Histone H3 phosphorylation is under the opposite tonic control of dopamine D2 and adenosine A2A receptors in striatopallidal neurons

Neuropsychopharmacology. 2009 Jun;34(7):1710-20. doi: 10.1038/npp.2008.228. Epub 2009 Jan 21.


The antipsychotic agent haloperidol regulates gene transcription in striatal medium spiny neurons (MSNs) by blocking dopamine D2 receptors (D2Rs). We examined the mechanisms by which haloperidol increases the phosphorylation of histone H3, a key step in the nucleosomal response. Using bacterial artificial chromosome (BAC)-transgenic mice that express EGFP under the control of the promoter of the dopamine D1 receptor (D1R) or the D2R, we found that haloperidol induced a rapid and sustained increase in the phosphorylation of histone H3 in the striatopallidal MSNs of the dorsal striatum, with no change in its acetylation. This effect was mimicked by raclopride, a selective D2R antagonist, and prevented by the blockade of adenosine A2A receptors (A2ARs), or genetic attenuation of the A2AR-associated G protein, Galpha(olf). Mutation of the cAMP-dependent phosphorylation site (Thr34) of the 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32) decreased the haloperidol-induced H3 phosphorylation, supporting the role of cAMP in H3 phosphorylation. Haloperidol also induced extracellular signal-regulated kinase (ERK) phosphorylation in striatopallidal MSNs, but this effect was not implicated in H3 phosphorylation. The levels of mitogen- and stress-activated kinase 1 (MSK1), which has been reported to mediate ERK-induced H3 phosphorylation, were lower in striatopallidal than in striatonigral MSNs. Moreover, haloperidol-induced H3 phosphorylation was unaltered in MSK1-knockout mice. These data indicate that, in striatopallidal MSNs, H3 phosphorylation is controlled by the opposing actions of D2Rs and A2ARs. Thus, blockade of D2Rs promotes histone H3 phosphorylation through the A2AR-mediated activation of Galpha(olf) and inhibition of protein phosphatase-1 (PP-1) through the PKA-dependent phosphorylation of DARPP-32.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Adenosine A2 Receptor Antagonists
  • Analysis of Variance
  • Animals
  • Corpus Striatum / cytology*
  • Dopamine Antagonists / pharmacology
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Protein alpha Subunits / deficiency
  • Gene Expression / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Green Fluorescent Proteins / genetics
  • Haloperidol / pharmacology
  • Histones / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Purines / pharmacology
  • Receptor, Adenosine A2A / metabolism*
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / deficiency
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Threonine / metabolism


  • Adenosine A2 Receptor Antagonists
  • Dopamine Antagonists
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • GTP-Binding Protein alpha Subunits
  • Histones
  • Ppp1r1b protein, mouse
  • Purines
  • Receptor, Adenosine A2A
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • dopamine D1A receptor
  • enhanced green fluorescent protein
  • olfactory G protein subunit alpha olf
  • Green Fluorescent Proteins
  • istradefylline
  • Threonine
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Extracellular Signal-Regulated MAP Kinases
  • Haloperidol