Methamphetamine (METH) is often abused as a psychostimulant, and its administration induces several abnormal behaviors. We propose that neuronal histamine has an inhibitory role on the METH-induced locomotor hyperactivity and development of behavioral sensitization. We examined the roles of the histaminergic neuron system on behavioral sensitization and conditioned place preference (CPP) induced by METH using single and multiple histamine receptors deficient mice. Mice were injected intraperitoneally seven times with METH (1mg/kg) once in every 3 days. After drug-free intervals of 7 days, METH was rechallenged. The locomotor activities were gradually increased in histamine H1, H3 receptor gene double knockout (H1/H3-DKO), H1, H2, and H3 receptor gene triple knockout (TKO), and their wild-type (WT) mice when METH was repeatedly administrated, suggesting that these mice developed behavioral sensitization. The ratios of the locomotor activity in METH-administrated group to saline-treated group were not significantly changed among the different genotypes. The order of ratios were H1/H3-DKO > WT mice > TKO mice. We also examined METH-induced CPP in histamine H1 receptor gene knockout mice (H1-KO), H3 receptor gene knockout mice (H3-KO), and their WT mice. The CPP scores were increased by repeated METH administration. Especially, H1-KO mice showed higher METH-induced CPP scores than those of the WT and H3-KO mice. Our results suggest that the neuronal histamine could inhibit the METH-induced abnormal behaviors through the interactions of H1, H2, and H3 receptors.