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Alcohol Suppresses Tonic GABA A Receptor Currents in Cerebellar Granule Cells in the Prairie Vole: A Neural Signature of High‐Alcohol‐Consuming Genotypes
Author(s) -
Kaplan Joshua S.,
Mohr Claudia,
Hostetler Caroline M.,
Ryabinin Andrey E.,
Finn Deborah A.,
Rossi David J.
Publication year - 2016
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13136
Subject(s) - gabaa receptor , tonic (physiology) , cerebellum , chemistry , patch clamp , tetrodotoxin , gamma aminobutyric acid , endocrinology , neuroscience , medicine , biology , electrophysiology , pharmacology , biophysics , receptor , biochemistry
Background Evidence indicates that the cerebellum plays a role in genetic predilection to excessive alcohol (ethanol [EtOH]) consumption in rodents and humans, but the molecular mechanisms mediating such predilection are not understood. We recently determined that Et OH has opposite actions (enhancement or suppression) on tonic GABA A receptor ( GABA A R ) currents in cerebellar granule cells ( GC s) in low‐ and high‐Et OH ‐consuming rodents, respectively, and proposed that variation in GC tonic GABA A R current responses to Et OH contributes to genetic variation in Et OH consumption phenotype. Methods Voltage‐clamp recordings of GC s in acutely prepared slices of cerebellum were used to evaluate the effect of Et OH on GC tonic GABA A R currents in another high‐Et OH ‐consuming rodent, prairie voles ( PV s). Results EtOH (52 mM) suppressed the magnitude of the tonic GABA A R current in 57% of cells, had no effect in 38% of cells, and enhanced the tonic GABA A R current in 5% of cells. This result is similar to GC s from high‐Et OH ‐consuming C57 BL /6J (B6) mice, but it differs from the enhancement of tonic GABA A R currents by Et OH in low‐Et OH ‐consuming DBA /2J (D2) mice and Sprague Dawley ( SD ) rats. Et OH suppression of tonic GABA A R currents was not affected by the sodium channel blocker, tetrodotoxin (500 nM), and was independent of the frequency of phasic GABA A R ‐mediated currents, suggesting that suppression is mediated by postsynaptic actions on GABA A R s, rather than a reduction of GABA release. Finally, immunohistochemical analysis of neuronal nitric oxide synthase ( nNOS ; which can mediate Et OH enhancement of GABA release) demonstrated that nNOS expression in the GC layer of PV cerebellum was similar to the levels seen in B6 mice, both being significantly reduced relative to D2 mice and SD rats. Conclusions Combined, these data highlight the GC GABA A R response to Et OH in another species, the high‐Et OH ‐consuming PV , which correlates with Et OH consumption phenotype and further implicates the GC GABA A R system as a contributing mechanism to high Et OH consumption.