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Journal of Neuroscience, Vol 16, 2365-2372, Copyright © 1996 by Society for Neuroscience
Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus
M Nibuya, EJ Nestler and RS Duman
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
The present study demonstrates that chronic, but not acute, adminstration
of several different classes of antidepressants, including serotonin- and
norepinephrine-selective reuptake inhibitors, increases the expression of
cAMP response element binding protein (CREB) mRNA in rat hippocampus. In
contrast, chronic administration of several nonantidepressant psychotropic
drugs did not influence expression of CREB mRNA, demonstrating the
pharmacological specificity of this effect. In situ hybridization analysis
demonstrates that antidepressant administration increases expression of
CREB mRNA in CA1 and CA3 pyramidal and dentate gyrus granule cell layers of
the hippocampus. In addition, levels of CRE immunoreactivity and of CRE
binding activity were increased by chronic antidepressant administration,
which indicates that expression and function of CREB protein are increased
along with its mRNA. Chronic administration of the phosphodiesterase (PDE)
inhibitors rolipram or papaverine also increased expression of CREB mRNA in
hippocampus, demonstrating a role for the cAMP cascade. Moreover,
coadministration of rolipram with imipramine resulted in a more rapid
induction of CREB than with either treatment alone. Increased expression
and function of CREB suggest that specific target genes may be regulated by
these treatments. We have found that levels of brain-derived neurotrophic
factor (BDNF) and trkB mRNA are also increased by administration of
antidepressants or PDE inhibitors. These findings indicate that
upregulation of CREB is a common action of chronic antidepressant
treatments that may lead to regulation of specific target genes, such as
BDNF and trkB, and to the long-term effects of these treatments on brain
function.
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