Increased alcohol-drinking induced by manipulations of mGlu5 phosphorylation within the bed nucleus of the stria terminalis

Rianne R. Campbell, Racquel D. Domingo, Amy R. Williams, Melissa G. Wroten, Hadley A. McGregor, Ryan S. Waltermire, Daniel I. Greentree, Scott P. Goulding, Andrew B. Thompson, Kaziya M. Lee, Sema G. Quadir, C. Leonardo Jimenez Chavez, Michal A. Coelho, Adam T. Gould, Georg Von Jonquieres, Matthias Klugmann, Paul F. Worley, Tod E. Kippin, Karen K. Szumlinski

Research output: Contribution to journalArticlepeer-review

Abstract

The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress, and glutamate transmission within this region has been implicated in the neurobiology of alcoholism. Herein, we used a combination of immunoblotting, neuropharmacological and transgenic procedures to investigate the role for metabotropic glutamate receptor 5 (mGlu5) signaling within the BNST in excessive drinking. We discovered that mGlu5 signaling in the BNST is linked to excessive alcohol consumption in a manner distinct from behavioral or neuropharmacological endophenotypes that have been previously implicated as triggers for heavy drinking. Our studies demonstrate that, in male mice, a history of chronic binge alcohol-drinking elevates BNST levels of the mGlu5-scaffolding protein Homer2 and activated extracellular signal-regulated kinase (ERK) in an adaptive response to limit alcohol consumption. Male and female transgenic mice expressing a point mutation of mGlu5 that cannot be phosphorylated by ERK exhibit excessive alcohol-drinking, despite greater behavioral signs of alcohol intoxication and reduced anxiety, and are insensitive to local manipulations of signaling in the BNST. These transgenic mice also show selective insensitivity to alcohol-aversion and increased novelty-seeking, which may be relevant to excessive drinking. Further, the insensitivity to alcohol-aversion exhibited by male mice can be mimicked by the local inhibition of ERK signaling within the BNST. Our findings elucidate a novel mGluR5-linked signaling state within BNST that plays a central and unanticipated role in excessive alcohol consumption.

Original languageEnglish (US)
Pages (from-to)2745-2761
Number of pages17
JournalJournal of Neuroscience
Volume39
Issue number14
DOIs
StatePublished - Apr 3 2019

Keywords

  • Anxiety
  • Bed nucleus of the stria terminalis
  • Binge-drinking
  • Extracellular signal-regulated kinase
  • Homer protein
  • Mglu5 receptor

ASJC Scopus subject areas

  • Neuroscience(all)

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