Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect

Samuel S. Newton, Johannes Thome, Tanya L. Wallace, Yukihikko Shirayama, Lee Schlesinger, Norio Sakai, Jingshan Chen, Rachael Neve, Eric J. Nestler, Ronald S. Duman

Research output: Contribution to journalArticle

242 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10883-10890
Number of pages8
JournalJournal of Neuroscience
Volume22
Issue number24
StatePublished - Dec 15 2002

Fingerprint

Dynorphins
Cyclic AMP Response Element-Binding Protein
Nucleus Accumbens
Antidepressive Agents
Learned Helplessness
Transgenic Mice
Depression
Neuronal Plasticity
Viral Genes
Brain
Prosencephalon
Inhibition (Psychology)
Reward
Motivation
Transcription Factors
Pharmacology
Phenotype
Neurons

Keywords

  • Behavior
  • Depression
  • Dysphoria
  • Learned helplessness
  • Prodynorphin
  • κ-opiate receptors

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Newton, S. S., Thome, J., Wallace, T. L., Shirayama, Y., Schlesinger, L., Sakai, N., ... Duman, R. S. (2002). Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. Journal of Neuroscience, 22(24), 10883-10890.

Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. / Newton, Samuel S.; Thome, Johannes; Wallace, Tanya L.; Shirayama, Yukihikko; Schlesinger, Lee; Sakai, Norio; Chen, Jingshan; Neve, Rachael; Nestler, Eric J.; Duman, Ronald S.

In: Journal of Neuroscience, Vol. 22, No. 24, 15.12.2002, p. 10883-10890.

Research output: Contribution to journalArticle

Newton, SS, Thome, J, Wallace, TL, Shirayama, Y, Schlesinger, L, Sakai, N, Chen, J, Neve, R, Nestler, EJ & Duman, RS 2002, 'Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect', Journal of Neuroscience, vol. 22, no. 24, pp. 10883-10890.
Newton, Samuel S. ; Thome, Johannes ; Wallace, Tanya L. ; Shirayama, Yukihikko ; Schlesinger, Lee ; Sakai, Norio ; Chen, Jingshan ; Neve, Rachael ; Nestler, Eric J. ; Duman, Ronald S. / Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 24. pp. 10883-10890.
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