MGluR5 activity is required for the induction of ethanol behavioral sensitization and associated changes in ERK MAP kinase phosphorylation in the nucleus accumbens shell and lateral habenula

Behav Brain Res. 2019 Jul 23:367:19-27. doi: 10.1016/j.bbr.2019.03.038. Epub 2019 Mar 23.

Abstract

Metabotropic glutamate receptor subtype-5 (mGluR5) activity regulates a variety of behavioral pathologies associated with alcohol addiction. The main goal of this study was to determine if mGluR5 regulates the induction of ethanol-induced locomotor sensitization, which is a model of experience-dependent plasticity following initial exposure to drugs of abuse. The extracellular signal-regulated kinase (ERK1/2) pathway is downstream of mGluR5 and implicated in alcohol addiction; however, its role in sensitization remains unexplored. We sought to determine if mGluR5-mediated changes in ethanol-induced sensitization are associated with changes in ERK1/2 phosphorylation (pERK1/2) in specific brain regions. Adult male DBA/2 J mice were tested for acute locomotor response to ethanol (0 or 2 g/kg, IP) followed by a 9-day induction period in which the mGluR5 antagonist MPEP (0 or 30 mg/kg, IP) was administered prior to ethanol (0 or 2.5 g/kg, IP). One day later, ethanol (2 g/kg) produced a robust within- and between-group increase in locomotor activity, indicating sensitization in mice that received MPEP (0 mg/kg) during induction. MPEP (30 mg/kg) treatment during induction resulted in locomotor response to ethanol (2 g/kg) challenge that was equivalent to an acute response, indicating full blockade of sensitization. Sensitization was associated with increased pERK1/2 immunoreactivity (IR) in nucleus accumbens shell (AcbSh) and a reduction in lateral habenula (LHb), both of which were blocked by MPEP treatment during induction. Sensitization was also associated with mGluR5-independent increases in pERK1/2 IR in the nucleus accumbens core and decreases in the dentate gyrus and lateral septum. These data indicate that mGluR5 activity is required for the induction of ethanol locomotor sensitization and associated changes in ERK1/2 phosphorylation in the AcbSh and LHb, which raises the hypothesis that mGluR5-mediated cell signaling in these brain regions may mediate the induction of sensitization. Elucidating mechanisms of sensitization may increase understanding of how ethanol hijacks behavioral functions during the development of addiction.

Keywords: Alcohol; ERK; Ethanol; Glutamate; Lateral habenula; Nucleus accumbens; Sensitization; mGluR5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System Depressants / pharmacology*
  • Central Nervous System Sensitization* / drug effects
  • Ethanol / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extracellular Signal-Regulated MAP Kinases* / drug effects
  • Extracellular Signal-Regulated MAP Kinases* / metabolism
  • Habenula* / drug effects
  • Habenula* / metabolism
  • Male
  • Mice
  • Mice, Inbred DBA
  • Nucleus Accumbens* / drug effects
  • Nucleus Accumbens* / metabolism
  • Phosphorylation / drug effects
  • Pyridines / pharmacology
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Signal Transduction* / drug effects

Substances

  • Central Nervous System Depressants
  • Excitatory Amino Acid Antagonists
  • Grm5 protein, mouse
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Ethanol
  • 6-methyl-2-(phenylethynyl)pyridine
  • Extracellular Signal-Regulated MAP Kinases