Cell type-specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs

Nat Neurosci. 2008 Aug;11(8):932-9. doi: 10.1038/nn.2153. Epub 2008 Jul 11.


DARPP-32 is a dual-function protein kinase/phosphatase inhibitor that is involved in striatal signaling. The phosphorylation of DARPP-32 at threonine 34 is essential for mediating the effects of both psychostimulant and antipsychotic drugs; however, these drugs are known to have opposing behavioral and clinical effects. We hypothesized that these drugs exert differential effects on striatonigral and striatopallidal neurons, which comprise distinct output pathways of the basal ganglia. To directly test this idea, we developed bacterial artificial chromosome transgenic mice that allowed the analysis of DARPP-32 phosphorylation selectively in striatonigral and striatopallidal neurons. Using this new methodology, we found that cocaine, a psychostimulant, and haloperidol, a sedation-producing antipsychotic, exert differential effects on DARPP-32 phosphorylation in the two neuronal populations that can explain their opposing behavioral effects. Furthermore, we found that a variety of drugs that target the striatum have cell type-specific effects that previous methods were not able to discern.

Publication types

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

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Caffeine / pharmacology
  • Central Nervous System Stimulants / pharmacology*
  • Chromosomes, Artificial, Bacterial / genetics
  • Clozapine / pharmacology
  • Cocaine / pharmacology
  • Corpus Striatum / cytology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / drug effects
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism*
  • Globus Pallidus / cytology
  • Globus Pallidus / drug effects
  • Globus Pallidus / metabolism
  • Haloperidol / pharmacology
  • Mice
  • Mice, Transgenic
  • Neurons / classification
  • Neurons / drug effects
  • Neurons / metabolism*
  • Organ Culture Techniques
  • Phosphorylation / drug effects
  • Substantia Nigra / cytology
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism


  • Antipsychotic Agents
  • Central Nervous System Stimulants
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Ppp1r1b protein, mouse
  • Caffeine
  • Cocaine
  • Clozapine
  • Haloperidol