Open accessAbstract
The cAMP response element-binding protein (CREB) is a critical integrator of neural plasticity that is responsive in a brain region-specific manner to a variety of environmental and pharmacological stimuli, including widely prescribed antidepressant medications. We developed inducible transgenic lines of mice that express either CREB or a dominant-negative mutant of CREB (mCREB) in forebrain regions and used these mice to determine the functional significance of this transcription factor in the learned helplessness paradigm, a behavioral model of depression. We also use a complementary viral-mediated gene transfer approach to directly test the effect of mCREB in the nucleus accumbens, a brain region important for motivation and reward. The results demonstrate that blockade of CREB by overexpression of mCREB in transgenic mice or by viral expression of mCREB in the nucleus accumbens produces an antidepressant-like effect, whereas overexpression of CREB in transgenic mice results in the opposite phenotype. In addition, mCREB expression was colocalized with and decreased the expression of prodynorphin in nucleus accumbens medium spiny neurons, and antagonism of dynorphin in the nucleus accumbens was sufficient to produce an antidepressant-like effect similar to that observed after blockade of CREB. Together, the results demonstrate that nucleus accumbens CREB-dynorphin influence behavior in the learned helplessness model and suggest that this signaling cascade may contribute to symptoms of depression.
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Inhibition of dynorphin in the nucleus accumbens produces antidepressant effects.
“Further, inhibition of dynorphin in the NAc produces antidepressant effects (75).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [75]
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- Authors
- Newton, S. S., Thome, J., Wallace, T. L., Shirayama, Y., Schlesinger, L., Sakai, N., Chen, J., Neve, R., Nestler, E. J., & Duman, R. S.
- Affiliations
- Yale University (US)
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-12-15
- Volume
- 22
- Issue
- 24
- Pages
- 10883-10890
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758459
- OpenAlex
- W1671833268
- Cited by
- 313
- References
- 47
- Citations by year
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- FWCI
- 11.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (2 PO1 MH25642, MH45481)
- National Institute of Mental Health (2-PO1-MH25642, MH-45481, R37MH045481, P01MH025642, R01MH045481)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- CREB, dynorphin, prodynorphin, nucleus accumbens, antidepressant-like effects, learned helplessness, depression, dominant-negative CREB, medium spiny neurons, viral gene delivery, transgenic mice, transcriptional regulation
- MeSH terms
- Animals, Antidepressive Agents, Behavior, Animal, Depression, Dynorphins, Enkephalins, Helplessness, Learned, Immunohistochemistry, Male, Mice, Transgenic, Mutation, Naltrexone, Nucleus Accumbens, Protein Precursors, Prosencephalon, Rats, Sprague-Dawley, Cyclic AMP Response Element-Binding Protein, Receptors, Opioid, kappa, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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