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Alcohol, Cell Membranes, and Signal Transduction in Brain pp 175–183Cite as

Alcohol: Effects on GABAA Receptor Function and Gene Expression

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Abstract

The GABA synapse is a site of action for a variety of centrally acting convulsant, anticonvulsant, depressant, and anxiolytic drugs (Barnard, 1988; Olsen and Tobin, 1990; Ticku, 1991). These drugs bind to one of several allosterically linked sites on the GABAA receptor complex and either enhance or inhibit GABAergic transmission. GABAA receptor is a member of the ligand-gated ion channel family of receptors (Schofield et al., 1987). There are numerous reports which indicate that ethanol affects the receptors belonging to this family. Several lines of behavioral, electrophysiological and biochemical functional evidences implicate an involvement of the GABA-benzodiazepine receptor system in the action of ethanol in the CNS (reviewed in Ticku, 1990; 1991; Buck and Harris, 1991). Ethanol potentiates GABA-induced 36Cl-flux in cultured embryonic spinal cord neurons (Mehta and Ticku, 1988, 1989), rat cerebral cortical synaptoneurosomes (Suzdak et al., 1986a) and microsacs (Allan and Harris, 1986, 1987). Chronic exposure to ethanol results in tolerance and physical dependence. The mechanism of these actions of ethanol, its tolerance, physical dependence and withdrawal have not been clearly established. Chronic exposure to ethanol might be leading to cellular adaptive changes in the central nervous system, which result in craving due to the requirement of ethanol for normal functioning, which is a physical dependence. This adaptive change in the excitability of neurons due to withdrawal of ethanol administration causes anxiety and seizures. However, which cellular changes lead to the development of tolerance, physical dependence, and withdrawal symptoms are not clear. Ethanol has a pharmacological profile very similar to benzodiazepines and barbiturates, and a partial inverse agonist of the benzodiazepine receptor, Ro15-4513 (ethyl - 8 - azido - 5, 6 - di hydro - 5 - methyl - 6 - oxo - 4H - imidazo [1, 5-α] - [1, 4]benzodiazepine-3-carboxyate) was reported to be a selective antagonist of the effects of pharmacologically relevant concentration of ethanol on GABA-gated chloride influx (Suzdak et al., 1986). Furthermore, behavioral studies have also demonstrated the ability of Ro15-4513 to antagonize some of the behavioral effects following acute administration of ethanol in animals (Suzdak et al., 1986; Ticku and Kulkarni, 1988). It is a known fact that ethanol withdrawal symptoms can be treated with benzodiazepines which potentiate GABAergic transmission. Also, the severity of withdrawal symptoms get enhanced by treatments which reduce GABAergic transmission e.g. Picrotoxin, as well as benzodiazepine inverse agonists. Thus, it is reasonable to assume that the molecular and cellular mechanisms underlying some of the behavioral effects of ethanol, including the development of tolerance and dependence, could be explained by understanding its unique interaction with the GABAA-benzodiazepine receptor complex.

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Authors and Affiliations

  1. Department of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78284-7764, USA

    Molina C. Mhatre & Maharaj K. Ticku

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  1. Molina C. Mhatre
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  2. Maharaj K. Ticku
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Editors and Affiliations

  1. University of Lund, Lund, Sweden

    Christer Alling

  2. The Ernest Gallo Clinic and Research Center, University of California, San Francisco, California, USA

    Ivan Diamond

  3. The University of Texas at Austin, Austin, Texas, USA

    Steven W. Leslie

  4. University of Missouri, Columbia, Missouri, USA

    Grace Y. Sun

  5. Veterans Affairs Medical Center, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA

    W. Gibson Wood

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© 1993 Springer Science+Business Media New York

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Mhatre, M.C., Ticku, M.K. (1993). Alcohol: Effects on GABAA Receptor Function and Gene Expression. In: Alling, C., Diamond, I., Leslie, S.W., Sun, G.Y., Wood, W.G. (eds) Alcohol, Cell Membranes, and Signal Transduction in Brain. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2470-0_16

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  • DOI: https://doi.org/10.1007/978-1-4615-2470-0_16

  • Publisher Name: Springer, Boston, MA

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  • Online ISBN: 978-1-4615-2470-0

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