1. Three histamine Hl-receptor antagonists (tripelennamine, diphenhydramine and cyclizine) and two H2-receptor antagonists rantidine and cimetidine)-1 and 10 mg/kg-were tested alone or in combination with the opioid partial agonist buprenorphine (1 mg/kg), the opioid antagonist naloxone (1 mg/kg) or dextroamphetamine (3 mg/kg) on locomotor activity in mice. 2. All three H1-antihistaminics tested and the H2-antihistaminic, cimetidine, enhance locomotor activity in a dose-dependent manner. 3. Furthermore, tripelennamine, diphenhydramine, cyclizine, ranitidine and cimetidine potentiate the buprenorphine-induced hyperactivity. 4. Previous administration of naloxone blocks the tripelennamine- and diphenhydramine-induced hyperactivity. 5. On the other hand, none of antihistaminics tested modifies the amphetamine-induced locomotor stimulation. 6. These results suggest that H1- and H2-receptor antagonists effects on locomotor behavior in mice may be related with opioid mechanisms, but not with amphetamine mechanisms.