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The γ-Aminobutyric Acid A (GABAA) Receptor Complex and Hepatic Encephalopathy: Some Recent Advances

E. Anthony Jones, MD; Phil Skolnick, PhD; Sergio H. Gammal, MD; Anthony S. Basile, PhD; and Kevin D. Mullen, MB
[+] Article and Author Information

Grant Support: Dr. Gammal was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Escola Paulista de Mediana, Sao Paulo, Brazil. Dr. Mullen was supported by the Cuyahoga Hospital Foundation, Cleveland, Ohio, and Case Western Reserve University, Cleveland, Ohio (biomedical research support grant no. RR-05410-26).

Requests for Reprints: E. Anthony Jones, MD, Liver Unit, Building 10, Room 4D52, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.

Current Author Addresses: Drs. Jones and Gammal: Liver Unit; Drs. Skolnick and Basile, Laboratory of Neuroscience; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.

Dr. Mullen: Department of Internal Medicine, Gastroenterology Division, Cleveland Metropolitan General Hospital, Case Western Reserve University, Cleveland, OH 44109.


Ann Intern Med. 1989;110(7):532-546. doi:10.7326/0003-4819-110-7-532
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This excerpt has been provided in the absence of an abstract.

Increased neural inhibition appears to be an important component of the syndrome of hepatic encephalopathy. The pathways subserved by the γ-aminobutyric acid (GABA)-benzodiazepine receptor complex are the principal inhibitory systems in the mammalian brain. Hyperpolarization of neural membranes is accomplished by an increase in transmembrane chloride flux through a GABA-gated chloride channel in the complex. The opening of the chloride channel is induced by the binding of GABA to its receptors, and it is potentiated by barbiturates or benzodiazepines that act at distinct recognition sites on the complex. Involvement of the GABA neurotransmitter system in hepatic encephalopathy is suggested by several findings in animal models of fulminant hepatic failure. For example, hepatic encephalopathy resembles encephalopathies induced by drugs (including benzodiazepines) that potentiate GABAergic neurotransmission. In addition, neurons from animals with hepatic encephalopathy show increased sensitivity to benzodiazepine and GABA receptor agonists. Moreover, these neurons are excited by benzodiazepine receptor antagonists at concentrations that do not affect control neurons. Also, elevated levels of a substance that inhibits radioligand binding to benzodiazepine receptors have been found in cerebrospinal fluid from animals with hepatic encephalopathy. Furthermore, manifestations of hepatic encephalopathy can be ameliorated by benzodiazepine receptor antagonists. The relevance of these findings to hepatic encephalopathy in human beings is supported by clinical observations showing that a benzodiazepine receptor antagonist can lessen the degree of hepatic encephalopathy. These findings suggest that an endogenous substance with benzodiazepine-like properties contributes to the neuropsychiatric manifestations of hepatic encephalopathy by augmenting GABAergic neurotransmission.

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