Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder.
BACKGROUND
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.


OBJECTIVE
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.
Einat
Haim
H
University of Minnesota, College of Pharmacy, Duluth, MN 55812, USA. heinat@d.umn.edu
Yuan
Peixiong
P
Szabo
Steven T
ST
Dogra
Samriti
S
Manji
Husseini K
HK
D000661:Amphetamine; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001714:Bipolar Disorder / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D019922:GAP-43 Protein / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D015999:Multivariate Analysis; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors
D004791:Enzyme Inhibitors; D019922:GAP-43 Protein; D013629:Tamoxifen; D000661:Amphetamine