Discriminative stimulus properties of 1.25 mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors

Abstract The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25 mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT 2A inverse agonist M100907 and the two preferential D 4 /5-HT 2 /α 1 receptor antagonists Lu 37-114 (( S )-1-(3-(2-(4-(1 H -indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1 H -indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1 H )-one). Partial substitution occurred with the D 4 receptor antagonist Lu 38-012 and the α 1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT 2C , 5-HT 6 muscarinic, histamine H 1 , and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT 2A inverse agonism and D 4 receptor antagonism mediate the discriminative stimulus properties of 1.25 mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus.