Clozapine and the mitogen-activated protein kinase signal transduction pathway: Implications for antipsychotic actions

Jeff L. Browning, Tushar Patel, Paul C. Brandt, Keith A. Young, Leigh A. Holcomb, Paul B. Hicks

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Background: Mitogen-activated protein kinase (MAPK) signaling pathways respond to dopaminergic and serotonergic agents and mediate short- and long-term effects of intracellular signaling in neurons. Here we show that the antipsychotic agent, clozapine, selectively activates the MEK/ERK MAPK pathway, and inhibition of this pathway reverses clozapine's actions in the conditioned avoidance response (CAR) paradigm, a rodent behavioral assay of antipsychotic activity. Methods: Phosphorylation patterns of MAPK pathway enzymes were determined by quantitative immunoblot analysis and immunohistochemistry of rat prefrontal cortex. Kinase inhibitors were used to assess the role of MAPK signaling pathways in mediating clozapine-induced suppression of CAR. Results: Clozapine administration selectively increased phosphorylation of MEK1/2 but had no effect on p38 or JNK phosphorylation. Pretreatment with the 5-HT 2A agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride blocked the clozapine-induced increase in MEK1/2 phosphorylation. Immunohistochemistry revealed that clozapine treatment elevated the number of cells in the prefrontal cortex positive for phosphoERK, the downstream substrate of MEK1/2. Prior administration of MEK1/2 inhibitors U0126 or Sl327, or ERK inhibitor 5-iodotubercidin, reversed suppression of CAR induced by clozapine, whereas administration of vehicle, JNK or p38 inhibitors (L-JNK-1 and SB203580, respectively) had no effect. Inhibition of kinases upstream to MEK1/2 (PI-3K, PKC, and CaMKII) by administration of LY294002, bisindolylmaleimide, or KN-62, respectively, also reversed clozapine-induced suppression of CAR. Conclusions: These data support the hypothesis that the MEK/ERK signal transduction cascade participates in clozapine's antipsychotic actions.

Original languageEnglish (US)
Pages (from-to)617-623
Number of pages7
JournalBiological psychiatry
Issue number6
StatePublished - Mar 15 2005


  • Antipsychotic
  • Avoidance
  • ERK
  • MAPK
  • Schizophrenia
  • Serotonin

ASJC Scopus subject areas

  • Biological Psychiatry


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