Reduction of cocaine place preference in mice lacking the protein phosphatase 1 inhibitors DARPP 32 or Inhibitor 1.
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.
Zachariou
Venetia
V
Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
Benoit-Marand
Marianne
M
Allen
Patrick B
PB
Ingrassia
Peter
P
Fienberg
Allen A
AA
Gonon
Francois
F
Greengard
Paul
P
Picciotto
Marina R
MR
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*
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