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.
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.
Philibin
Scott D
SD
Department of Behavioral Neuroscience, Oregon Health & Science University, VA Medical Center, Portland, OR, USA.
Walentiny
D Matthew
DM
Vunck
Sarah A
SA
Prus
Adam J
AJ
Meltzer
Herbert Y
HY
Porter
Joseph H
JH
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
D058668:Adrenergic alpha-1 Receptor Antagonists; D014150:Antipsychotic Agents; D058830:Serotonin 5-HT2 Receptor Antagonists; D003024:Clozapine