title: In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles.
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.
authors.affiliation: Neurobiology II, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106, Castres Cedex, France. marie.bernadette.assie@pierre-fabre.com
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Assié
authors.forename: Hélène
authors.initials: H
authors.lastname: Dominguez
authors.forename: Nathalie
authors.initials: N
authors.lastname: Consul-Denjean
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000378:metabolism; D001667:Binding, Competitive; D002375:Catalepsy / Q000139:chemically induced / Q000503:physiopathology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000378:metabolism*; D009830:Olfactory Bulb / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D017366:Serotonin Receptor Agonists; D001058:Apomorphine; C030265:nemonapride