Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150mg/kg, i.p.), tamoxifen (1.0mg/kg, i.p.) and chelerythrine (1μg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0mg/g) and higher (6.0mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.