Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus.
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.
Kaidanovich-Beilin
Oksana
O
Departments of Human Genetics and Molecular Medicine, Felsenstein Medical Research Center, Beilinson Campus, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Milman
Anat
A
Weizman
Abraham
A
Pick
Chaim G
CG
Eldar-Finkelman
Hagit
H
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007103:Immobilization; D007276:Injections, Intraventricular / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011817:Rabbits; D013550:Swimming; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
D000928:Antidepressive Agents; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010455:Peptides; D015534:Trans-Activators; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3