GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid

Bipolar Disord. 2005 Jun;7(3):260-5. doi: 10.1111/j.1399-5618.2005.00194.x.


Objectives: Lithium (Li(+)) has been suggested to target the enzyme glycogen synthase kinase 3 (GSK-3) as a mechanism of mood stabilization. Inhibition of GSK-3 by a second mood-stabilizer, valproic acid (VPA), has also been reported, but this effect is dependent on cell type. It is currently unknown if carbamazepine (CBZ) inhibits GSK-3 activity. We have sought to compare the inhibitory effect of Li(+), VPA and CBZ on GSK-3 activity.

Methods: We treated rat primary cultured neurones at three times therapeutic drug concentration with CBZ, VPA and Li(+) and examined changes in GSK-3 protein levels, activity and phosphorylation of downstream targets. To eliminate a possible direct effect of these drugs at higher concentrations, we also looked for direct inhibition of both GSK-3 isoforms at a range of concentrations.

Results: CBZ, VPA and Li(+) did not change the levels of the GSK-3 or produce an irreversible in vivo effect on GSK-3 activity. Only Li(+) inhibited the phosphorylation of a cytoskeletal target of GSK-3, tau, whereas CBZ and VPA did not. Surprisingly, none of these drugs altered beta-catenin levels in these cells, a process attenuated by GSK-3 activity. Finally, only Li(+) directly inhibits GSK-3 activity (both alpha and beta isoforms) at therapeutic levels in direct biochemical assays.

Conclusion: Thus we show that neither GSK-3 nor the altered GSK-3 signalling pathway can provide a common mechanism of action of mood-stabilizing drugs in the mammalian brain.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antimanic Agents / pharmacology*
  • Carbamazepine / pharmacology
  • Cells, Cultured
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Isoenzymes / antagonists & inhibitors
  • Lithium / pharmacology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats
  • Valproic Acid / pharmacology


  • Antimanic Agents
  • Isoenzymes
  • Carbamazepine
  • Valproic Acid
  • Lithium
  • Glycogen Synthase Kinase 3