title: Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo.
abstract: BACKGROUND
  The basis of the unique clinical profile of the antipsychotic clozapine is not yet elucidated. Brain histamine receptors may play a role in schizophrenia and its treatment, but their involvement in the profile of clozapine remained unknown.
  
  
  OBJECTIVE
  We explored the properties of clozapine and its two metabolites, N-desmethylclozapine (NDMC) and clozapine N-oxide, at the four human histaminergic receptors. We compared their active concentrations with their blood concentrations in patients treated by clozapine. We investigated the changes in receptor densities induced in rat brain by repeated administration of a therapeutic dose of clozapine.
  
  
  RESULTS
  Clozapine and NDMC behaved as very potent, and partial, H(1)-receptor inverse agonists, weak, and full, H(2)-receptor inverse agonists, moderate, and protean, H(3)-receptor agonists, and moderate, and partial, H(4)-receptor agonists. Taking into account their micromolar mean blood concentrations found in 75 treated patients, and assuming that they are enriched in human brain as they are in rat brain, a full occupation of H(1)-, H(3)-, and H(4)-receptors, and a partial occupation of H(2) receptors, is expected. In agreement, repeated administration of clozapine at a therapeutic dose (20 mg/kg/day for 20 days) induced an up-regulation of H(1)- and H(2)-receptors in rat brain.
  
  
  CONCLUSIONS
  Clozapine and its active metabolite NDMC interact with the four human histamine receptors at clinically relevant concentrations. This interaction may substantiate, at least in part, the atypical antipsychotic profile of clozapine, as well as its central and peripheral side effects such as sedation and weight gain.
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Centre de Psychiatrie et Neurosciences (CPN, U 894), INSERM, 2 ter rue d'Alésia, 75014 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Humbert-Claude
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davenas
authors.forename: Florence
authors.initials: F
authors.lastname: Gbahou
authors.forename: Ludwig
authors.initials: L
authors.lastname: Vincent
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Arrang
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D054314:Drug Inverse Agonism; D017442:Histamine Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011968:Receptors, Histamine / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D017442:Histamine Agonists; D011968:Receptors, Histamine; C058272:norclozapine; D003024:Clozapine; C079149:clozapine N-oxide