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tRNA epitranscriptomic alterations associated with opioid-induced reward-seeking and long-term opioid withdrawal in male mice.
Blaze, Jennifer; Browne, Caleb J; Futamura, Rita; Javidfar, Behnam; Zachariou, Venetia; Nestler, Eric J; Akbarian, Schahram.
Afiliação
  • Blaze J; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Jennifer.blaze@mssm.edu.
  • Browne CJ; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Jennifer.blaze@mssm.edu.
  • Futamura R; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Jennifer.blaze@mssm.edu.
  • Javidfar B; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Zachariou V; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Nestler EJ; Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
  • Akbarian S; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Neuropsychopharmacology ; 49(8): 1276-1284, 2024 Jul.
Article em En | MEDLINE | ID: mdl-38332016
ABSTRACT
DNA cytosine methylation has been documented as a potential epigenetic mechanism of transcriptional regulation underlying opioid use disorder. However, methylation of RNA cytosine residues, which would drive another level of biological influence as an epitranscriptomic mechanism of gene and protein regulation has not been studied in the context of addiction. Here, we probed whether chronic morphine exposure could alter tRNA cytosine methylation (m5C) and resulting expression levels in the medial prefrontal cortex (mPFC), a brain region crucial for reward processing and executive function that exhibits opioid-induced molecular restructuring. We identified dynamic changes in glycine tRNA (tRNAGlyGCC) cytosine methylation, corresponding to altered expression levels of this tRNA at multiple timepoints following 15 days of daily morphine. Additionally, a robust increase in methylation, coupled with decreased expression, was present after 30 days of withdrawal, suggesting that repeated opioid administration produces changes to the tRNA regulome long after discontinuation. Furthermore, forebrain-wide knockout of neuronal Nsun2, a tRNA methyltransferase, was associated with disruption of opioid conditioned place preference, and this effect was recapitulated by regional mPFC Nsun2 knockout. Taken together, these studies provide a foundational link between the regulation of tRNA cytosine methylation and opioid reward and highlight the tRNA machinery as a potential therapeutic target in addiction.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Recompensa / Síndrome de Abstinência a Substâncias / RNA de Transferência / Córtex Pré-Frontal / Camundongos Endogâmicos C57BL / Morfina Tipo de estudo: Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Recompensa / Síndrome de Abstinência a Substâncias / RNA de Transferência / Córtex Pré-Frontal / Camundongos Endogâmicos C57BL / Morfina Tipo de estudo: Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article