Schizophrenia resistant to treatments with D(2) antagonists is thought to have the changes of extradopaminergic systems. In addition, histamine has been suggested to be a neurotransmitter in the mammalian brain that regulates many brain functions. We have recently found evidence of the role of brain histamine in 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 histamine 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 histamine metabolite, were elevated in the cerebrospinal fluid of schizophrenics. Moreover, H(1) receptor binding sites decreased in schizophrenics. Many atypical antipsychotics also increased histamine turnovers. Therefore, the dysfunction of the histamine neuron system may participate in the extradopaminergic brain dysfunction of schizophrenia, and histamine agents may improve the refractory schizophrenia.
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