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The Journal of Neuroscience, December 15, 2001, 21(24):9930-9943
cAMP Response Element-Binding Protein Is Required for
Dopamine-Dependent Gene Expression in the Intact But Not the
Dopamine-Denervated Striatum
Malin
Andersson1,
Christine
Konradi2, and
M.
Angela
Cenci1
1 Department of Physiological Sciences, Neurobiology
Division, Lund University, Wallenberg Neuroscience Centre, 221 84 Lund,
Sweden, and 2 Laboratory of Neuroplasticity, McLean
Hospital and Harvard Medical School, Belmont, Massachusetts 02478
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/ FosB, 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. FosB-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.
Key words:
Parkinson's disease; immediate-early genes; direct
pathway; opioid precursor; psychostimulant; sensitization; protooncogenes; motor stereotypies
Copyright © 2001 Society for Neuroscience 0270-6474/01/21249930-14$05.00/0
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