Elsevier

Life Sciences

Volume 39, Issue 21, 24 November 1986, Pages 2005-2015
Life Sciences

Gamma-aminobutyric acid and alcohol actions: Neurochemical studies of long sleep and short sleep mice

https://doi.org/10.1016/0024-3205(86)90324-3Get rights and content

Abstract

Effects of ethanol and pentobarbital on the GABA receptor-chloride channel complex were evaluated in mice selected for differential sensitivity to the hypnotic effects of ethanol (long sleep and short sleep lines). 36Cl influx, [35S]t-butylbicyclophosphorothionate (TBPS) and [3H]muscimol binding were measured in a membrane vesicle suspension (microsacs) from cerebellum or forebrain. Muscimol was found to be a more potent stimulator of 36Cl flux in the LS cerebellum, as compared to the SS cerebellum, but a similar maximal level of uptake was achieved in the two lines. Muscimol displaced [35S]TBPS (a ligand for the convulsant site) from cerebellar microsacs, and LS mice were also more sensitive than SS mice to this action of muscimol. However, the number or affinity of high affinity [3H]muscimol binding sites did not differ between the lines. Physiologically relevant concentrations of ethanol (15–50 mM) potentiated muscimol stimulation of 36Cl uptake in LS cerebellum but had no effect in SS cerebellum. Ethanol failed to alter stimulated chloride flux hippocampal microsacs from either line. Both the LS and SS lines responded similarly to pentobarbital potentiation of muscimol stimulated chloride uptake regardless of brain region. The demonstrated difference between the LS and SS mice in muscimol stimulated chloride uptake as well as in muscimol displacement of [35S]TBPS binding offers a biochemical explanation for the line differences in behavioral responses to GABAergic agents. Moreover, the findings suggest that genetic differences in ethanol hypnosis are related to differences in the sensitivity of GABA-operated chloride channels to ethanol.

References (29)

  • M.K. Ticku et al.

    Pharmacol. Biochem. Behav.

    (1983)
  • M.S. Dar et al.

    Pharmacol. Biochem. Behav.

    (1985)
  • A. Martz et al.

    Eur. J. Pharmacol.

    (1983)
  • M.K. Ticku et al.

    Pharmacol. Biochem. Behav.

    (1984)
  • K. Krnjevic

    Physiol. Review.

    (1974)
  • R.A. Harris et al.

    Science

    (1985)
  • R.A. Davidoff

    Arch. Neurol.

    (1973)
  • N.R. Banna

    Experientia

    (1969)
  • R. Davidson et al.

    J. Physiol.

    (1972)
  • R.F. Squires et al.

    Mol. Pharmacol.

    (1983)
  • M.K. Ticku et al.

    J. Neurochem.

    (1980)
  • D.A. Greenberg et al.

    J. Neurochem.

    (1984)
  • J.M. Hakkinen et al.

    J. Neurochem.

    (1976)
  • G.D. Frye et al.

    J. Pharmacol. Exp. Ther.

    (1982)
  • Cited by (249)

    • Hippocampal circuits

      2022, Neurocircuitry of Addiction
    • FACTORS CONTRIBUTING TO THE ESCALATION OF ALCOHOL CONSUMPTION

      2022, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Increased ethanol intoxication is observed in male and female long-sleep mice and also in mice with reduced levels of protein kinase C (Harris et al., 1995). Long-sleep mice have an increased latency to regain the righting reflex following acute ethanol injections, and elevated ethanol induced Cl- uptake (Allan and Harris, 1986). Indeed, many of the top candidate genes implicated in AUD code for particular GABAA receptor subunits, including the α2, α6 and γ2 subunits ((Li et al., 2014); and see review by Trudell et al. (2014)).

    • Alcohol: Neurobiology of Addiction

      2021, Alcohol: Neurobiology of Addiction
    • Ethanol's Action Mechanisms in the Brain: From Lipid General Alterations to Specific Protein Receptor Binding

      2017, Addictive Substances and Neurological Disease: Alcohol, Tobacco, Caffeine, and Drugs of Abuse in Everyday Lifestyles
    • Extrasynaptic GABA<inf>A</inf> Receptors and Alcohol

      2014, Neurobiology of Alcohol Dependence
    View all citing articles on Scopus
    View full text