Journal
NATURE NEUROSCIENCE
Volume 16, Issue 12, Pages 1783-1793Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3559
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Funding
- National Institute of Neurological Disorders and Stroke [R0INS051561]
- National Institute on Alcohol Abuse and Alcoholism [R01AA012439]
- American Heart Association
- Research Foundation of Oregon [T32 AA007468, F31 AA022267]
- National Institute on Alcohol Abuse and Alcoholism
- Oregon Health and Science University Research Scholars Award
- Neuroscience Imaging Center at Oregon Health and Science University [P30NS061800]
- National Institute of Neurological Disorders and Stroke
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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 C57BU6 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.
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