title: Regulation of extinction of cocaine-induced place preference by midkine is related to a differential phosphorylation of peroxiredoxin 6 in dorsal striatum.
abstract: 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 15mg/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 (15mg/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.
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Food Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Gramage
authors.forename: Carmen
authors.initials: C
authors.lastname: Pérez-García
authors.forename: Marta
authors.initials: M
authors.lastname: Vicente-Rodríguez
authors.forename: Silke
authors.initials: S
authors.lastname: Bollen
authors.forename: Loreto
authors.initials: L
authors.lastname: Rojo
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Herradón
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects*; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000078792:Midkine; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000494:pharmacology*; D054465:Peroxiredoxin VI / Q000378:metabolism*; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D040901:Proteomics
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D009414:Nerve Growth Factors; C066845:pleiotrophin; D000078792:Midkine; D054465:Peroxiredoxin VI; D017027:Protein Tyrosine Phosphatases; D000154:Aconitate Hydratase; D003042:Cocaine
keywords: Aconitase; Addiction; Amphetamine; Conditioned place preference; Pleiotrophin; Prefrontal cortex