Opposite regulation by typical and atypical anti-psychotics of ERK1/2, CREB and Elk-1 phosphorylation in mouse dorsal striatum.
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.
Pozzi
Laura
L
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Håkansson
Kerstin
K
Usiello
Alessandro
A
Borgkvist
Anders
A
Lindskog
Maria
M
Greengard
Paul
P
Fisone
Gilberto
G
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012457:Salicylamides / Q000494:pharmacology; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1
D014150:Antipsychotic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C494113:Elk1 protein, mouse; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012457:Salicylamides; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D003024:Clozapine; D006220:Haloperidol; C045989:eticlopride