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

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.); 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. >= 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 M-1 agonist N-desmethylclozapine, the nicotinic antagonist mecamylamine, the D-1 antagonist SCH 23390, the D-4 antagonist LU 38-012, the 5-HT1A agonist (+)-B-OH-DPAT, the 5-HT1A antagonist WAY 100635, the 5-HT2A/2B/2C antagonist ritanserin, the 5-HT6 antagonist RO4368554, the alpha(1) antagonist prazosin, the alpha(2) antagonist yohimbine, and the histamine H, 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, falls 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.