Regulation of activin mRNA and Smad2 phosphorylation by antidepressant treatment in the rat brain: effects in behavioral models.
Activin is a member of the transforming growth factor-beta 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 betaA and the phosphorylation of Smad2 in the rat hippocampus and frontal cortex. Chronic ECSs (10 d) resulted in a significant increase in activin betaA mRNA expression and Smad2 phosphorylation in both the hippocampus and frontal cortex. Chronic fluoxetine did not influence activin betaA 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.
Dow
Antonia L
AL
Laboratory of Molecular Psychiatry, Department of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Russell
David S
DS
Duman
Ronald S
RS
D028341:Activins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D003863:Depression / Q000628:therapy; D003891:Desipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004597:Electroshock / Q000379:methods*; D005473:Fluoxetine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D028322:Inhibin-beta Subunits / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D007265:Inhibins / Q000008:administration & dosage; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000528:radiation effects; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000378:metabolism*; D013997:Time Factors
D000928:Antidepressive Agents; D012333:RNA, Messenger; D051899:Smad2 Protein; C422405:activin A; C422362:inhibin A; D005473:Fluoxetine; D028341:Activins; D007265:Inhibins; D028322:Inhibin-beta Subunits; D003891:Desipramine