title: Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT(2A) serotonergic and alpha (1) adrenergic antagonism.
abstract: BACKGROUND
  The discriminative stimulus properties of the atypical antipsychotic drug (APD) clozapine (CLZ) have recently been studied in C57BL/6 mice, a common background strain for genetic alterations. However, further evaluation is needed to fully characterize CLZ's discriminative cue in this strain of mice.
  
  
  OBJECTIVE
  The objectives of the study were to confirm the previous findings using a shorter pretreatment time and to further characterize the receptor mechanisms mediating the discriminative stimulus properties of CLZ by testing APDs, selective ligands, and N-desmethylclozapine (CLZ's major metabolite) in C57BL/6 mice.
  
  
  METHODS
  C57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ (s.c.) from vehicle in a two-lever drug discrimination task.
  
  
  RESULTS
  Generalization testing with CLZ yielded an ED(50) = 1.19 mg/kg. Substitution testing with APDs showed that the atypical APDs quetiapine, sertindole, zotepine, iloperidone, and melperone fully substituted for CLZ (> or =80% CLZ-appropriate responding), but aripiprazole did not. The typical APDs chlorpromazine and thioridazine substituted for CLZ (fluphenazine and perphenazine did not). The serotonin (5-HT) (2A) antagonist M100907 and the alpha(1)-adrenoceptor antagonist prazosin fully substituted for CLZ. The H(1) histaminergic antagonist pyrilamine, dopamine agonist amphetamine, and the selective serotonin reuptake inhibitor fluoxetine did not substitute for CLZ. While N-desmethylclozapine did not substitute for CLZ when tested alone, N-desmethylclozapine plus a low dose of CLZ combined in an additive manner produced full substitution.
  
  
  CONCLUSIONS
  CLZ's discriminative cue in C57BL/6 mice is a "compound" cue mediated in part by antagonism of 5-HT(2A) and alpha(1) receptors.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, VA Medical Center, Portland, OR, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Philibin
authors.forename: D Matthew
authors.initials: DM
authors.lastname: Walentiny
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Vunck
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Prus
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Porter
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058830:Serotonin 5-HT2 Receptor Antagonists
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D014150:Antipsychotic Agents; D058830:Serotonin 5-HT2 Receptor Antagonists; D003024:Clozapine