title: The metabolites N-desmethylclozapine and N-desmethylolanzapine produce cross-tolerance to the discriminative stimulus of the atypical antipsychotic clozapine in C57BL/6 mice.
abstract: It has been previously shown that cross-tolerance to the discriminative stimulus properties of clozapine can be demonstrated with the drug discrimination paradigm. This study examined the ability of N-desmethylclozapine and N-desmethylolanzapine (metabolites of the atypical antipsychotic drugs clozapine and olanzapine, respectively) to induce cross-tolerance to the discriminative stimulus effects of clozapine. After C57BL/6 mice were trained to reliably discriminate 2.5 mg/kg clozapine from vehicle, a clozapine generalization curve was generated. Next, training was suspended and the mice received a maintenance dosing regimen in which they were injected twice daily with 10 mg/kg N-desmethylclozapine for 10 days. Then a second clozapine generalization curve was generated. This was followed by a 10-day washout period during which the mice did not receive drug injections or discrimination training. Finally, a third clozapine generalization curve was generated. These same procedures were followed for N-desmethylolanzapine (10 mg/kg twice daily during maintenance dosing). Both N-desmethylclozapine and N-desmethylolanzapine produced significant rightward shifts in the clozapine generalization curve indicating cross-tolerance between N-desmethylclozapine and clozapine and between N-desmethylolanzapine and clozapine. After a washout period with no training or drug administration this cross-tolerance effect was lost for both metabolites. This cross-tolerance drug discrimination procedure demonstrated in-vivo similarities between these two metabolites and clozapine and suggests that common underlying pharmacological mechanisms were responsible for the cross-tolerance that was observed. These findings also demonstrated that this procedure may be useful for identifying drugs with therapeutic efficacy similar to the atypical antipsychotic clozapine under repeated dosing conditions.
authors.affiliation: Department of Psychology, Virginia Commonwealth University, Richmond, Virginia 23284-2018, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Wiebelhaus
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Webster
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Porter
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D001569:Benzodiazepines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects*; D004361:Drug Tolerance; D005795:Generalization, Stimulus / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077152:Olanzapine; D010890:Pirenzepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D010890:Pirenzepine; C425329:desmethylolanzapine; D003024:Clozapine; C024581:N-desmethylclobazam; D000077152:Olanzapine