Pharmacological inhibition of Receptor Protein Tyrosine Phosphatase ß/ζ (PTPRZ1) modulates behavioral responses to ethanol.
Neuropharmacology
; 137: 86-95, 2018 07 15.
Article
en En
| MEDLINE
| ID: mdl-29753117
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) ß/ζ (a.k.a. PTPRZ1, RPTPß, PTPζ), suggesting a potential role for this phosphatase in the regulation of alcohol effects. To determine if RPTPß/ζ regulates ethanol consumption, we treated mice with recently developed small-molecule inhibitors of RPTPß/ζ (MY10, MY33-3) before testing them for binge-like drinking using the drinking in the dark protocol. Mice treated with RPTPß/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 RPTPß/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 RPTPß/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 RPTPß/ζ modulates signaling pathways activated by alcohol and behavioral responses to this drug. The data support the hypothesis that RPTPß/ζ might be a novel target of pharmacotherapy for reducing excessive alcohol consumption.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Depresores del Sistema Nervioso Central
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Etanol
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Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores
/
Consumo Excesivo de Bebidas Alcohólicas
Tipo de estudio:
Guideline
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Neuropharmacology
Año:
2018
Tipo del documento:
Article
País de afiliación:
España