Differential profile of antipsychotics at serotonin 5-HT1A and dopamine D2S receptors coupled to extracellular signal-regulated kinase

Abstract The effects of antipsychotics targeting dopamine D 2 and serotonin 5-HT 1A receptors were compared with conventional antipsychotics on phosphorylation of Extracellular signal-Regulated Kinase 1/2 (ERK 1/2) in CHO cell lines stably expressing either the human serotonin 5-HT 1A or human dopamine D 2S receptor. All antipsychotics except haloperidol and olanzapine exhibited agonist properties at serotonin 5-HT 1A receptors. E max values (% effect of 10 μM 5-HT) were : bifeprunox (74), SSR181507 (73), SLV313 (72), aripiprazole (60), ziprasidone (56), clozapine (33). At dopamine D 2S receptors, partial agonist activity (% effect of 10 μM dopamine) was observed for bifeprunox (76), SSR181507 (66) and aripiprazole (59). Other antipsychotics attenuated dopamine-induced ERK phosphorylation, with pK B values of : SLV313 (8.5), haloperidol (8.1), olanzapine (7.8), ziprasidone (7.7), and clozapine (6.4). Amongst the dopamine D 2 /serotonin 5-HT 1A receptor compounds, aripiprazole acts as a partial dopamine D 2S and serotonin 5-HT 1A receptor agonist. SSR181507 and bifeprunox possess a profile of action similar to each other, efficaciously stimulating both serotonin 5-HT 1A and dopamine D 2S receptors. In contrast, SLV313, also an efficacious serotonin 5-HT 1A receptor agonist, acted as a high potency dopamine D 2 receptor antagonist. Thus, antipsychotics display varying efficacies at serotonin 5-HT 1A and dopamine D 2S receptors which may play a major role in their differential functional profiles in blocking the diverse symptoms of schizophrenia.