Opposite regulation by typical and atypical anti‐psychotics of ERK1/2, CREB and Elk‐1 phosphorylation in mouse dorsal striatum

• Published in: Journal of neurochemistry 2003-07, Vol.86 (2), p.451-459
• Main Authors: Pozzi, Laura, Håkansson, Kerstin, Usiello, Alessandro, Borgkvist, Anders, Lindskog, Maria, Greengard, Paul, Fisone, Gilberto
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - pharmacology; Biological and medical sciences; clozapine; Clozapine - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; DARPP‐32; DNA-Binding Proteins; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists - pharmacology; dopamine D2 receptors; Drug Interactions; eticlopride; ets-Domain Protein Elk-1; haloperidol; Haloperidol - pharmacology; Male; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; mitogen‐activated protein kinases; Nerve Tissue Proteins; Neuropharmacology; Pharmacology. Drug treatments; Phosphoproteins - metabolism; Phosphorylation - drug effects; Proto-Oncogene Proteins - metabolism; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Salicylamides - pharmacology; Transcription Factors
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.01851.x

The two mitogen‐activated protein kinases (MAPKs), extracellular signal‐regulated protein kinase 1 and 2 (ERK1/2), are involved in the control of gene expression via phosphorylation and activation of the transcription factors cyclic AMP response element binding protein (CREB) and Elk‐1. Here, we have examined the effect of haloperidol and clozapine, two anti‐psychotic drugs, and eticlopride, a selective dopamine D2 receptor antagonist, on the state of phosphorylation of ERK1/2, CREB and Elk‐1, in the mouse dorsal striatum. Administration of the typical anti‐psychotic haloperidol stimulated the phosphorylation of ERK1/2, CREB and Elk‐1. Virtually identical results were obtained using eticlopride. In contrast, the atypical anti‐psychotic clozapine reduced ERK1/2, CREB and Elk‐1 phosphorylation. This opposite regulation was specifically exerted by haloperidol and clozapine on ERK, CREB, and Elk‐1 phosphorylation, as both anti‐psychotic drugs increased the phosphorylation of the dopamine‐ and cyclic AMP‐regulated phosphoprotein of 32 kDa (DARPP‐32) at the cyclic AMP‐dependent protein kinase (PKA) site. The activation of CREB and Elk‐1 induced by haloperidol appeared to be achieved via different signalling pathways, as inhibition of ERK1/2 activation abolished the stimulation of Elk‐1 phosphorylation without affecting CREB phosphorylation. This study shows that haloperidol and clozapine induce distinct patterns of phosphorylation in the dorsal striatum. The results provide a novel biochemical paradigm elucidating the molecular mechanisms underlying the distinct therapeutic actions of typical and atypical anti‐psychotic agents.