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Research Articles, Behavioral/Cognitive

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 and Karen K. Szumlinski
Journal of Neuroscience 8 February 2019, 1909-18; DOI: https://doi.org/10.1523/JNEUROSCI.1909-18.2018
Rianne R. Campbell
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Racquel D. Domingo
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Amy R. Williams
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Melissa G. Wroten
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Hadley A. McGregor
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Ryan S. Waltermire
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Daniel I. Greentree
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Scott P. Goulding
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Andrew B. Thompson
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Kaziya M. Lee
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Sema G. Quadir
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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C. Leonardo Jimenez Chavez
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Michal A. Coelho
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Adam T. Gould
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Georg von Jonquieres
Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia.
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Matthias Klugmann
Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia.
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Paul F. Worley
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.
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Tod E. Kippin
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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Karen K. Szumlinski
Department of Psychological and Brain Sciences, the Neuroscience Research Institute, Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-9660, U.S.A.
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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 employed 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.

Significance Statement

The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress and alcohol, and glutamate transmission within BNST is implicated in the neurobiology of alcoholism. The present study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase (ERK) within this brain region induces excessive alcohol-drinking,that reflects a selective insensitivity to the aversive properties of alcohol intoxication. These data indicate that a specific signaling state of mGlu5 within BNST plays a central and unanticipated role in excessive alcohol consumption.

Footnotes

  • The authors declare no competing financial interests.

  • We thank Andrew Lang and Rachel Turner for their assistance with the behavioral studies and Mackayla Class for her assistance with BACs. We also thank the National Institute on Drug Abuse for their generous donation of cocaine and Drs. Schwartz and Seeburg (University of Heidleberg, Germany) for their assistance in creating the Homer1 KO mouse. This work was supported by grants from the National Institute on Alcohol and Alcoholism (K.K.S.) and the National Institute on Drug Abuse (K.K.S., P.F.W., T.E.K.), as well as by funds from the Australian Research Council (M.K.).

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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
Journal of Neuroscience 8 February 2019, 1909-18; DOI: 10.1523/JNEUROSCI.1909-18.2018

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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
Journal of Neuroscience 8 February 2019, 1909-18; DOI: 10.1523/JNEUROSCI.1909-18.2018
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JNeurosci   Print ISSN: 0270-6474   Online ISSN: 1529-2401