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Original Paper

Editor's Choice - Free Access

Protein Kinase C Inhibition by Tamoxifen Antagonizes Manic-Like Behavior in Rats: Implications for the Development of Novel Therapeutics for Bipolar Disorder

Einat H.a · Yuan P.b · Szabo S.T.b · Dogra S.b · Manji H.K.b

Author affiliations

aUniversity of Minnesota, College of Pharmacy, Duluth, Minn., and bLaboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Md., USA

Corresponding Author

Haim Einat, PhD

University of Minnesota, College of Pharmacy, Duluth

376 Kirby Plaza, 1208 Kirby Dr.

Duluth, MN 55812 (USA)

Tel. +1 218 726 6029, Fax +1 218 726 6500, E-Mail heinat@d.umn.edu

Related Articles for ""

Neuropsychobiology 2007;55:123–131

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Rationale: In the context of bipolar disorder (BPD) research it was demonstrated that administration of the structurally dissimilar mood stabilizers lithium and valproate produced a striking reduction in protein kinase C (PKC) in rat brain. In a small clinical study, tamoxifen (a PKC inhibitor) had antimanic efficacy. However, both lithium and valproate exert many biochemical changes and attribution of therapeutic relevance to any molecular findings needs to be based on linking them to behavioral effects. Objectives: The present study was designed to explore such relationship by studying the effects of PKC inhibition in amphetamine-induced behavioral animal models of mania and changes in GAP-43. Methods: The effects of two daily tamoxifen (1 mg/kg) i.p. injections on acute or chronic (7 injections) amphetamine (0.5 mg/kg) -induced behaviors and GAP-43 phosphorylation were tested. Results: The study demonstrates that tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity levels and normalized amphetamine-induced increase in visits to the center of an open field (representing risk-taking behavior). Tamoxifen also attenuated amphetamine-induced phosphorylation of GAP-43, a result that is consistent with the behavioral findings. Conclusions: These results support the possibility that PKC signaling may play an important role in the pathophysiology and treatment of BPD. These findings may have direct clinical implications as they offer a new avenue for attempts to develop more specific drugs for the disorder.

© 2007 S. Karger AG, Basel

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: November 10, 2006
Accepted: March 24, 2007
Published online: July 18, 2007
Issue release date: October 2007

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 2

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: http://www.karger.com/NPS

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