Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP

Neuropharmacology. 2008 Sep;55(4):546-54. doi: 10.1016/j.neuropharm.2008.06.057. Epub 2008 Jul 4.

Abstract

Relapse to alcohol use after periods of abstinence is a hallmark behavioral pathology of alcoholism and a major clinical problem. Emerging evidence indicates that metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate relapse to alcohol-seeking behavior but the molecular mechanisms of this potential therapeutic effect remain unexplored. The extracellular signal-regulated kinase (ERK1/2) pathway is downstream of mGluR5 and has been implicated in addiction. We sought to determine if cue-induced reinstatement of alcohol-seeking behavior, and its reduction by an mGluR5 antagonist, is associated with changes in ERK1/2 activation in reward-related limbic brain regions. Selectively-bred alcohol-preferring (P) rats were trained to lever press on a concurrent schedule of alcohol (15% v/v) vs. water reinforcement. Following 9 days of extinction, rats were given an additional extinction trial or injected with the mGluR5 antagonist MPEP (0, 1, 3, or 10mg/kg) and tested for cue-induced reinstatement. Brains were removed 90-min later from the rats in the extinction and MPEP (0 or 10mg/kg) conditions for analysis of p-ERK1/2, total ERK1/2, and p-ERK5 immunoreactivity (IR). Cue-induced reinstatement of alcohol-seeking behavior was associated with a three to five-fold increase in p-ERK1/2 IR in the basolateral amygdala and nucleus accumbens shell. MPEP administration blocked both the relapse-like behavior and increase in p-ERK1/2 IR. p-ERK1/2 IR in the central amygdala and NAcb core was dissociated with the relapse-like behavior and the pharmacological effect of mGluR5 blockade. No changes in total ERK or p-ERK5 were observed. These results suggest that exposure to cues previously associated with alcohol self-administration is sufficient to produce concomitant increases in relapse-like behavior and ERK1/2 activation in specific limbic brain regions. Pharmacological compounds, such as mGluR5 antagonists, that reduce cue-induced ERK1/2 activation may be useful for treatment of relapse in alcoholics that is triggered by exposure to environmental events.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol-Related Disorders / psychology*
  • Alcohols / administration & dosage*
  • Animals
  • Behavior, Animal
  • Brain / anatomy & histology
  • Brain / drug effects
  • Brain / metabolism
  • Conditioning, Operant / drug effects*
  • Cues*
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Extinction, Psychological / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Male
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Pyridines / pharmacology*
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology
  • Self Administration / methods

Substances

  • Alcohols
  • Excitatory Amino Acid Antagonists
  • Grm5 protein, rat
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • 6-methyl-2-(phenylethynyl)pyridine
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 7