Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior

J Neurochem. 2008 Aug;106(4):1780-90. doi: 10.1111/j.1471-4159.2008.05518.x. Epub 2008 Jun 28.

Abstract

Environment-induced relapse is a major concern in drug addiction because of the strong associations formed between drug reward and environment. Cocaine-conditioned place preference is an ideal experimental tool to examine adaptations in the molecular pathways that are activated upon re-exposure to an environment previously paired with drug reward. To better understand the mechanism of cocaine-conditioned place preference we have used western blot analysis to examine changes in phosphorylation of cAMP-response element binding protein (CREB), dopamine- and cyclic AMP-regulated phosphoprotein 32 (DARPP-32), extracellular signal-regulated kinase (ERK) and GluR1, key molecular substrates altered by cocaine, in the nucleus accumbens (NAc) and dorsal hippocampus (DHC) of C57BL/6 mice. Our studies revealed that re-exposing mice to an environment in which they were previously given cocaine resulted in increased levels of Ser133 phospho-CREB and Thr34 phospho-DARPP-32 with a corresponding decrease in Thr75 phospho-DARPP-32 in the NAc. In DHC there were increased levels of phospho-CREB, Thr183/Tyr185 phospho-ERK, and Ser845 phospho-GluR1. These data suggest that the formation of contextual drug reward associations involves recruitment of the DHC-NAc circuit with activation of the DARPP-32/CREB pathway in the NAc and the ERK/CREB pathway in the DHC.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Hippocampus / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / enzymology
  • Nucleus Accumbens / metabolism
  • Phosphorylation / drug effects
  • Receptors, AMPA / metabolism*
  • Telencephalon / drug effects
  • Telencephalon / enzymology
  • Telencephalon / metabolism*

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Ppp1r1b protein, mouse
  • Receptors, AMPA
  • Extracellular Signal-Regulated MAP Kinases
  • Cocaine
  • glutamate receptor ionotropic, AMPA 1