Opposite actions of alcohol on tonic GABA A receptor currents mediated by nNOS and PKC activity

Joshua S. Kaplan; Claudia Mohr; David J. Rossi

doi:10.1038/nn.3559

Opposite actions of alcohol on tonic GABA A receptor currents mediated by nNOS and PKC activity

Joshua S. Kaplan
, Claudia Mohr
, David J. Rossi

Neurology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

The molecular mechanisms that mediate genetic variability in response to alcohol are unclear. We found that alcohol had opposite actions (enhancement or suppression) on GABA A receptor (GABA A R) inhibition in granule cells from the cerebellum of behaviorally sensitive, low alcohol-consuming Sprague-Dawley rats and DBA/2 mice and behaviorally insensitive, high alcohol-consuming C57BL/6 mice, respectively. The effect of alcohol on granule cell GABA A R inhibition was determined by a balance between two opposing effects: enhanced presynaptic vesicular release of GABA via alcohol inhibition of nitric oxide synthase (NOS) and a direct suppression of the activity of postsynaptic GABA A Rs. The balance of these two processes was determined by differential expression of neuronal NOS (nNOS) and postsynaptic PKC activity, both of which varied across the rodent genotypes. These findings identify opposing molecular processes that differentially control the magnitude and polarity of GABA A R responses to alcohol across rodent genotypes.

Original language	English (US)
Pages (from-to)	1783-1793
Number of pages	11
Journal	Nature Neuroscience
Volume	16
Issue number	12
DOIs	https://doi.org/10.1038/nn.3559
State	Published - 2013

Funding

We thank J. Crabbe, D. Finn and K. Wiren (Oregon Health and Science University) for discussions about the research and D. Attwell (University College London) for comments on the manuscript. This study was supported by National Institute of Neurological Disorders and Stroke grant R01NS051561, National Institute on Alcohol Abuse and Alcoholism grant R01AA012439, an American Heart Association Grant in Aid, and a Medical Research Foundation of Oregon grant to D.J.R., training grants T32 AA007468 and F31 AA022267 from the National Institute on Alcohol Abuse and Alcoholism, and an Oregon Health and Science University Research Scholars Award to J.S.K., and the Neuroscience Imaging Center at Oregon Health and Science University grant P30NS061800 from the National Institute of Neurological Disorders and Stroke.

Funders	Funder number
Oregon Medical Research Foundation	T32 AA007468, F31 AA022267
Neuroscience Imaging Center
National Institute of Alcohol Abuse and Alcoholism	F31AA022267, R01AA012439
National Institute of Neurological Disorders and Stroke	R01NS051561, P30NS061800
American Heart Association/American Stroke Association
Oregon State University/Oregon Health and Science University

ASJC Scopus subject areas

General Neuroscience

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title = "Opposite actions of alcohol on tonic GABA A receptor currents mediated by nNOS and PKC activity",

abstract = "The molecular mechanisms that mediate genetic variability in response to alcohol are unclear. We found that alcohol had opposite actions (enhancement or suppression) on GABA A receptor (GABA A R) inhibition in granule cells from the cerebellum of behaviorally sensitive, low alcohol-consuming Sprague-Dawley rats and DBA/2 mice and behaviorally insensitive, high alcohol-consuming C57BL/6 mice, respectively. The effect of alcohol on granule cell GABA A R inhibition was determined by a balance between two opposing effects: enhanced presynaptic vesicular release of GABA via alcohol inhibition of nitric oxide synthase (NOS) and a direct suppression of the activity of postsynaptic GABA A Rs. The balance of these two processes was determined by differential expression of neuronal NOS (nNOS) and postsynaptic PKC activity, both of which varied across the rodent genotypes. These findings identify opposing molecular processes that differentially control the magnitude and polarity of GABA A R responses to alcohol across rodent genotypes.",

author = "Kaplan, \{Joshua S.\} and Claudia Mohr and Rossi, \{David J.\}",

note = "Funding Information: We thank J. Crabbe, D. Finn and K. Wiren (Oregon Health and Science University) for discussions about the research and D. Attwell (University College London) for comments on the manuscript. This study was supported by National Institute of Neurological Disorders and Stroke grant R01NS051561, National Institute on Alcohol Abuse and Alcoholism grant R01AA012439, an American Heart Association Grant in Aid, and a Medical Research Foundation of Oregon grant to D.J.R., training grants T32 AA007468 and F31 AA022267 from the National Institute on Alcohol Abuse and Alcoholism, and an Oregon Health and Science University Research Scholars Award to J.S.K., and the Neuroscience Imaging Center at Oregon Health and Science University grant P30NS061800 from the National Institute of Neurological Disorders and Stroke.",

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Opposite actions of alcohol on tonic GABA A receptor currents mediated by nNOS and PKC activity

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