ABSTRACT

Schizophrenia resistant to the treatments with D2 antagonists is supposed to have the possible changes of extradopaminergic systems. Meanwhile, histamine was recently suggested to be a neurotransmitter in the mammalian brains, which regulates many brain functions. We have recently found the interesting results about the role of brain histamine on schizophrenia in basic and clinical studies. Methamphetamine-induced behavioral sensitization, which has been well established as the animal model of schizophrenia, induced the enhanced histamine release, and HA agonists inhibited the development of behavioral sensitization. As another animal model of schizophrenia, phencyclidine also increased the histamine release. In clinical studies, the levels of N- tele-methylhistamine, a major brain HA metabolite, were elevated in the cerebrospinal fluid of schizophrenics. Moreover, the H1 receptor gene variant was related to schizophrenia, and H1 receptor binding sites decreased in schizophrenics. Many atypical antipsychotics also increased HA turnovers and had the strong affinities of H1 receptors. Therefore, the dysfunction of HA neuron system may participate in the extradopaminergic brain dysfunction of schizophrenia, and HA agents may improve the refractory schizophrenia.