Alcohol Suppresses Tonic GABAA Receptor Currents in Cerebellar Granule Cells in the Prairie Vole: A Neural Signature of High-Alcohol-Consuming Genotypes

Joshua S. Kaplan, Claudia Mohr, Caroline M. Hostetler, Andrey Ryabinin, Deborah (Deb) Finn, David J. Rossi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 EtOH has opposite actions (enhancement or suppression) on tonic GABAA receptor (GABAAR) currents in cerebellar granule cells (GCs) in low- and high-EtOH-consuming rodents, respectively, and proposed that variation in GC tonic GABAAR current responses to EtOH contributes to genetic variation in EtOH consumption phenotype. Methods: Voltage-clamp recordings of GCs in acutely prepared slices of cerebellum were used to evaluate the effect of EtOH on GC tonic GABAAR currents in another high-EtOH-consuming rodent, prairie voles (PVs). Results: EtOH (52 mM) suppressed the magnitude of the tonic GABAAR current in 57% of cells, had no effect in 38% of cells, and enhanced the tonic GABAAR current in 5% of cells. This result is similar to GCs from high-EtOH-consuming C57BL/6J (B6) mice, but it differs from the enhancement of tonic GABAAR currents by EtOH in low-EtOH-consuming DBA/2J (D2) mice and Sprague Dawley (SD) rats. EtOH suppression of tonic GABAAR currents was not affected by the sodium channel blocker, tetrodotoxin (500 nM), and was independent of the frequency of phasic GABAAR-mediated currents, suggesting that suppression is mediated by postsynaptic actions on GABAARs, rather than a reduction of GABA release. Finally, immunohistochemical analysis of neuronal nitric oxide synthase (nNOS; which can mediate EtOH 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 GABAAR response to EtOH in another species, the high-EtOH-consuming PV, which correlates with EtOH consumption phenotype and further implicates the GC GABAAR system as a contributing mechanism to high EtOH consumption.

Original languageEnglish (US)
Pages (from-to)1617-1626
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Volume40
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Arvicolinae
GABA-A Receptors
Genotype
Alcohols
Cerebellum
Rodentia
Inbred DBA Mouse
gamma-Aminobutyric Acid
Rats
Sprague Dawley Rats
Grassland
Sodium Channel Blockers
Nitric Oxide Synthase Type I
Phenotype
Tetrodotoxin
Clamping devices
Ethanol

Keywords

  • Alcohol Use Disorder
  • Cerebellum
  • GABA
  • Genetic Predilection
  • Nitric Oxide

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Alcohol Suppresses Tonic GABAA Receptor Currents in Cerebellar Granule Cells in the Prairie Vole : A Neural Signature of High-Alcohol-Consuming Genotypes. / Kaplan, Joshua S.; Mohr, Claudia; Hostetler, Caroline M.; Ryabinin, Andrey; Finn, Deborah (Deb); Rossi, David J.

In: Alcoholism: Clinical and Experimental Research, Vol. 40, No. 8, 01.08.2016, p. 1617-1626.

Research output: Contribution to journalArticle

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abstract = "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 EtOH has opposite actions (enhancement or suppression) on tonic GABAA receptor (GABAAR) currents in cerebellar granule cells (GCs) in low- and high-EtOH-consuming rodents, respectively, and proposed that variation in GC tonic GABAAR current responses to EtOH contributes to genetic variation in EtOH consumption phenotype. Methods: Voltage-clamp recordings of GCs in acutely prepared slices of cerebellum were used to evaluate the effect of EtOH on GC tonic GABAAR currents in another high-EtOH-consuming rodent, prairie voles (PVs). Results: EtOH (52 mM) suppressed the magnitude of the tonic GABAAR current in 57{\%} of cells, had no effect in 38{\%} of cells, and enhanced the tonic GABAAR current in 5{\%} of cells. This result is similar to GCs from high-EtOH-consuming C57BL/6J (B6) mice, but it differs from the enhancement of tonic GABAAR currents by EtOH in low-EtOH-consuming DBA/2J (D2) mice and Sprague Dawley (SD) rats. EtOH suppression of tonic GABAAR currents was not affected by the sodium channel blocker, tetrodotoxin (500 nM), and was independent of the frequency of phasic GABAAR-mediated currents, suggesting that suppression is mediated by postsynaptic actions on GABAARs, rather than a reduction of GABA release. Finally, immunohistochemical analysis of neuronal nitric oxide synthase (nNOS; which can mediate EtOH 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 GABAAR response to EtOH in another species, the high-EtOH-consuming PV, which correlates with EtOH consumption phenotype and further implicates the GC GABAAR system as a contributing mechanism to high EtOH consumption.",
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T2 - A Neural Signature of High-Alcohol-Consuming Genotypes

AU - Kaplan, Joshua S.

AU - Mohr, Claudia

AU - Hostetler, Caroline M.

AU - Ryabinin, Andrey

AU - Finn, Deborah (Deb)

AU - Rossi, David J.

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N2 - 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 EtOH has opposite actions (enhancement or suppression) on tonic GABAA receptor (GABAAR) currents in cerebellar granule cells (GCs) in low- and high-EtOH-consuming rodents, respectively, and proposed that variation in GC tonic GABAAR current responses to EtOH contributes to genetic variation in EtOH consumption phenotype. Methods: Voltage-clamp recordings of GCs in acutely prepared slices of cerebellum were used to evaluate the effect of EtOH on GC tonic GABAAR currents in another high-EtOH-consuming rodent, prairie voles (PVs). Results: EtOH (52 mM) suppressed the magnitude of the tonic GABAAR current in 57% of cells, had no effect in 38% of cells, and enhanced the tonic GABAAR current in 5% of cells. This result is similar to GCs from high-EtOH-consuming C57BL/6J (B6) mice, but it differs from the enhancement of tonic GABAAR currents by EtOH in low-EtOH-consuming DBA/2J (D2) mice and Sprague Dawley (SD) rats. EtOH suppression of tonic GABAAR currents was not affected by the sodium channel blocker, tetrodotoxin (500 nM), and was independent of the frequency of phasic GABAAR-mediated currents, suggesting that suppression is mediated by postsynaptic actions on GABAARs, rather than a reduction of GABA release. Finally, immunohistochemical analysis of neuronal nitric oxide synthase (nNOS; which can mediate EtOH 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 GABAAR response to EtOH in another species, the high-EtOH-consuming PV, which correlates with EtOH consumption phenotype and further implicates the GC GABAAR system as a contributing mechanism to high EtOH consumption.

AB - 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 EtOH has opposite actions (enhancement or suppression) on tonic GABAA receptor (GABAAR) currents in cerebellar granule cells (GCs) in low- and high-EtOH-consuming rodents, respectively, and proposed that variation in GC tonic GABAAR current responses to EtOH contributes to genetic variation in EtOH consumption phenotype. Methods: Voltage-clamp recordings of GCs in acutely prepared slices of cerebellum were used to evaluate the effect of EtOH on GC tonic GABAAR currents in another high-EtOH-consuming rodent, prairie voles (PVs). Results: EtOH (52 mM) suppressed the magnitude of the tonic GABAAR current in 57% of cells, had no effect in 38% of cells, and enhanced the tonic GABAAR current in 5% of cells. This result is similar to GCs from high-EtOH-consuming C57BL/6J (B6) mice, but it differs from the enhancement of tonic GABAAR currents by EtOH in low-EtOH-consuming DBA/2J (D2) mice and Sprague Dawley (SD) rats. EtOH suppression of tonic GABAAR currents was not affected by the sodium channel blocker, tetrodotoxin (500 nM), and was independent of the frequency of phasic GABAAR-mediated currents, suggesting that suppression is mediated by postsynaptic actions on GABAARs, rather than a reduction of GABA release. Finally, immunohistochemical analysis of neuronal nitric oxide synthase (nNOS; which can mediate EtOH 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 GABAAR response to EtOH in another species, the high-EtOH-consuming PV, which correlates with EtOH consumption phenotype and further implicates the GC GABAAR system as a contributing mechanism to high EtOH consumption.

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