Differential profile of antipsychotics at serotonin 5-HT1A and dopamine D2S receptors coupled to extracellular signal-regulated kinase.
The effects of antipsychotics targeting dopamine D2 and serotonin 5-HT1A 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-HT1A or human dopamine D2S receptor. All antipsychotics except haloperidol and olanzapine exhibited agonist properties at serotonin 5-HT1A receptors. Emax values (% effect of 10 microM 5-HT) were: bifeprunox (74), SSR181507 (73), SLV313 (72), aripiprazole (60), ziprasidone (56), clozapine (33). At dopamine D2S receptors, partial agonist activity (% effect of 10 microM 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 D2/serotonin 5-HT1A receptor compounds, aripiprazole acts as a partial dopamine D2S and serotonin 5-HT1A receptor agonist. SSR181507 and bifeprunox possess a profile of action similar to each other, efficaciously stimulating both serotonin 5-HT1A and dopamine D2S receptors. In contrast, SLV313, also an efficacious serotonin 5-HT1A receptor agonist, acted as a high potency dopamine D2 receptor antagonist. Thus, antipsychotics display varying efficacies at serotonin 5-HT1A and dopamine D2S receptors which may play a major role in their differential functional profiles in blocking the diverse symptoms of schizophrenia.
Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, F 81106 Castres Cedex, France. liesbeth.bruins.slot@pierre-fabre.com
Liesbeth A
LA
Bruins Slot
Luc
L
De Vries
Adrian
A
Newman-Tancredi
Didier
D
Cussac
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014326:Tropanes / Q000494:pharmacology
C480819:(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride; C504317:1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-((5-(4-fluorophenyl)-3-pyridinyl)methyl)piperazine; D014150:Antipsychotic Agents; D004146:Dioxanes; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D014326:Tropanes; C113776:dopamine D2L receptor; D044282:Receptor, Serotonin, 5-HT1A; D000068180:Aripiprazole; D048049:Extracellular Signal-Regulated MAP Kinases