The effects of chronic treatment with verapamil(VP) on monoamine release and metabolism in rat brain in vivo were compared with the effects of methamphetamine(MAP) and reserpine(RES). These drugs were administered to rats in drinking water for two weeks. The contents of monoamines (DA and 5HT) and their major metabolites(DOPAC, HVA and 5HIAA) in eight discrete brain regions were measured by HPLC-ECD. After treatment with VP, DA levels decreased in the nucleus accumbens(N.ACC) and the suprachiasmatic nucleus(SCN), but no significant changes were demonstrated in the metabolites(DOPAC, HVA). 5HT levels decreased in the N.ACC, SCN and amygdara(AMY), and 5HIAA levels decreased in the raphe dorsalis(RD). GABA contents were increased in the N.ACC. After treatment with MAP, DA levels decreased in the N.ACC, striatum(STR) and ventro-medial hypothalamic regions(VMH). No significant change was shown in the metabolites. 5HT contents decreased in the N.ACC, STR, AMY, VMH and RD. 5HIAA contents decreased significantly in the RD. After treatment with RES, DA levels decreased in the N.ACC, STR and SCN. HVA contents decreased in the N.ACC and SCN, though they increased in the LH and SN. 5HT levels decreased in the N.ACC, SCN, AMY and RD. High 5HIAA concentrations were found in the N.ACC, STR, LH and VMH. DA, DOPAC and HVA levels were reduced more in several regions by co-administration of VP and MAP than by MAP treatment alone. DA was lowered more in the RD and HVA was lowered more in several regions by co-administration of VP and RES than by RES treatment alone. The well known locomotor hyperactivity induced by MAP was enhanced by VP. The present study suggests that there are at least two classes of voltage-gated calcium channels in the central nervous system related to the release of monioamines, one sensitive to VP and other not. In addition, chronic VP treatment may have an inhibitory effect on the release and synthesis of monoamines.