Differential effects of olanzapine at dopamine D-1 and D-2 receptors in dopamine depleted animals

The aim of the present study was to investigate the locomotor stimulant eff ects of the atypical antipsychotic agent, olanzapine, in mice depleted of t heir dopamine by reserpine and alpha-methyl-DL-p-tyrosine pretreatment. Ola nzapine (0.5, 1 and 2 mg/kg) dose-dependently increased locomotor activity, which was completely blocked by the selective dopamine D-2 receptor antago nist, pimozide (0.5 mg/kg) but not by selective dopamine D-1 receptor antag onist, SCH 23390 (0.5 and 1 mg/kg). Unlike olanzapine, the selective dopami ne D-2 receptor antagonists such as haloperidol (0.25 and 0.5 mg/kg) and pi mozide (0.5 and 1 mg/kg), the selective 5-HT2A receptor antagonist, ritanse rin (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 D-1 receptor agonist, SKF 38393 (10 and 25 mg/kg). Olanzapine (1 and 2 mg/kg) blocked hyperlocomotion and stereotyp y induced by B-HT 920 (1 and 2 mg/kg), a selective dopamine D-2 receptor ag onist, 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 hyper locomotion induced by apomorphine. Olanzapine, in mice depleted of their do pamine stores, exhibited properties consistent with those of a D-2 partial agonist having strong D-1 antagonist property. The atypical nature of its c linical effect may be explained by a dual effect, partial agonistic-like ac tion at D-2 receptors and antagonist-like activity at D-1 receptors, respec tively.