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, 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.
Nibuya
M
M
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Nestler
E J
EJ
Duman
R S
RS
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001483:Base Sequence; D015152:Blotting, Northern; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects* / Q000235:genetics; D003891:Desipramine / Q000494:pharmacology; D004558:Electric Stimulation; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D007099:Imipramine / Q000494:pharmacology; D017403:In Situ Hybridization; D008297:Male; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics; D020813:Receptor, trkB; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000235:genetics; D020889:Rolipram; D020280:Sertraline; D013997:Time Factors; D014191:Tranylcypromine / Q000494:pharmacology
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D005473:Fluoxetine; D014191:Tranylcypromine; D015057:1-Naphthylamine; D020794:Receptor Protein-Tyrosine Kinases; D020813:Receptor, trkB; D020889:Rolipram; D007099:Imipramine; D020280:Sertraline; D003891:Desipramine