Increased Alcohol-Drinking Induced by Manipulations of mGlu5 Phosphorylation within the Bed Nucleus of the Stria Terminalis
| Autor: | Tod E. Kippin, Karen K. Szumlinski, Ryan S. Waltermire, Amy R. Williams, Michal A. Coelho, Kaziya M. Lee, Racquel D. Domingo, Rianne R. Campbell, Matthias Klugmann, Andrew B. Thompson, Adam T. Gould, Melissa G. Wroten, Paul F. Worley, Hadley A. McGregor, Sema G. Quadir, C. Leonardo Jimenez Chavez, Daniel I. Greentree, Scott P. Goulding, Georg von Jonquieres |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
Male Underage Drinking Inbred C57BL Cardiovascular Medical and Health Sciences Transgenic Oral and gastrointestinal Substance Misuse Alcohol Use and Health Mice 0302 clinical medicine Alcohol intoxication Phosphorylation Receptor extracellular signal-regulated kinase Research Articles Pediatric Mice Knockout 0303 health sciences Homer protein Metabotropic glutamate receptor 5 General Neuroscience Glutamate receptor anxiety Metabotropic Glutamate 5 Stroke Alcoholism Female medicine.medical_specialty binge-drinking Alcohol Drinking Transgene Knockout Receptor Metabotropic Glutamate 5 Binge drinking Mice Transgenic Biology Basic Behavioral and Social Science 03 medical and health sciences Internal medicine bed nucleus of the stria terminalis Behavioral and Social Science medicine Animals 030304 developmental biology Neurology & Neurosurgery Psychology and Cognitive Sciences Neurosciences medicine.disease Brain Disorders Mice Inbred C57BL Stria terminalis Endocrinology Good Health and Well Being mGlu5 receptor Septal Nuclei 030217 neurology & neurosurgery |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience, vol 39, iss 14 |
| Popis: | 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.SIGNIFICANCE STATEMENTThe 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 within this brain region induces excessive alcohol-drinking, which 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. |
| Databáze: | OpenAIRE |
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