title: Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation.
abstract: It was previously shown that mice with genetic deletion of the neurotrophic factor pleiotrophin (PTN-/-) show enhanced amphetamine neurotoxicity and impair extinction of amphetamine conditioned place preference (CPP), suggesting a modulatory role of PTN in amphetamine neurotoxicity and reward. We have now studied the effects of amphetamine (10mg/kg, 4 times, every 2h) in the striatum of mice with transgenic PTN overexpression (PTN-Tg) in the brain and in wild type (WT) mice. Amphetamine caused an enhanced loss of striatal dopaminergic terminals, together with a highly significant aggravation of amphetamine-induced increase in the number of GFAP-positive astrocytes, in the striatum of PTN-Tg mice compared to WT mice. Given the known contribution of D1 and D2 dopamine receptors to the neurotoxic effects of amphetamine, we also performed quantitative receptor autoradiography of both receptors in the brains of PTN-Tg and WT mice. D1 and D2 receptors binding in the striatum and other regions of interest was not altered by genotype or treatment. Finally, we found that amphetamine CPP was significantly reduced in PTN-Tg mice. The data demonstrate that PTN overexpression in the brain blocks the conditioning effects of amphetamine and enhances the characteristic striatal dopaminergic denervation caused by this drug. These results indicate for the first time deleterious effects of PTN in vivo by mechanisms that are probably independent of changes in the expression of D1 and D2 dopamine receptors. The data also suggest that PTN-induced neuroinflammation could be involved in the enhanced neurotoxic effects of amphetamine in the striatum of PTN-Tg mice.
authors.affiliation: Pharmacology lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vicente-Rodríguez
authors.affiliation: Department of Biochemistry & Physiology, Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK.
authors.forename: Loreto
authors.initials: L
authors.lastname: Rojo Gonzalez
authors.affiliation: Pharmacology lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Gramage
authors.affiliation: Pharmacology lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Fernández-Calle
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, Division of Academic Psychiatry London, Kings College London, London, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Pharmacology lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pérez-García
authors.affiliation: BRAINco Biopharma, S.L., Bizkaia Technology Park, Spain.
authors.forename: Marcel
authors.initials: M
authors.lastname: Ferrer-Alcón
authors.affiliation: BRAINco Biopharma, S.L., Bizkaia Technology Park, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Uribarri
authors.affiliation: Department of Biochemistry & Physiology, Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK; Institute of Medical and Biomedical Education, St George׳s University of London, London SW17 0RE, UK.
authors.forename: Alexis
authors.initials: A
authors.lastname: Bailey
authors.affiliation: Pharmacology lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain. Electronic address: herradon@ceu.es.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Herradón
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001345:Autoradiography; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003714:Denervation; D059290:Dopaminergic Neurons / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017447:Receptors, Dopamine D1 / Q000096:biosynthesis*; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis*
chemical_list: D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D016207:Cytokines; C000600618:DRD2 protein, mouse; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C066845:pleiotrophin; D000661:Amphetamine
keywords: Astrogliosis; Inflammation; Methamphetamine; Midkine; Pleiotrophin; Reward