Differential effect of clozapine and haloperidol on rats treated with methylphenidate in the open field test

Development of atypical antipsychotic compounds is an important task in pharmacology in order to improve therapeutic features and avoid side effects shown by classical antipsychotic compounds. The prototype of the second generation compounds, clozapine differs from typical antipsychotics by having a high D4 and 5HT(2A) and low D2 receptor affinity. Clozapine is the prototype agent for screening new atypical antipsychotic compounds. Clozapine was compared to haloperidol in the open field animal model in which crossings, rearings and rearing time were analyzed. Clozapine (0.5 and 1 mg/kg) and haloperidol (0.03 mg/kg) were administered by intraperitoneal injection. Five days before experiments, animals were given methylphenidate (12 mg/kg, orally). The experiments were performed 24 hr after the last methylphenidate dose. In the open field test, clozapine blocked the increase in rearing time and rearings elicited by methylphenidate administration in a dose-dependent fashion. No effect was observed in crossings at 1 mg/kg, but there was at 0.5 mg/kg. This could be related to an anxiolytic action at this dose. Haloperidol blocked the increase in rearing time, rearings and crossings. Results are discussed in terms of the putative participation of D4 subtype receptors in the mediation of time and rearing behavior. This approach could be used for the screening of atypical antipsychotic drugs.