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Opposite regulation by typical and atypical anti‐psychotics of ERK1/2, CREB and Elk‐1 phosphorylation in mouse dorsal striatum
Author(s) -
Pozzi Laura,
Håkansson Kerstin,
Usiello Alessandro,
Borgkvist Anders,
Lindskog Maria,
Greengard Paul,
Fisone Gilberto
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01851.x
Subject(s) - creb , phosphorylation , eticlopride , cyclic amp response element binding protein , protein kinase a , haloperidol , striatum , mapk/erk pathway , kinase , chemistry , dopaminergic , dopamine , medicine , endocrinology , biology , pharmacology , microbiology and biotechnology , biochemistry , transcription factor , sch 23390 , gene
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 D 2 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.