Knockin mice with ethanol-insensitive α1-containing γ-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol

David F. Werner, Yuri A. Blednov, Olusegun J. Ariwodola, Yuval Silberman, Exazevia Logan, Raymond B. Berry, Cecilia M. Borghese, Douglas B. Matthews, Jeffrey L. Weiner, Neil L. Harrison, R. Adron Harris, Gregg E. Homanics

Research output: Contribution to journalArticle

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Abstract

Despite the pervasiveness of alcohol (ethanol) use, it is unclear how the multiple molecular targets for ethanol contribute to its many behavioral effects. The function of GABA type A receptors (GABAA-Rs) is altered by ethanol, but there are multiple subtypes of these receptors, and thus far, individual subunits have not been definitively linked with specific behavioral actions. The α1 subunit of the GABAA-R is the most abundant α subunit in the brain, and the goal of this study was to determine the role of receptors containing this subunit in alcohol action. We designed an α1 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity and constructed knockin mice containing this mutant subunit. Hippocampal slice recordings from these mice indicated that the mutant receptors were less sensitive to ethanol's potentiating effects. Behaviorally, we observed that mutant mice recovered more quickly from the motor-impairing effects of ethanol and etomidate, but not pentobarbital, and showed increased anxiolytic effects of ethanol. No differences were observed in ethanol-induced hypnosis, locomotor stimulation, cognitive impairment, or in ethanol preference and consumption. Overall, these studies demonstrate that the postsynaptic effects of ethanol at GABAergic synapses containing the α1 subunit are important for specific ethanol-induced behavioral effects.

Original languageEnglish (US)
Pages (from-to)219-227
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume319
Issue number1
DOIs
StatePublished - Oct 2 2006

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Aminobutyrates
Ethanol
Alcohols
Etomidate
Hypnosis
Anti-Anxiety Agents
Pentobarbital
GABA-A Receptors
Histidine
Leucine
Alanine
Synapses
gamma-Aminobutyric Acid
Serine

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Werner, David F. ; Blednov, Yuri A. ; Ariwodola, Olusegun J. ; Silberman, Yuval ; Logan, Exazevia ; Berry, Raymond B. ; Borghese, Cecilia M. ; Matthews, Douglas B. ; Weiner, Jeffrey L. ; Harrison, Neil L. ; Harris, R. Adron ; Homanics, Gregg E. / Knockin mice with ethanol-insensitive α1-containing γ-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 319, No. 1. pp. 219-227.
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abstract = "Despite the pervasiveness of alcohol (ethanol) use, it is unclear how the multiple molecular targets for ethanol contribute to its many behavioral effects. The function of GABA type A receptors (GABAA-Rs) is altered by ethanol, but there are multiple subtypes of these receptors, and thus far, individual subunits have not been definitively linked with specific behavioral actions. The α1 subunit of the GABAA-R is the most abundant α subunit in the brain, and the goal of this study was to determine the role of receptors containing this subunit in alcohol action. We designed an α1 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity and constructed knockin mice containing this mutant subunit. Hippocampal slice recordings from these mice indicated that the mutant receptors were less sensitive to ethanol's potentiating effects. Behaviorally, we observed that mutant mice recovered more quickly from the motor-impairing effects of ethanol and etomidate, but not pentobarbital, and showed increased anxiolytic effects of ethanol. No differences were observed in ethanol-induced hypnosis, locomotor stimulation, cognitive impairment, or in ethanol preference and consumption. Overall, these studies demonstrate that the postsynaptic effects of ethanol at GABAergic synapses containing the α1 subunit are important for specific ethanol-induced behavioral effects.",
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Werner, DF, Blednov, YA, Ariwodola, OJ, Silberman, Y, Logan, E, Berry, RB, Borghese, CM, Matthews, DB, Weiner, JL, Harrison, NL, Harris, RA & Homanics, GE 2006, 'Knockin mice with ethanol-insensitive α1-containing γ-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol', Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 1, pp. 219-227. https://doi.org/10.1124/jpet.106.106161

Knockin mice with ethanol-insensitive α1-containing γ-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol. / Werner, David F.; Blednov, Yuri A.; Ariwodola, Olusegun J.; Silberman, Yuval; Logan, Exazevia; Berry, Raymond B.; Borghese, Cecilia M.; Matthews, Douglas B.; Weiner, Jeffrey L.; Harrison, Neil L.; Harris, R. Adron; Homanics, Gregg E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 319, No. 1, 02.10.2006, p. 219-227.

Research output: Contribution to journalArticle

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T1 - Knockin mice with ethanol-insensitive α1-containing γ-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol

AU - Werner, David F.

AU - Blednov, Yuri A.

AU - Ariwodola, Olusegun J.

AU - Silberman, Yuval

AU - Logan, Exazevia

AU - Berry, Raymond B.

AU - Borghese, Cecilia M.

AU - Matthews, Douglas B.

AU - Weiner, Jeffrey L.

AU - Harrison, Neil L.

AU - Harris, R. Adron

AU - Homanics, Gregg E.

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