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.[1]References
- Reduction of cocaine place preference in mice lacking the protein phosphatase 1 inhibitors DARPP 32 or Inhibitor 1. Zachariou, V., Benoit-Marand, M., Allen, P.B., Ingrassia, P., Fienberg, A.A., Gonon, F., Greengard, P., Picciotto, M.R. Biol. Psychiatry (2002) [Pubmed]
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