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The Journal of Neuroscience, May 18, 2005, 25(20):4908-4916; doi:10.1523/JNEUROSCI.5155-04.2005

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Behavioral/Systems/Cognitive
Regulation of Activin mRNA and Smad2 Phosphorylation by Antidepressant Treatment in the Rat Brain: Effects in Behavioral Models

Antonia L. Dow, David S. Russell, and Ronald S. Duman

Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06508

Activin is a member of the transforming growth factor- family that is involved in cell differentiation, hormone secretion, and regulation of neuron survival. The cellular responses to activin are mediated by phosphorylation of a downstream target, Smad2. The current study examines the influence of chronic electroconvulsive seizures (ECSs), as well as chemical antidepressants, on the expression of activin A and the phosphorylation of Smad2 in the rat hippocampus and frontal cortex. Chronic ECSs (10 d) resulted in a significant increase in activin A mRNA expression and Smad2 phosphorylation in both the hippocampus and frontal cortex. Chronic fluoxetine did not influence activin A expression, but fluoxetine as well as desipramine did increase Smad2 phosphorylation in the frontal cortex. The functional significance of increased activin was further tested by examining the effects of activin infusions into the hippocampus on a behavioral model of depression, the forced swim test (FST). A single bilateral infusion of activin A or activin B into the dentate gyrus of the hippocampus produced an antidepressant-like effect in the FST that was comparable in magnitude with fluoxetine. In contrast, infusion of the activin antagonist inhibin A did not influence behavior but blocked the effect of activin A. The results suggest that regulation of activin and Smad signaling may contribute to the actions of antidepressant treatment and may represent novel targets for antidepressant drug development.

Key words: antidepressant; cytokine; dentate gyrus; neurotrophic; seizure; TGF- signaling

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Received Dec 17, 2004; revised April 7, 2005; accepted April 8, 2005.

This article has been cited by other articles:

				J. L. Warner-Schmidt and R. S. Duman VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants PNAS, March 13, 2007; 104(11): 4647 - 4652. [Abstract] [Full Text] [PDF]

				M. R. Muller, F. Zheng, S. Werner, and C. Alzheimer Transgenic Mice Expressing Dominant-negative Activin Receptor IB in Forebrain Neurons Reveal Novel Functions of Activin at Glutamatergic Synapses J. Biol. Chem., September 29, 2006; 281(39): 29076 - 29084. [Abstract] [Full Text] [PDF]

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