Evidence for an interaction between nicotine and morphine has been found in several studies. In the present study mice withdrawn from a 7-week oral nicotine treatment were administered morphine, following which their locomotor activities were recorded and the concentrations of dopamine, 5-hydroxytryptamine (5-HT), noradrenaline and their metabolites were measured in the caudate putamen (CPu) and nucleus accumbens (NAc). For comparison, the effect of cocaine on locomotor activity was studied in mice withdrawn from nicotine. Morphine (15 mg/kg s.c.) enhanced locomotor activity significantly more in the nicotine-withdrawn mice than in the controls, whereas cocaine (20 mg/kg i.p.) stimulated the locomotor activity similarly in the nicotine-withdrawn and in the control mice. Morphine (10 mg/kg s.c.) elevated dopamine and 5-HT metabolites to the same degree in the NAc of the nicotine-withdrawn and the control mice. However, in the CPu morphine enhanced the metabolism of dopamine and also that of 5-HT in the nicotine-withdrawn mice but not in the controls. In addition, the basal concentrations of dopamine metabolites were reduced in the CPu of the nicotine-withdrawn mice. Thus, the enhancement of morphine-induced locomotor activation in the nicotine-withdrawn mice could be related to nicotine-induced changes in the regulation of the nigrostriatal dopaminergic and serotonergic systems.