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.
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.
Department of Pediatrics, Division of Pediatric Neurology, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, and University of New England, College of Osteopathic Medicine, Biddeford, Maine, USA.
Thomas F
TF
Tropea
Barry E
BE
Kosofsky
Anjali M
AM
Rajadhyaksha
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism*; D013687:Telencephalon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D003042:Cocaine; D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D048049:Extracellular Signal-Regulated MAP Kinases; D018091:Receptors, AMPA; C497929:Ppp1r1b protein, mouse