The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic drug clozapine in rats.
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.
Prus
Adam J
AJ
Department of Psychology, Northern Michigan University, Marquette, MI, USA.
Pehrson
Alan L
AL
Philibin
Scott D
SD
Wood
Jesse T
JT
Vunck
Sarah A
SA
Porter
Joseph H
JH
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
D014150:Antipsychotic Agents; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; C058272:norclozapine; D014282:Trihexyphenidyl; D003024:Clozapine