Erk-directed phosphorylation of mglu5 gates methamphetamine reward and reinforcement in mouse

Elissa K. Fultz, Sema G. Quadir, Douglas Martin, Daniel M. Flaherty, Paul F. Worley, Tod E. Kippin, Karen K. Szumlinski

Research output: Contribution to journalArticlepeer-review


Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule im-plicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring,-neutral, or-avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphory-lated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the re-ceptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-in-duced conditioned place-preference (MA-CPP), but is necessary for this drug’s reinforcing proper-ties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA.

Original languageEnglish (US)
Article number1473
Pages (from-to)1-21
Number of pages21
JournalInternational journal of molecular sciences
Issue number3
StatePublished - Feb 1 2021


  • Addiction
  • Metabotropic glutamate receptor 5
  • Methamphetamine
  • Place-conditioning
  • Reinforcement
  • Self-administra-tion
  • Vulnerability

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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