title: Reduction of cocaine place preference in mice lacking the protein phosphatase 1 inhibitors DARPP 32 or Inhibitor 1.
abstract: BACKGROUND
  Modulation of protein phosphorylation by dopamine is thought to play an important role in drug reward. Protein phosphatase-1 (PP-1) is known to mediate some of the changes in neuronal signaling that occur following activation of the dopaminergic system.
  
  
  METHODS
  Two endogenous inhibitors of PP-1 are dopamine and cyclic 3', 5' adenosine monophosphate-regulated phosphoprotein (DARPP-32) and Inhibitor-1 (I-1). Knockout mice lacking one or both of these PP-1 inhibitors were tested for responses to cocaine using in vivo amperometry and conditioned place preference.
  
  
  RESULTS
  Presynaptic dopaminergic function appears to be unaffected by these mutations because stimulation-evoked changes in extracellular dopamine levels were unchanged between wild type mice and mice lacking one or both of these PP-1 inhibitors. In contrast, conditioned place preference to cocaine is reduced in mice lacking DARPP-32, I-1, or both phosphoproteins. This does not appear to be due to a learning deficit because mice lacking both DARPP-32 and I-1 show normal passive avoidance learning.
  
  
  CONCLUSIONS
  These data imply that increased PP-1 function as a result of deficits in DARPP-32 or I-1 is sufficient to decrease the rewarding properties of cocaine. Furthermore, the mechanism for this altered cocaine place preference does not involve alteration of dopamine release or reuptake.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
authors.forename: Venetia
authors.initials: V
authors.lastname: Zachariou
authors.forename: Marianne
authors.initials: M
authors.lastname: Benoit-Marand
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Allen
authors.forename: Peter
authors.initials: P
authors.lastname: Ingrassia
authors.forename: Allen A
authors.initials: AA
authors.lastname: Fienberg
authors.forename: Francois
authors.initials: F
authors.lastname: Gonon
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004558:Electric Stimulation; D004563:Electrochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000235:genetics*; D054645:Protein Phosphatase 1; D011506:Proteins / Q000235:genetics*
chemical_list: D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011506:Proteins; C073882:phosphoprotein phosphatase inhibitor 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D003042:Cocaine; D004298:Dopamine