CHRONIC ANTIDEPRESSANT ADMINISTRATION INCREASES THE EXPRESSION OF CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB) IN RAT HIPPOCAMPUS

The present study demonstrates that chronic, but not acute, administra tion of several different classes of antidepressants, including seroto nin- and norepinephrine-selective reuptake inhibitors, increases the e xpression of cAMP response element binding protein (CREB) mRNA in rat hippocampus. In contrast, chronic administration of several nonantidep ressant 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 dentat e gyrus granule cell layers of the hippocampus. In addition, levels of CRE immunoreactivity and of CRE binding activity were increased by ch ronic antidepressant administration, which indicates that expression a nd 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, demo nstrating a role for the cAMP cascade. Moreover, coadministration of r olipram with imipramine resulted in a more rapid induction of CREB tha n with either treatment alone. Increased expression and function of CR EB suggest that specific target genes may be regulated by these treatm ents. We have found that levels of brain-derived neurotrophic factor ( BDNF) and trkB mRNA are also increased by administration of antidepres sants 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, an d to the long-term effects of these treatments on brain function.