Behavioral assessment of atypical antipsychotics in rats: studies of the effects of olanzapine (Zyprexa)

Abstract 

Rationale: Previous work has shown that clozapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. Objective: The novel atypical antipsychotic olanzapine was assessed in these behavioral tests. Methods: The effect of acute olanzapine on the suppression of tacrine-induced tremulous jaw movements was examined. In order to determine the relative potency of this effect compared with other behavioral effects of olanzapine, suppression of lever pressing also was studied. In a second series of experiments, rats received olanzapine for 14 consecutive days to study the effects of repeated injections of this drug on jaw movements and lever pressing. Results: Acute olanzapine administration decreased tacrine-induced jaw movements (ED₅₀: 0.4 mg/kg), and also reduced lever pressing (ED₅₀: 1.12 mg/kg). The ratio of the ED₅₀ for suppression of jaw movements to that for suppression of lever pressing was used as an index of liability to produce extrapyramidal side effects, and the present results demonstrate that olanzapine has a ratio similar to that previously shown for clozapine. In the repeated administration studies, rats were observed on day 13 of drug treatment for the ability of olanzapine to induce jaw movements, and olanzapine failed to induce jaw movements. On day 14, olanzapine reduced tacrine-induced tremulous jaw movements (ED₅₀: 1.12 mg/kg). In a separate experiment, olanzapine significantly suppressed lever pressing, and this effect showed sensitization with repeated administration (day 14, ED₅₀: 0.76 mg/kg). Thus, repeated injections of olanzapine reduced tacrine-induced jaw movements in a dose range similar to or slightly higher than that which suppressed lever pressing. Conclusions: On tests of jaw-movement activity and lever pressing after both acute and repeated drug administration, olanzapine demonstrated a profile somewhat similar to clozapine, and both of these drugs differ substantially from the typical antipsychotic haloperidol.