Potentiation of olanzapine substitution in rats discriminating clozapine by the D2/3 agonist quinpirole

The D2/3 agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) has been reported to enhance the ability of olanzapine to substitute for clozapine and attenuate olanzapine-induced response suppression in monkeys. These data suggest that the relatively marked D2/3 antagonist actions of olanzapine limit its substitution for clozapine. The work reported here replicated and extended these findings. Twelve rats were trained to discriminate clozapine (5 mg/kg, intraperitoneal) from vehicle in an FR30 quantal food rewarded assay. The substitution curve for olanzapine (0-2.5 mg/kg) was then computed after treatment with either vehicle or a high dose (0.1 mg/kg) of the D2/3 agonist quinpirole. The olanzapine substitution curve was shifted significantly 5.2-fold in parallel to the left by quinpirole. Olanzapine suppressed responding significantly, but this effect was not attenuated or enhanced by quinpirole, which suppressed responding itself. Thus antagonist actions at D2/3 receptors clearly limit the ability of olanzapine to substitute for clozapine. These findings suggest that the clozapine versus vehicle discrimination is probably a bioassay for agents that resemble clozapine but which do not necessarily induce D2/3 antagonism. This discrimination may therefore not specifically detect clozapine-like antipsychotics, although it may be of value in developing such antipsychotics. The low discriminability of antipsychotics in general may be because antagonist actions at D2/3 receptors limit incentive salience in discrimination assays. These data are compatible with recent theorizing that therapeutic actions of antipsychotics in schizophrenia involve D2/3 receptor-mediated attenuation of stimulus salience.