¹Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr HK Manji, Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, 35 Convent Drive, Bldg 35, Rm 1C-912, Bethesda, MD 20892-3711, USA. Tel: +1 301 402 9802; Fax: +1 301 480 0123; E-mail: manjih@mail.nih.gov

²Current address: Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota Duluth, Duluth, MN, USA.

³Current address: Department of Pharmacology, Columbia College of Physicians and Surgeons, New York, NY, USA.

Received 24 February 2006; Revised 20 November 2006; Accepted 18 December 2006; Published online 14 February 2007.

Abstract

Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is unclear if this inhibition and its downstream effects on specific signaling pathways are relevant to the treatment of bipolar disorder and depression. One of the targets of GSK-3 is the transcription factor -catenin. Normally active GSK-3 phosphorylates -catenin, leading to its degradation. Inhibition of GSK-3 therefore increases -catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS -catenin overexpression. Transgenic mice overexpressing -catenin demonstrated behavioral changes similar to those observed following the administration of lithium, including decreased immobility time in the forced swim test (FST). Further, we show that although acute administration of lithium and overexpression of the -catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the -catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithium-treated and -catenin mice had an elevated response to d-amphetamine following multiple administrations of the stimulant, though the difference in absolute locomotion was maintained throughout the sensitization time-course. Neither acute lithium nor -catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which -catenin transgenic mice exhibited behaviors identical to those observed in lithium-treated mice, are consistent with the hypothesis that the behavioral effects of lithium in these models are mediated through its direct inhibition of GSK-3 and the consequent increase in -catenin. By associating the behavioral effects of lithium with -catenin levels, these data suggest that increasing -catenin might be a novel therapeutic strategy for mood disorders.