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
- Protein kinase C
- Affective disorders
- Animal model
- Growth-associated protein of 43 kDa
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Haim Einat, PhD
University of Minnesota, College of Pharmacy, Duluth
376 Kirby Plaza, 1208 Kirby Dr.
Duluth, MN 55812 (USA)
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Received: November 10, 2006
Accepted after revision: March 24, 2007
Published online: July 18, 2007
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 2, Number of References : 80
Neuropsychobiology (International Journal of Experimental and Clinical Research in Biological Psychiatry, Pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography)
Vol. 55, No. 3-4, Year 2007 (Cover Date: October 2007)
Journal Editor: Strik, W. (Bern)
ISSN: 0302–282X (print), 1423–0224 (Online)
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