摘要：

Interaction with dopamine D 2 -like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D 2 receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1h after administration of the compound, using [ 3 H]nemonapride as a ligand. All the compounds reduced in vivo binding of [ 3 H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D 2 antagonists, nemonapride (ID 50 : 0.034mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [ 3 H]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 D 2 -like receptors. New compounds, displaying marked agonism at 5-HT 1A receptors in addition to D 2 receptor affinity, exhibited varying D 2 receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID 50 values for inhibition of [ 3 H]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 D 2 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 ID 50 values herein and previously-reported ED 50 values for catalepsy in mice. These data indicate that: (1) there is no difference in D 2 receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D 2 receptors can be dissociated from catalepsy, if the drugs also activate 5-HT 1A receptors. Taken together, these data support the strategy of simultaneously targeting D 2 receptor blockade and 5-HT 1A receptor activation for new antipsychotics.

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