title: The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic drug clozapine in rats.
abstract: BACKGROUND
  The discriminative stimulus properties of clozapine (CLZ) have been studied for decades because it remains the prototype for atypical antipsychotic drug effects and yet is unique in many ways, including increased efficacy in treatment-resistant schizophrenia and in reducing suicidality. Recent studies have indicated that the active CLZ metabolite N-desmethylclozapine (NDMC) may play a role in mediating the cognitive efficacy of CLZ and may also have atypical antipsychotic properties.
  
  
  OBJECTIVE
  The present study sought to determine if NDMC has discriminative stimulus properties similar to that of its parent drug CLZ.
  
  
  METHODS
  Rats were trained to discriminate 1.25 mg/kg CLZ from vehicle in a two-choice drug discrimination task.
  
  
  RESULTS
  Although NDMC (2.5-20.0 mg/kg) failed to substitute for CLZ, the combination of NDMC (5.0 and 10.0 mg/kg) with a low dose (0.3125 mg/kg) of CLZ produced full substitution (>80% CLZ-appropriate responding) for the 1.25 mg/kg CLZ training dose. Co-administration of the M1-preferring receptor antagonist trihexyphenidyl (6.0 mg/kg) with a 5.0 mg/kg dose of NDMC produced partial substitution (>60% to <80% CLZ-appropriate responding) for CLZ, while administration of trihexyphenidyl alone (0.3-12.0 mg/kg) failed to substitute for CLZ.
  
  
  CONCLUSIONS
  These findings suggest that NDMC produces discriminative stimulus effects that are different from those elicited by its parent drug CLZ. This difference may be due to the agonist properties of NDMC at M(1) muscarinic cholinergic receptors.
authors.affiliation: Department of Psychology, Northern Michigan University, Marquette, MI, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Prus
authors.forename: Alan L
authors.initials: AL
authors.lastname: Pehrson
authors.forename: Scott D
authors.initials: SD
authors.lastname: Philibin
authors.forename: Jesse T
authors.initials: JT
authors.lastname: Wood
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Vunck
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Porter
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000378:metabolism / Q000502:physiology*; D014282:Trihexyphenidyl / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; C058272:norclozapine; D014282:Trihexyphenidyl; D003024:Clozapine