Discriminative stimulus properties of the atypical antipsychotic drug clozapine in rats trained to discriminate 1.25 mg/kg clozapine vs. 5.0 mg/kg clozapine vs. vehicle

Abstract

Clozapine, the prototype for atypical antipsychotic drugs, is used in the drug discrimination paradigm as a model for screening atypical from typical antipsychotic drugs. Previous drug discrimination studies in rats have shown that a 1.25 mg/kg clozapine training dose provides full stimulus generalization (i.e.) >or=80% condition-appropriate responding) to most atypical antipsychotic drugs, although a 5.0 mg/kg clozapine training dose appears necessary to provide stimulus generalization to other atypical antipsychotic drugs. The present study sought to characterize the pharmacological mechanisms that mediate these clozapine training doses. In rats trained to discriminate 1.25 vs. 5.0 mg/kg clozapine vs. vehicle in a three-choice drug discrimination task, various receptor-selective compounds were tested for stimulus generalization. The antidepressant mianserin was also tested. Full stimulus generalization from the 1.25 mg/kg clozapine training dose occurred only to mianserin (98.8%). Partial substitution (i.e. >or=60% and <80% condition-appropriate responding) to the 5.0 mg/kg clozapine training dose occurred for the muscarinic receptor antagonist scopolamine. The combined total percentage of responding on the 1.25 and 5.0 mg/kg clozapine levers, however, was well above the full substitution criteria at the 0.25, 0.5, and 1.0 mg/kg scopolamine doses. The M1 agonist N-desmethylclozapine, the nicotinic antagonist mecamylamine, the D1 antagonist SCH 23390, the D4 antagonist LU 38-012, the 5-HT1A agonist (+)-8-OH-DPAT, the 5-HT1A antagonist WAY 100 635, the 5-HT2A/2B/2C antagonist ritanserin, the 5-HT6 antagonist RO4368554, the alpha1 antagonist prazosin, the alpha2 antagonist yohimbine, and the histamine H1 antagonist pyrilamine all failed to substitute for either the 1.25 or the 5.0 mg/kg clozapine training doses. These results are consistent with previous evidence that antidepressant drugs have a tendency to substitute for clozapine and that muscarinic receptor antagonism may mediate the discriminative stimulus properties of 5.0 mg/kg clozapine. The lack of stimulus generalization from either clozapine training dose to other receptor-selective compounds, however, fails to explain how this model screens atypical from typical antipsychotic drugs and suggests that the discriminative stimulus properties of clozapine consist of a compound cue.

Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

“…6). This finding is similar to that reported by Prus et al (2006) in a threelever CLZ discrimination task with rats. In the present study, a very low dose of CLZ (0.625 mg/kg) was tested in combination with NDMC.…”

“…However, it should be noted that the CLZ training dose influences this greatly. Porter et al (2000) found that with a low (1.25 mg/kg) training dose of CLZ, more atypical APDs generalized to CLZ's discriminative cue and that muscarinic antagonism does not engender CLZ-appropriate responding (Prus et al 2006). Goudie et al (2004a) found that the atypical APD zotepine fully substituted for CLZ at a 2.0 mg/kg training dose, but not at a 5.0 mg/kg training dose.…”

Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies

“…All of the drugs that produced full substitution for clozapine in that study display low nanomolar affinity for muscarinic receptors, except for mianserin which has a KD of 469.0 nM (Golds et al 1980). Interestingly, Prus et al (2006) found that in rats trained to discriminate 1.25 mg/kg clozapine from 5.0 mg/kg clozapine from vehicle (i.p.) in a three-lever drug discrimination task, mianserin was the only drug among several selective ligands that produced full substitution for clozapine (on the 5.0 mg/kg training-dose lever).…”

“…N-desmethylclozapine also failed to substitute for clozapine in rats trained to discriminate 1.25 mg/kg clozapine from 5.0 mg/kg clozapine from vehicle (i.p. ; Prus et al 2006). In C57Bl/6 mice, N-desmethylclozapine also does not substitute for clozapine (2.5 mg/kg training dose, s.c.; Philibin et al 2008); however, as in the Prus et al (2008) study, Ndesmethylclozapine produced full substitution when combined with a low dose of clozapine (0.625 mg/kg) that did not substitute for the clozapine training dose.…”

“…Finally, the nicotinic receptor antagonist mecamylamine failed to substitute for either dose of clozapine in rats trained to discriminate 1.25 mg/kg versus 5.0 mg/kg clozapine versus vehicle (i.p.) in a threelever task (Prus et al 2006). Hoenicke et al (1992) have argued that the discriminative stimulus properties of clozapine are mediated by blockade of both 5-HT 2A AND 5-HT 2C receptors.…”