Abstract
Regulation of gene expression represents a major component in antidepressant drug action. The effect of antidepressant treatments on the function of cAMP-responsive element binding protein (CREB), a transcription factor that regulates expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. Although there is general agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, drug dosage, and different experimental paradigms. CREB function is activated by a vast array of physiological stimuli, conveyed through a number of signaling pathways acting in concert, but thus far the effects of antidepressants on CREB have been analyzed mostly with regard to the cAMP-protein kinase A pathway. A growing body of data shows that other major pathways, such as the calcium/calmodulin-dependent kinase and the mitogen-activated kinase cascades, are involved in activity-dependent regulation of gene expression and may also be implicated in the mechanism of action of antidepressants. In this article the available evidence is reviewed with an attempt to identify the reasons for experimental discrepancies and possible directions for future research. Particularemphasis is given to the regulation of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene, which has been implicated in both the pathophysiology and pharmacology of mood disorders. The array of different results obtained by various groups is analyzed with an eye on recent advancements in the regulation of BDNF transcription, in an attempt to understand better the mechanisms of drug action and dissect molecular requirements for faster and more efficient antidepressant treatment.
Footnotes
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↵1 Abbreviations: CREB, cAMP-responsive element binding protein; PKA, protein kinase A; CRE, cAMP-responsive element; BDNF, brain-derived neurotrophic factor; ECT, electroconvulsive treatment; FLX, fluoxetine; SSRI, selective serotonin reuptake inhibitor; TCP, tranylcypromine; DG, dentate gyrus; DMI, desipramine; wt, wild-type; tg, transgenic; CaM, calmodulin; RBX, reboxetine; IMI, imipramine; DARPP-32, dopamine and cAMP-regulated phosphoprotein of Mr 32,000; PP, protein phosphatase; MAPK, mitogen-activated protein kinase; VGCC, voltage-gated calcium channel; NMDA, N-methyl d-aspartate; CaRE, calcium-responsive element; CaMK, calcium/calmodulin-dependent protein kinase; Erk, extracellular signal-regulated kinase; Rsk, ribosomal S6 kinase; Msk, mitogen- and stress-activated protein kinase; ELISA, enzyme-linked immunosorbent assay; ESC, escitalopram; LH, learned helplessness; KO, knockout. CaRF, calcium response factor; Org 4428, 1,3,4,13b-tetrahydro-2,10-dimethyl-dibenz[2,3:6,7]oxepino[4,5c]pyridin-4a(2H)-ol.
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This work was supported by a grant from the National Alliance for Research on Schizophrenia and Depression (U.S.) to M.P., by a European Union (6th Framework Program) grant for project GENDEP (Contract LSHB-CT-2003-503428) to M.P., and by grants from the Ministry of University and Scientific Research (PRIN Grants 2001054224 and 2003053993) and the Ministry of Health (Italy) to M.P., G.R., and J.P.
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Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.
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doi:10.1124/pr.58.1.7.
- The American Society for Pharmacology and Experimental Therapeutics
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