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.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Kaplan
authors.forename: Claudia
authors.initials: C
authors.lastname: Mohr
authors.forename: David J
authors.initials: DJ
authors.lastname: Rossi
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018682:GABA Agents; D018756:GABA Antagonists; D011963:Receptors, GABA-A; D000431:Ethanol; D052248:Nitric Oxide Synthase Type I; D011493:Protein Kinase C