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

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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 α-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.

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Received: 8 May 1998/Final version: 18 August 1998

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Ninan, I., Kulkarni, S. Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals. Psychopharmacology 142, 175–181 (1999). https://doi.org/10.1007/s002130050877

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  • DOI: https://doi.org/10.1007/s002130050877

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