Histamine and schizophrenia.

With the availability of an increased number of experimental tools, for example potent and brain-penetrating H1-, H2-, and H3-receptor ligands and mutant mice lacking the histamine synthesis enzyme or the histamine receptors, the functional roles of histaminergic neurons in the brain have been considerably clarified during the recent years, particularly their major role in the control of arousal, cognition, and energy balance. Various approaches tend to establish the implication of histaminergic neurons in schizophrenia. A strong hyperactivity of histamine neurons is induced in rodent brain by administration of methamphetamine or NMDA-receptor antagonists. Histamine neuron activity is modulated by typical and atypical neuroleptics. H3-receptor antagonists/inverse agonists display antipsychotic-like properties in animal models of the disease. Because of the limited predictability value of most animal models and the paucity of drugs affecting histaminergic transmission that were tried so far in human, the evidence remains therefore largely indirect, but supports a role of histamine neurons in schizophrenia.