Research reportRegulation of extinction of cocaine-induced place preference by midkine is related to a differential phosphorylation of peroxiredoxin 6 in dorsal striatum

•We studied the effects of cocaine in MK and PTN genetically deficient mice.•Acquisition of cocaine-induced CPP was similar in MK−/−, PTN−/− and wild type mice.•MK is a novel genetic factor with a role in the extinction of cocaine CPP.•Phosphorylation of striatal Prdx6 may be involved in the extinction of cocaine CPP.

The neurotrophic factors Midkine (MK) and Pleiotrophin (PTN) have been suggested to modulate drugs of abuse-induced effects. To test this hypothesis, cocaine (10 and 15 mg/kg)-induced conditioned place preference (CPP) was rendered in PTN knockout (PTN−/−), MK knockout (MK−/−) and wild type (WT+/+) mice, and then extinguished after repeated saline injections (distributed in 4 extinction sessions). Cocaine induced a similar CPP in all the three genotypes. We found a significantly increased percentage of MK−/− mice that did not extinguish cocaine CPP at the end of the extinction sessions. Particularly, 40% of MK−/− mice did not extinguish cocaine (15 mg/kg)-induced CPP compared to WT+/+ and PTN−/− mice (∼0-6%). Interestingly, we found that a greater magnitude of extinction of CPP after the first extinction session (5 days after last administration of cocaine) correlates with increased tyrosine phosphorylation of the enzyme peroxiredoxin 6 in the dorsal striatum of MK−/− mice. On the other hand, a greater magnitude of CPP extinction correlates with increased tyrosine phosphorylation of aconitase 2 in the prefrontal cortex of WT+/+ mice. In contrast, a lower magnitude of CPP extinction correlates with increased phosphorylation of aconitase 2 in the prefrontal cortex of PTN−/− mice, suggesting that the correlation between the tyrosine phosphorylation levels of aconitase 2 and magnitude of CPP extinction depends on the genotype considered. The data demonstrate that MK is a novel genetic factor that plays a role in the extinction of cocaine-induced CPP by mechanisms that may involve specific phosphorylation of striatal peroxiredoxin 6.