1. Academic Validation
  2. Pharmacological inhibition of Receptor Protein Tyrosine Phosphatase β/ζ (PTPRZ1) modulates behavioral responses to ethanol

Pharmacological inhibition of Receptor Protein Tyrosine Phosphatase β/ζ (PTPRZ1) modulates behavioral responses to ethanol

  • Neuropharmacology. 2018 Jul 15;137:86-95. doi: 10.1016/j.neuropharm.2018.04.027.
Rosalía Fernández-Calle 1 Marta Vicente-Rodríguez 2 Miryam Pastor 3 Esther Gramage 1 Bruno Di Geronimo 3 José María Zapico 3 Claire Coderch 3 Carmen Pérez-García 1 Amy W Lasek 4 Beatriz de Pascual-Teresa 3 Ana Ramos 3 Gonzalo Herradón 5
Affiliations

Affiliations

  • 1 Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925, Alcorcón, Madrid, Spain.
  • 2 Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925, Alcorcón, Madrid, Spain; Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
  • 3 Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925, Alcorcón, Madrid, Spain.
  • 4 Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA.
  • 5 Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925, Alcorcón, Madrid, Spain. Electronic address: herradon@ceu.es.
Abstract

Pleiotrophin (PTN) and Midkine (MK) are Neurotrophic Factors that are upregulated in the prefrontal cortex after alcohol administration and have been shown to reduce ethanol drinking and reward. PTN and MK are the endogenous inhibitors of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ (a.k.a. PTPRZ1, RPTPβ, PTPζ), suggesting a potential role for this Phosphatase in the regulation of alcohol effects. To determine if RPTPβ/ζ regulates ethanol consumption, we treated mice with recently developed small-molecule inhibitors of RPTPβ/ζ (MY10, MY33-3) before testing them for binge-like drinking using the drinking in the dark protocol. Mice treated with RPTPβ/ζ inhibitors, particularly with MY10, drank less ethanol than controls. MY10 treatment blocked ethanol conditioned place preference, showed limited effects on ethanol-induced ataxia, and potentiated the sedative effects of ethanol. We also tested whether RPTPβ/ζ is involved in ethanol signaling pathways. We found that ethanol treatment of neuroblastoma cells increased phosphorylation of anaplastic lymphoma kinase (ALK) and TrkA, known substrates of RPTPβ/ζ. Treatment of neuroblastoma cells with MY10 or MY33-3 also increased levels of phosphorylated ALK and TrkA. However, concomitant treatment of neuroblastoma cells with ethanol and MY10 or MY33-3 prevented the increase in pTrkA and pALK. These results demonstrate for the first time that ethanol engages TrkA signaling and that RPTPβ/ζ modulates signaling pathways activated by alcohol and behavioral responses to this drug. The data support the hypothesis that RPTPβ/ζ might be a novel target of pharmacotherapy for reducing excessive alcohol consumption.

Keywords

ALK; Alcohol use disorder; Binge-drinking; Midkine; Pleiotrophin; TrkA.

Figures
Products