The central hisiamine (HA) neurons that originate from the posterior hypothalamus modulate a variety of physiological functions. In order to investigate the roles of brain histaminergic neuron system in the behavioral effects of methamphetamine (METH), we administrated METH repeatedly to L-histidine decarboxylase (HDC)-, histamine H1 receptor-, H2 receptor-gene knockout (KO) mice, H1/H2 receptor-gene double KO mice, and wild type (WT) mice corresponding to each of them, and we measured locomotor activities. We also measured the contents of monoamines and amino acids in the brain of HDC-gene KO and WT mice after a single administration of METH. METH-induced locomotor hyperactivity and the development of behavioral sensitization were facilitated more in the HDC-gene KO mice and H1/H2 gene double KO mice than the WT mice, suggesting that brain histamine has an inhibitory effect on the METH action through both H1 and H2 receptors. In addition, neurochemical study suggested the involvement of the GABAergic neuron system in the inhibitory effect of brain histamine.