Although best known as a selective estrogen receptor modulator (SERM), tamoxifen 
is a drug with a wide range of activities. Tamoxifen has demonstrated some 
efficacy has a therapeutic for bipolar mania and is believed to exert these 
effects through inhibition of protein kinase C (PKC). As the symptoms of 
amphetamine treatment in rodents are believed to mimic the symptoms of a manic 
episode, many of the preclinical studies for this indication have demonstrated 
that tamoxifen inhibits amphetamine action. The amphetamine-induced increase in 
extracellular dopamine which gives rise to the 'manic' effects is due to 
interaction of amphetamine with the dopamine transporter. We and others have 
demonstrated that PKC reduces amphetamine-induced reverse transport through the 
dopamine transporter. In this review, we will outline the actions of tamoxifen 
as a SERM and further detail another known action of tamoxifen-inhibition of 
PKC. We will summarize the literature showing how tamoxifen affects amphetamine 
action. Finally, we will present our hypothesis that tamoxifen, or an analog, 
could be used therapeutically to reduce amphetamine abuse in addition to 
treating mania.