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cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum

Andersson, M; Konradi, Christine and Angela Cenci, M. LU (2001) In Journal of Neuroscience 21(24). p.9930-9943
Abstract

The cAMP response element-binding protein (CREB) is believed to play a pivotal role in dopamine (DA) receptor-mediated nuclear signaling and neuroplasticity. Here we demonstrate that the significance of CREB for gene expression depends on the experimental paradigm. We compared the role of CREB in two different but related models: L-DOPA administration to unilaterally 6-hydroxydopamine lesioned rats, and cocaine administration to neurologically intact animals. Antisense technology was used to produce a local knockdown of CREB in the lateral caudate-putamen, a region that mediates the dyskinetic or stereotypic manifestations associated with L-DOPA or cocaine treatment, respectively. In intact rats, CREB antisense reduced both basal and... (More)

The cAMP response element-binding protein (CREB) is believed to play a pivotal role in dopamine (DA) receptor-mediated nuclear signaling and neuroplasticity. Here we demonstrate that the significance of CREB for gene expression depends on the experimental paradigm. We compared the role of CREB in two different but related models: L-DOPA administration to unilaterally 6-hydroxydopamine lesioned rats, and cocaine administration to neurologically intact animals. Antisense technology was used to produce a local knockdown of CREB in the lateral caudate-putamen, a region that mediates the dyskinetic or stereotypic manifestations associated with L-DOPA or cocaine treatment, respectively. In intact rats, CREB antisense reduced both basal and cocaine-induced expression of c-Fos, FosB/ΔFosB, and prodynorphin mRNA. In the DA-denervated striatum, CREB was not required for L-DOPA to induce these gene products, nor did CREB contribute considerably to DNA binding activity at cAMP responsive elements (CREs) and CRE-like enhancers. ΔFosB-related proteins and JunD were the main contributors to both CRE and AP-1 DNA-protein complexes in L-DOPA-treated animals. In behavioral studies, intrastriatal CREB knockdown caused enhanced activity scores in intact control animals and exacerbated the dyskinetic effects of acute L-DOPA treatment in 6-OHDA-lesioned animals. These data demonstrate that CREB is not required for the development of L-DOPA-induced dyskinesia in hemiparkinsonian rats. Moreover, our results reveal an unexpected alteration of nuclear signaling mechanisms in the parkinsonian striatum treated with L-DOPA, where AP-1 transcription factors appear to supersede CREB in the activation of CRE-containing genes.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Direct pathway, Immediate-early genes, Motor stereotypies, Opioid precursor, Parkinson's disease, Protooncogenes, Psychostimulant, Sensitization
in
Journal of Neuroscience
volume
21
issue
24
pages
14 pages
publisher
Society for Neuroscience
external identifiers
  • scopus:0035894879
ISSN
0270-6474
language
English
LU publication?
yes
id
8edd3b9c-e20b-4cce-acd5-0e802afdf95c
date added to LUP
2017-04-24 12:56:45
date last changed
2018-03-04 05:01:18
@article{8edd3b9c-e20b-4cce-acd5-0e802afdf95c,
  abstract     = {<p>The cAMP response element-binding protein (CREB) is believed to play a pivotal role in dopamine (DA) receptor-mediated nuclear signaling and neuroplasticity. Here we demonstrate that the significance of CREB for gene expression depends on the experimental paradigm. We compared the role of CREB in two different but related models: L-DOPA administration to unilaterally 6-hydroxydopamine lesioned rats, and cocaine administration to neurologically intact animals. Antisense technology was used to produce a local knockdown of CREB in the lateral caudate-putamen, a region that mediates the dyskinetic or stereotypic manifestations associated with L-DOPA or cocaine treatment, respectively. In intact rats, CREB antisense reduced both basal and cocaine-induced expression of c-Fos, FosB/ΔFosB, and prodynorphin mRNA. In the DA-denervated striatum, CREB was not required for L-DOPA to induce these gene products, nor did CREB contribute considerably to DNA binding activity at cAMP responsive elements (CREs) and CRE-like enhancers. ΔFosB-related proteins and JunD were the main contributors to both CRE and AP-1 DNA-protein complexes in L-DOPA-treated animals. In behavioral studies, intrastriatal CREB knockdown caused enhanced activity scores in intact control animals and exacerbated the dyskinetic effects of acute L-DOPA treatment in 6-OHDA-lesioned animals. These data demonstrate that CREB is not required for the development of L-DOPA-induced dyskinesia in hemiparkinsonian rats. Moreover, our results reveal an unexpected alteration of nuclear signaling mechanisms in the parkinsonian striatum treated with L-DOPA, where AP-1 transcription factors appear to supersede CREB in the activation of CRE-containing genes.</p>},
  author       = {Andersson, M and Konradi, Christine and Angela Cenci, M.},
  issn         = {0270-6474},
  keyword      = {Direct pathway,Immediate-early genes,Motor stereotypies,Opioid precursor,Parkinson's disease,Protooncogenes,Psychostimulant,Sensitization},
  language     = {eng},
  number       = {24},
  pages        = {9930--9943},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum},
  volume       = {21},
  year         = {2001},
}