Regional variations in the effects of chronic ethanol administration on GABAA receptor expression: potential mechanisms

Gamma-aminobutyric acid type A (GABA(A)) receptors in brain adapt to chronic ethanol exposure via changes in receptor function and subunit expression. The present review summarizes currently available data regarding changes in GABA(A) receptor subunit mRNA and peptide expression. Data are presented from various different brain regions and the variations between specific brain regions used to draw conclusions about mechanisms that may underlie GABA(A) receptor adaptations during chronic ethanol exposure. In the whole cerebral cortex, chronic ethanol exposure leads to a reduction of GABA(A) receptor alpha1 subunit mRNA and peptide levels and a near equivalent increase in alpha4 subunit mRNA and peptide levels. This observation is the primary support for the hypothesis that altered receptor composition is a mechanism for GABA(A) receptor adaptation produced by chronic ethanol exposure. However, other brain regions do not display similar patterns of subunit changes. Moreover, subregions within cortex (prefrontal, cingulate, parietal, motor, and piriform) exhibit patterns of changes in subunit expression that differ from whole cortex. Therefore, regional differences in GABA(A) receptor subunit expression are evident following chronic ethanol administration, thus suggesting that multiple mechanisms contribute to the regulation of GABA(A) receptor expression. These mechanisms may include the involvement of other neurotransmitter systems, endogenous steroids and second or third messenger cross-talk.

[1]  R. Gruen,et al.  Alterations in GABAA receptor binding in the prefrontal cortex following exposure to chronic stress , 1995, Brain Research.

[2]  D. B. Matthews,et al.  Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol , 2000, The Journal of Neuroscience.

[3]  M. Ticku,et al.  Effect of chronic treatment of ethanol on benzodiazepine and picrotoxin sites on the GABA receptor complex in regions of the brain of the rat , 1986, Neuropharmacology.

[4]  J. Fritschy,et al.  Influence of gender on chronic ethanol-induced alterations in GABAA receptors in rats , 1998, Brain Research.

[5]  J. Sikela,et al.  Ethanol sensitivity of the GABAA receptor expressed in xenopus oocytes requires 8 amino acids contained in the γ2L subunit , 1991, Neuron.

[6]  R. Olsen,et al.  Chronic Intermittent Ethanol Treatment in Rats Increases GABAA Receptor α4‐Subunit Expression: Possible Relevance to Alcohol Dependence , 1997, Journal of neurochemistry.

[7]  A. Morrow,et al.  The Neurosteroid, 3α‐Hydroxy‐5α‐pregnan‐20‐one, Protects against Bicuculline‐Induced Seizures during Ethanol Withdrawal in Rats , 1995 .

[8]  J. Ballenger,et al.  Alcohol detoxification and withdrawal seizures: Clinical support for a kindling hypothesis , 1988, Biological Psychiatry.

[9]  E. Jones,et al.  Area and lamina-specific expression of GABAA receptor subunit mRNAs in monkey cerebral cortex. , 1997, Canadian journal of physiology and pharmacology.

[10]  G. Koob Neural Mechanisms of Drug Reinforcement a , 1992, Annals of the New York Academy of Sciences.

[11]  A. Morrow,et al.  Effects of chronic ethanol administration on [3H]zolpidem binding in rat brain. , 1994, European journal of pharmacology.

[12]  R. Roth,et al.  Regulation of the prefrontal cortical dopamine system by the neuroactive steroid 3a,21-dihydroxy-5a-pregnane-20-one , 1992, Brain Research.

[13]  M. Beauregard,et al.  Dopamine modulates the inhibition induced by GABA in rat cerebral cortex: an iontophoretic study. , 1991, European journal of pharmacology.

[14]  G. Biggio,et al.  Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Crane,et al.  Expression of the α 1, α 2 and α 3 isoforms of the GABAA receptor in human alcoholic brain , 1997, Brain Research.

[16]  G. Freund,et al.  Decrease of benzodiazepine receptors in frontal cortex of alcoholics. , 1988, Alcohol.

[17]  W. Sieghart,et al.  Differential Regulation of GABAA Receptor Gene Expression by Ethanol in the Rat Hippocampus Versus Cerebral Cortex , 1998, Journal of neurochemistry.

[18]  J. Bolz,et al.  Area-specific regulation of gamma-aminobutyric acid type A receptor subtypes by thalamic afferents in developing rat neocortex. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  F. Crews,et al.  Effects of ethanol on ion channels. , 1996, International review of neurobiology.

[20]  H. Kalluri,et al.  Up-regulation of NMDA receptor subunits in rat brain following chronic ethanol treatment. , 1998, Brain research. Molecular brain research.

[21]  R. Roth,et al.  Regionally specific alterations in the low-affinity GABAA receptor following perinatal exposure to diazepam , 1990, Brain Research.

[22]  P. Seeburg,et al.  Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology , 1989, Nature.

[23]  L. Volicer GABA levels and receptor binding after acute and chronic ethanol administration , 1979, Brain Research Bulletin.

[24]  X. Leinekugel,et al.  GABAA, NMDA and AMPA receptors: a developmentally regulated `ménage à trois' , 1997, Trends in Neurosciences.

[25]  R. Huganir,et al.  Selective clustering of glutamate and gamma-aminobutyric acid receptors opposite terminals releasing the corresponding neurotransmitters. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[26]  S H Snyder,et al.  GABA receptors are increased in brains of alcoholics , 1981, Annals of neurology.

[27]  C. Frye,et al.  Endogenous levels of 5 alpha-reduced progestins and androgens in fetal vs. adult rat brains. , 1999, Brain research. Developmental brain research.

[28]  M. Ticku,et al.  Prevalence of the GABAA receptor assemblies containing alpha1-subunit in the rat cerebellum and cerebral cortex as determined by immunoprecipitation: lack of modulation by chronic ethanol administration. , 1999, Brain research. Molecular brain research.

[29]  N. Goeders Cocaine differentially affects benzodiazepine receptors in discrete regions of the rat brain: persistence and potential mechanisms mediating these effects. , 1991, The Journal of pharmacology and experimental therapeutics.

[30]  Feng Chen,et al.  Distribution of GABAA receptors in the limbic system of alcohol-preferring and non-preferring rats: in situ hybridisation histochemistry and receptor autoradiography , 1998, Neurochemistry International.

[31]  J. Oehler,et al.  Influences of housing conditions and ethanol intake on binding characteristics of D2, 5-HT1A, and benzodiazepine receptors of rats , 1995, Pharmacology Biochemistry and Behavior.

[32]  W. Sieghart,et al.  Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. , 1995, Pharmacological reviews.

[33]  A. Morrow,et al.  Differential effects of chronic ethanol administration on GABAA receptor α1 and α6 subunit mRNA levels in rat cerebellum , 1992, Molecular and Cellular Neuroscience.

[34]  A. Morrow,et al.  Effects of progesterone or neuroactive steroid? , 1998, Nature.

[35]  C. J. Henrich,et al.  Chronic ethanol exposure increases levels of protein kinase C δ and ε and protein kinase C-mediated phosphorylation in cultured neural cells , 1991 .

[36]  J. Sikela,et al.  Chronic Ethanol Treatment Alters Brain Levels of γ‐Aminobutyric AcidA Receptor Subunit mRNAs: Relationship to Genetic Differences in Ethanol Withdrawal Seizure Severity , 1991, Journal of neurochemistry.

[37]  G. Breese,et al.  Molecular basis for regionally specific action of ethanol on gamma-aminobutyric acidA receptors: generalization to other ligand-gated ion channels. , 1993, The Journal of pharmacology and experimental therapeutics.

[38]  T. Dunwiddie,et al.  Ethanol enhances synaptically evoked GABAA receptor-mediated responses in cerebral cortical neurons in rat brain slices , 1992, Brain Research.

[39]  L. Snell,et al.  Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion. , 1996, Brain research. Molecular brain research.

[40]  J. Paysan,et al.  Activity‐Dependent Regulation of GABAA Receptors , 1999, Annals of the New York Academy of Sciences.

[41]  E. Nestler,et al.  Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system , 1995, Synapse.

[42]  J. Kril,et al.  Amino Acid Neurotransmitter Receptor Changes in Cerebral Cortex in Alcoholism: Effect of Cirrhosis of the Liver , 1992, Journal of neurochemistry.

[43]  M. Ticku,et al.  Chronic ethanol administration increases the binding of the benzodiazepine inverse agonist and alcohol antagonist [3H]RO15-4513 in rat brain. , 1988, European journal of pharmacology.

[44]  P. Seeburg,et al.  Structural and functional basis for GABAA receptor heterogeneity , 1988, Nature.

[45]  S. Paul,et al.  Chronic ethanol and pentobarbital administration in the rat: effects on GABAA receptor function and expression in brain. , 1990, Alcohol.

[46]  S. Tonegawa,et al.  Mutant mice lacking the gamma isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of gamma-aminobutyrate type A receptors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[47]  B. E. Collins,et al.  Brain neurosteroids during the mouse oestrous cycle , 1997, Brain Research.

[48]  W. Sieghart,et al.  Antibodies Specific for GABAA Receptor α Subunits Reveal that Chronic Alcohol Treatment Down‐Regulates α‐Subunit Expression in Rat Brain Regions , 1993 .

[49]  M. Hsu,et al.  Ethanol enhances muscarinic cholinergic neurotransmission in rat hippocampus in vitro , 1995, Brain Research.

[50]  D. B. Matthews,et al.  The role of GABAA receptors in the acute and chronic effects of ethanol , 1998, Psychopharmacology.

[51]  S. Paul,et al.  Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor alpha subunit mRNAs in the rat cerebral cortex. , 1991, Molecular pharmacology.

[52]  G. Breese,et al.  Distribution of [3H]zolpidem binding sites in relation to messenger RNA encoding the α1, β2 and γ2 subunits of GABAA receptors in rat brain , 1995, Neuroscience.

[53]  A. Morrow,et al.  Chronic ethanol consumption differentially alters the expression of gamma-aminobutyric acidA receptor subunit mRNAs in rat cerebral cortex: competitive, quantitative reverse transcriptase-polymerase chain reaction analysis. , 1995, Molecular pharmacology.

[54]  P B Hoffer,et al.  Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[55]  J. Seamans,et al.  Electrophysiological and morphological properties of layers V-VI principal pyramidal cells in rat prefrontal cortex in vitro , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[56]  S. Heinemann,et al.  Rapid Communication Chronic Ingestion of Ethanol Up‐Regulates NMDAR1 Receptor Subunit Immunoreactivity in Rat Hippocampus , 1994, Journal of neurochemistry.

[57]  A. Guidotti,et al.  Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[58]  J. Fritschy,et al.  GABAA‐receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits , 1995, The Journal of comparative neurology.

[59]  E. Sellers,et al.  Alcohol intoxication and withdrawal. , 1976, The New England journal of medicine.

[60]  M. Ticku,et al.  Chronic GABA treatment downregulates the GABA A receptor α2 and α3 subunit mRNAS as well as polypeptide expression in primary cultured cerebral cortical neurons , 1994 .

[61]  I. Diamond,et al.  The Role of Protein Kinase C in Cellular Tolerance to Ethanol* , 1996, The Journal of Biological Chemistry.

[62]  M. Ticku,et al.  Chronic ethanol administration alters gamma-aminobutyric acidA receptor gene expression. , 1992, Molecular pharmacology.

[63]  Eric J. Nestler,et al.  Chronic Ethanol Administration Regulates the Expression of GABAA Receptor α1 and α5 Subunits in the Ventral Tegmental Area and Hippocampus , 1997 .

[64]  D. B. Matthews,et al.  Chronic Blockade of N‐Methyl‐D‐Aspartate Receptors Alters γ‐Aminobutyric Acid Type A Receptor Peptide Expression and Function in the Rat , 2000, Journal of neurochemistry.

[65]  M. Ticku,et al.  Alterations in γ‐Aminobutyric Acid Receptor Sensitivity Following Acute and Chronic Ethanol Treatments , 1980, Journal of neurochemistry.

[66]  W. Sieghart,et al.  Bidirectional Alterations of GABAA Receptor Subunit Peptide Levels in Rat Cortex During Chronic Ethanol Consumption and Withdrawal , 1997, Journal of neurochemistry.

[67]  P. H. Moore,et al.  Radioimmunoassay of 3α-hydroxy-5α-pregnan-20-one in rat and human plasma , 1990, Steroids.