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In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles

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Abstract

Interaction with dopamine D2-like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D2 receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1 h after administration of the compound, using [3H]nemonapride as a ligand. All the compounds reduced in vivo binding of [3H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D2 antagonists, nemonapride (ID50: 0.034 mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [3H]nemonapride binding. The ‘atypical’ antipsychotics, risperidone (0.18), ziprasidone (0.38), aripiprazole (1.6), olanzapine (0.99), and clozapine (11.1) were less potent for occupying D2-like receptors. New compounds, displaying marked agonism at 5-HT1A receptors in addition to D2 receptor affinity, exhibited varying D2 receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID50 values for inhibition of [3H]nemonapride binding in the striatum correlated with those in the olfactory tubercles (r=0.95, P<0.0001). These values also correlated with previously-reported in vitro affinity of the compounds at rat D2 receptors (r=0.85, P=0.0001) and with inhibition of apomorphine-induced climbing in mice (r=0.79 P=0.0005). In contrast, there was no significant correlation between ID50 values herein and previously-reported ED50 values for catalepsy in mice. These data indicate that: (1) there is no difference in D2 receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D2 receptors can be dissociated from catalepsy, if the drugs also activate 5-HT1A receptors. Taken together, these data support the strategy of simultaneously targeting D2 receptor blockade and 5-HT1A receptor activation for new antipsychotics.

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Acknowledgements

We thank Solvay Duphar for the gift of SLV313 sample, Dr. Pierre Sokoloff for helpful comments, and Valérie Faucillon and Virginie Archimbeaud for excellent technical assistance.

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  1. Neurobiology II, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106, Castres Cedex, France

    Marie-Bernadette Assié, Hélène Dominguez, Nathalie Consul-Denjean & Adrian Newman-Tancredi

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  1. Marie-Bernadette Assié
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  2. Hélène Dominguez
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Assié, MB., Dominguez, H., Consul-Denjean, N. et al. In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles. Naunyn-Schmied Arch Pharmacol 373, 441–450 (2006). https://doi.org/10.1007/s00210-006-0092-z

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