Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus

Abstract

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.

Regulation of Adult Neurogenesis by Antidepressant Treatment

“…Previous studies demonstrate that a selective PDE4 inhibitor, rolipram, increases the expression of BDNF in hippocampus and this drug was used for the neurogenesis experiments (Nibuya et al 1996). In preliminary studies we have found that chronic administration of rolipram increases adult neurogenesis in hippocampus .…”

“…This has led to the discovery that repeated long-term antidepressant administration up-regulates the cAMP-CREB (cAMP response element binding protein) cascade and expression of brain derived neurotrophic factor (BDNF) in hippocampus ( Figure 2) (Nibuya et al 1995(Nibuya et al , 1996Thome et al 2000). Both CREB and BDNF are known to play a role in synaptic plasticity as well as neuronal survival (see Finkbeiner 2000;Duman et al 2000).…”

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…The first clues linking expression of BDNF to the therapeutic actions of SRIs came from studies showing chronic antidepressant treatment leads to elevations in BDNF transcript levels in the rodent in both the hippocampus and the cortex (Nibuya et al, 1995(Nibuya et al, , 1996. In studies extended to humans, it has been shown that expression of BDNF is increased in patients receiving antidepressant mediation at the time of suicidal death (Chen et al, 2001b;Dwivedi et al, 2003;Karege et al, 2005).…”

“…One idea postulates that stress and/or antidepressants can alter the expression or activation (phosphorylation) of CREB, a key transcription factor involved in activity-dependent promoter III-mediated BDNF transcription (Nibuya et al, 1996;Conti et al, 2002). Extensive studies have shown that CREB can be activated via phosphorylation at serine 133 by three signaling pathways: cAMP-PKA, Ca 2 + -CaMKIV, and MAPK pathways (Shaywitz and Greenberg, 1999).…”

Maintenance Treatment with Fluoxetine is Necessary to Sustain Normal Levels of Synaptic Markers in an Experimental Model of Depression: Correlation with Behavioral Response

“…Regarding the antidepressant action on these plastic phenomena, a well-established effect is to stimulate the synthesis of neurotrophic factors (Nibuya et al, 1995(Nibuya et al, , 1996Chen et al, 2001) and to promote neurogenesis in the hippocampus (Malberg et al, 2000). On the contrary, the effect of antidepressant treatment on cytoskeletal and synaptic plasticity remains controversial.…”