title: Quetiapine and aripiprazole signal differently to ERK, p90RSK and c-Fos in mouse frontal cortex and striatum: role of the EGF receptor.
abstract: BACKGROUND
  Signaling pathways outside dopamine D2 receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia. One postulated mechanism causal to APD action may regulate synaptic plasticity and neuronal connectivity via the extracellular signal-regulated kinase (ERK) cascade that links G-protein coupled receptors (GPCR) and ErbB growth factor signaling, systems disturbed in schizophrenia. This was based upon our finding that the low D2 receptor affinity APD clozapine induced initial down-regulation and delayed epidermal growth factor receptor (EGFR or ErbB1) mediated activation of the cortical and striatal ERK response in vivo distinct from olanzapine or haloperidol. Here we map whether the second generation atypical APDs aripiprazole and quetiapine affect the EGFR-ERK pathway and its substrates p90RSK and c-Fos in mouse brain, given their divergent agonist and antagonist properties on dopaminergic transmission, respectively.
  
  
  RESULTS
  In prefrontal cortex, aripiprazole triggered triphasic ERK phosphorylation that was EGFR-independent but had no significant effect in striatum. Conversely quetiapine did not alter cortical ERK signaling but elevated striatal ERK levels in an EGFR-dependent manner. Induction of ERK by aripiprazole did not affect p90RSK signaling but quetiapine decreased RSK phosphorylation within 1-hour of administration. The transcription factor c-Fos by comparison was a direct target of ERK phosphorylation induced by aripiprazole in cortex and quetiapine in striatum with protein levels in temporal alignment with that of ERK.
  
  
  CONCLUSIONS
  These data indicate that aripiprazole and quetiapine signal to specific nuclear targets of ERK, which for quetiapine occurs via an EGFR-linked mechanism, possibly indicating involvement of this system in its action.
authors.affiliation: Department of Molecular Psychopharmacology, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Kenneth Myer Building, At Genetics Lane on Royal Parade, Parkville, VIC 3010, Australia. avril.pereira@florey.edu.au.
authors.forename: Avril
authors.initials: A
authors.lastname: Pereira
authors.forename: Betty
authors.initials: B
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Malcolm
authors.forename: Anthony
authors.initials: A
authors.lastname: Sugiharto-Winarno
authors.forename: Suresh
authors.initials: S
authors.lastname: Sundram
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003987:Dibenzothiazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D000069348:Quetiapine Fumarate; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000069348:Quetiapine Fumarate; D000068180:Aripiprazole; D066246:ErbB Receptors; D038744:Ribosomal Protein S6 Kinases, 90-kDa