Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus

Biol Psychiatry. 2004 Apr 15;55(8):781-4. doi: 10.1016/j.biopsych.2004.01.008.


Background: Inhibition of glycogen synthase kinase-3 (GSK-3) is thought to be a key feature in the therapeutic mechanism of several mood stabilizers; however, the role of GSK-3 in depressive behavior has not been determined. In these studies, we evaluated the antidepressive effect of L803-mts, a novel GSK-3 peptide inhibitor, in an animal model of depression, the mouse forced swimming test (FST).

Methods: Animals were intracerebroventricularly injected with L803-mts or with respective control peptide (cp) 1 hour, 3 hours, or 12 hours before their subjection to FST.

Results: Animals administered L803-mts showed reduced duration of immobility at all three time points tested, as compared with cp-treated animals. Expression levels of beta-catenin, the endogenous substrate of GSK-3, increased in the hippocampus of L803-mts-treated animals by 20%-50%, as compared with cp-treated animals.

Conclusions: Our studies show, for the first time, that in-vivo inhibition of GSK-3 produces antidepressive-like behavior and suggest the potential of GSK-3 inhibitors as antidepressants.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Blotting, Western / methods
  • Cytoskeletal Proteins / metabolism*
  • Depression / drug therapy
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Immobilization
  • Injections, Intraventricular / methods
  • Mice
  • Mice, Inbred C57BL
  • Oligopeptides / pharmacology*
  • Peptides / pharmacology
  • Rabbits
  • Swimming
  • Trans-Activators / metabolism*
  • beta Catenin


  • Antidepressive Agents
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Oligopeptides
  • Peptides
  • Trans-Activators
  • beta Catenin
  • Glycogen Synthase Kinase 3