Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals.

The aim of the present study was to investigate the locomotor stimulant effects of the atypical antipsychotic agent, olanzapine, in mice depleted of their dopamine by reserpine and alpha-methyl-DL-p-tyrosine pretreatment. Olanzapine (0.5, 1 and 2 mg/kg) dose-dependently increased locomotor activity, which was completely blocked by the selective dopamine D2 receptor antagonist, pimozide (0.5 mg/kg) but not by selective dopamine D1 receptor antagonist, SCH 23390 (0.5 and 1 mg/kg). Unlike olanzapine, the selective dopamine D2 receptor antagonists such as haloperidol (0.25 and 0.5 mg/kg) and pimozide (0.5 and 1 mg/kg), the selective 5-HT2A receptor antagonist, ritanserin (0.5 and 1 mg/kg) or the antimuscarinic agent scopolamine (0.5 and 1 mg/kg) failed to produce any locomotor stimulant effect. Olanzapine (1 and 2 mg/kg) and SCH 23390 (0.5 and 1 mg/kg) blocked hyperlocomotion and stereotypy induced by the selective dopamine D1 receptor agonist, SKF 38393 (10 and 25 mg/kg). Olanzapine (1 and 2 mg/kg) blocked hyperlocomotion and stereotypy induced by B-HT 920 (1 and 2 mg/kg), a selective dopamine D2 receptor agonist, whereas it blocked the hyperlocomotion but not stereotypy induced by the non-selective dopamine receptor agonist, apomorphine (0.5 and 1 mg/kg). The higher dose (4 mg/kg) of olanzapine blocked both stereotypy and hyperlocomotion induced by apomorphine. Olanzapine, in mice depleted of their dopamine stores, exhibited properties consistent with those of a D2 partial agonist having strong D1 antagonist property. The atypical nature of its clinical effect may be explained by a dual effect, partial agonistic-like action at D2 receptors and antagonist-like activity at D1 receptors, respectively.