In Vivo Evidence in the Brain for Lithium Inhibition of Glycogen Synthase Kinase-3

There is considerable interest in the possibility that small-molecule glycogen synthase kinase-3 inhibitors may have utility in the treatment of bipolar disorder, since glycogen synthase kinase-3 is a target of lithium. Although the in vitro inhibition of glycogen synthase kinase-3 by lithium occurs with a Ki of 1–2 mM, the degree of inhibition of this enzyme in the mammalian brain at therapeutically relevant concentrations has not fully been established. The transcription factor β-catenin is an established marker of glycogen synthase kinase-3 inactivation because cytoplasmic levels are increased by inhibition of the enzyme. In this study, we measured β-catenin protein levels after treatment with therapeutically relevant doses of lithium, valproate, and carbamazepine. Western blot revealed that 9 days of treatment with lithium and valproate, but not carbamazepine, increased β-catenin protein levels in soluble fractions from the frontal cortex. The level of β-catenin in the particulate fraction, which is not directly regulated by glycogen synthase kinase-3, did not change with any of the three drugs. Furthermore, real-time PCR revealed that lithium significantly decreased β-catenin mRNA levels, which may represent compensation for an increase in β-catenin stability. These results strongly suggest that lithium significantly inhibits brain glycogen synthase kinase-3 in vivo at concentrations relevant for the treatment of bipolar disorder.