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

J Neurochem. 2003 Jul;86(2):451-9. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Clozapine / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • DNA-Binding Proteins*
  • Dopamine Antagonists / pharmacology
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Drug Interactions
  • Haloperidol / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Nerve Tissue Proteins*
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Salicylamides / pharmacology
  • Transcription Factors*
  • ets-Domain Protein Elk-1


  • Antipsychotic Agents
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Dopamine Antagonists
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Elk1 protein, mouse
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Salicylamides
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Clozapine
  • Haloperidol
  • eticlopride