title: Midkine regulates amphetamine-induced astrocytosis in striatum but has no effects on amphetamine-induced striatal dopaminergic denervation and addictive effects: functional differences between pleiotrophin and midkine.
abstract: Midkine (MK), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is upregulated in different brain areas after administration of different drugs of abuse suggesting MK could modulate drugs of abuse-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in MK genetically deficient (MK-/-) and wild-type (MK+/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference (CPP) similarly in both MK-/- and MK+/+ mice. In immunohistochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 h) causes a similar striatal dopaminergic denervation in both MK-/- and MK+/+ mice. However, we detected a significant increase of glial fibrillary acidic protein (GFAP)-positive cells in the striatum of amphetamine-treated MK-/- mice compared to MK+/+ mice, suggesting an enhanced amphetamine-induced astrocytosis in absence of endogenous MK. Interestingly, the levels of expression of the MK receptor, receptor protein tyrosine phosphatase (RPTP) β/ζ, in the striatum were not found to be changed by the drug administration or the mouse genotype. In a similar manner the phosphorylation levels of RPTP β/ζ substrates with important roles in survival of dopaminergic neurons, Fyn kinase and TrkA, and of the MAP kinases ERK1/2, were unaffected by the drug or the genotype. The data clearly suggest that endogenous MK limits amphetamine-induced astrocytosis through Fyn-, TrkA- and ERK1/2-independent mechanisms and identify previously unexpected functional differences between MK and pleiotrophin, the only other member of the MK family of growth factors, in the modulation of effects of drugs of abuse.
authors.affiliation: Laboratory of Pharmacology and Toxicology, University San Pablo CEU, 28668 Boadilla del Monte, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Gramage
authors.forename: Y B
authors.initials: YB
authors.lastname: Martín
authors.forename: P
authors.initials: P
authors.lastname: Ramanah
authors.forename: C
authors.initials: C
authors.lastname: Pérez-García
authors.forename: G
authors.initials: G
authors.lastname: Herradón
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D003714:Denervation; D004298:Dopamine / Q000378:metabolism*; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D000078792:Midkine; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D016207:Cytokines; C066845:pleiotrophin; D000078792:Midkine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D048052:Mitogen-Activated Protein Kinase 3; D004298:Dopamine