Stimulation by antipsychotic agents of mitogen-activated protein kinase (MAPK) coupled to cloned, human (h)serotonin (5-HT)(1A) receptors.
BACKGROUND
There is evidence that serotonergic mechanisms contribute to the functional profiles of antipsychotic drugs, several of which display affinity for human (h)5-HT(1A) receptors.


OBJECTIVE
Here, we compared the interaction of several antipsychotic agents at h5-HT(1A) receptors employing mitogen-activated protein kinase (MAPK), an intracellular marker.


METHODS
The influence of antipsychotics on MAPK phosphorylation was quantified in Chinese hamster ovary (CHO) cells stably transfected with h5-HT(1A) receptors by use of a highly selective antibody.


RESULTS
The novel antipsychotic agent, S16924, concentration-dependently (pEC(50), 8.10) stimulated the phosphorylation of MAPK. Its maximal effect (96%) was similar to that of the prototypical 5-HT(1A) agonist, (+)8-OH-DPAT (pEC(50), 8.54) (defined as 100%). The selective 5-HT(1A) receptor antagonist WAY100,635, which was inactive alone, abolished stimulation of MAPK by S16924 with a pK(b) of 9.66. This stimulatory influence of S16924 on MAPK was potently mimicked by the benzoisoxazole, antipsychotic ziprasidone (pEC(50), 7.25; 93%). The atypical antipsychotic clozapine also activated MAPK, albeit with lower potency and efficacy (pEC(50), 5.43 and 43%). These actions of ziprasidone and clozapine were also blocked by WAY100,635. Evaluated at a single, high concentration, several other antipsychotics stimulated MAPK phosphorylation with variable efficacy: quetiapine (75%), ocaperidone (74%), tiospirone (57%), olanzapine (54%) and risperidone (21%). In all cases, their actions were abolished by WAY100,635. In contrast, haloperidol, thioridazine and sertindole did not stimulate MAPK.


CONCLUSIONS
Antipsychotics display contrasting efficacies in modulating MAPK phosphorylation at h5-HT(1A) receptors, ranging from high (e.g. S16924 and ziprasidone), via intermediate (e.g. clozapine) to low (e.g. haloperidol). Differential modulation of 5-HT(1A) receptor-coupled MAPK may contribute to their contrasting functional profiles.
Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
Didier
D
Cussac
Delphine
D
Duqueyroix
Adrian
A
Newman-Tancredi
Mark J
MJ
Millan
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D003024:Clozapine / Q000494:pharmacology; D006224:Cricetinae; D004789:Enzyme Activation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D014150:Antipsychotic Agents; D010879:Piperazines; D011759:Pyrrolidines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C114530:S 16924; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C092292:ziprasidone; D020928:Mitogen-Activated Protein Kinases; D003024:Clozapine