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The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

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Abstract

The past decade has brought many advances in our understanding of GABAA receptor-mediated ethanol action in the central nervous system. We now know that specific GABAA receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABAA receptors promoting increases in GABA sensitivity. Ethanol’s effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABAA receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.

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References

  • Abi-Dargham A, Krystal JH, Anjilvel S, Scanley BE, Zoghbi S, Baldwin RM, Rajeevan N, Ellis S, Petrakis IL, Seibyl JP, Charney DS, Laruelle M, Innis RB (1998) Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil. Am J Psychiatry 155:1550–1555

    PubMed  CAS  Google Scholar 

  • Acheson SK, Richardson R, Swartzwelder HS (1999) Developmental changes in seizure susceptibility during ethanol withdrawal. Alcohol 18:23–26

    Article  PubMed  CAS  Google Scholar 

  • Acheson SK, Ross EL, Swartzwelder HS (2001) Age-independent and dose–response effects of ethanol on spatial memory in rats. Alcohol 23:167–175

    Article  PubMed  CAS  Google Scholar 

  • Agrawal A, Edenberg HJ, Foroud T, Bierut LJ, Dunne G, Hinrichs AL, Nurnberger JI, Crowe R, Kuperman S, Schuckit MA, Begleiter H, Porjesz B, Dick DM (2006) Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample. Behav Genet 36:640–650

    Article  PubMed  Google Scholar 

  • Allan AM, Harris RA (1987) Acute and chronic ethanol treatments alter GABA receptor-operated chloride channels. Pharmacol Biochem Behav 27:665–670

    Article  PubMed  CAS  Google Scholar 

  • Anderson NJ, Daunais JB, Friedman DP, Grant KA, McCool BA (2007) Long-term ethanol self-administration by the nonhuman primate, Macaca fascicularis, decreases the benzodiazepine sensitivity of amygdala GABAA receptors. Alcohol Clin Exp Res 31:1061–1070

    Article  PubMed  CAS  Google Scholar 

  • Ariwodola OJ, Weiner JL (2004) Ethanol potentiation of GABAergic synaptic transmission may be self-limiting: role of presynaptic GABAB receptors. J Neurosci 24:10679–10686

    Article  PubMed  CAS  Google Scholar 

  • Atack JR (2003) Anxioselective compounds acting at the GABAA receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord 2:213–232

    Article  PubMed  CAS  Google Scholar 

  • Atkins AL, Rustay NR, Crabbe JC (2000) Anxiety and sensitivity to ethanol and pentobarbital in alcohol withdrawal seizure-prone and withdrawal seizure-resistant mice. Alcohol Clin Exp Res 24:1743–1749

    Article  PubMed  CAS  Google Scholar 

  • Barbaccia ML, Affricano D, Trabucchi M, Purdy RH, Colombo G, Agabio R, Gessa GL (1999) Ethanol markedly increases “GABAergic” neurosteroids in alcohol-preferring rats. Eur J Pharmacol 384:R1–R2

    Article  PubMed  CAS  Google Scholar 

  • Bauer LO, Covault J, Harel O, Das S, Gelernter J, Anton R, Kranzler HR (2007) Variation in GABRA2 predicts drinking behavior in project MATCH subjects. Alcohol Clin Exp Res 31:1780–1787

    Article  PubMed  CAS  Google Scholar 

  • Becker HC, Veatch LM (2002) Effects of lorazepam treatment for multiple ethanol withdrawals in mice. Alcohol Clin Exp Res 26:371–380

    PubMed  CAS  Google Scholar 

  • Becker HC, Diaz-Granados JL, Weathersby RT (1997) Repeated ethanol withdrawal experience increases the severity and duration of subsequent withdrawal seizures in mice. Alcohol 14:319–326

    Article  PubMed  CAS  Google Scholar 

  • Bell RL, Rodd ZA, Sable HJ, Schultz JA, Hsu CC, Lumeng L, Murphy JM, McBride WJ (2006) Daily patterns of ethanol drinking in peri-adolescent and adult alcohol-preferring (P) rats. Pharmacol Biochem Behav 83:35–46

    Article  PubMed  CAS  Google Scholar 

  • Ben-Ari Y (2002) Excitatory actions of gaba during development: the nature of the nurture. Nat Rev Neurosci 3:728–739

    Article  PubMed  CAS  Google Scholar 

  • Bencsits E, Ebert V, Tretter V, Sieghart W (1999) A significant part of native gamma-aminobutyric AcidA receptors containing alpha4 subunits do not contain gamma or delta subunits. J Biol Chem 274:19613–19616

    Article  PubMed  CAS  Google Scholar 

  • Besheer J, Hodge CW (2005) Pharmacological and anatomical evidence for an interaction between mGluR5- and GABAA α1-containing receptors in the discriminative stimulus effects of ethanol. Neuropsychopharmacology 30:747–757

    PubMed  CAS  Google Scholar 

  • Besheer J, Cox AA, Hodge CW (2003) Coregulation of ethanol discrimination by the nucleus accumbens and amygdala. Alcohol Clin Exp Res 27:450–456

    Article  PubMed  Google Scholar 

  • Biggio G, Purdy RH (2001) Neurosteroids and brain function (International Review of Neurobiology, vol 46) Academic Press, New York

  • Blednov YA, Jung S, Alva H, Wallace D, Rosahl T, Whiting PJ, Harris RA (2003a) Deletion of the α1 or β2 subunit of GABAA receptors reduces actions of alcohol and other drugs. J Pharmacol Exp Ther 304:30–36

    Article  PubMed  CAS  Google Scholar 

  • Blednov YA, Walker D, Alva H, Creech K, Findlay G, Harris RA (2003b) GABAA receptor α1 and β2 subunit null mutant mice: behavioral responses to ethanol. J Pharmacol Exp Ther 305:854–863

    Article  PubMed  CAS  Google Scholar 

  • Boehm SL 2nd, Peden L, Jennings AW, Kojima N, Harris RA, Blednov YA (2004a) Over-expression of the fyn-kinase gene reduces hypnotic sensitivity to ethanol in mice. Neurosci Lett 372:6–11

    Article  PubMed  CAS  Google Scholar 

  • Boehm SL 2nd, Ponomarev I, Jennings AW, Whiting PJ, Rosahl TW, Garrett EM, Blednov YA, Harris RA (2004b) γ-Aminobutyric acid A receptor subunit mutant mice: new perspectives on alcohol actions. Biochem Pharmacol 68:1581–1602

    Article  PubMed  CAS  Google Scholar 

  • Boehm SL II, Peden L, Harris RA, Blednov Y (2004c) Deletion of the fyn-kinase gene alters sensitivity to GABAergic drugs: dependence on β2/β3 GABAA receptor subunits. J Pharmacol Exp Ther 309:1154–1159

    Article  PubMed  CAS  Google Scholar 

  • Boehm SL 2nd, Ponomarev I, Blednov YA, Harris RA (2006) From gene to behavior and back again: new perspectives on GABAA receptor subunit selectivity of alcohol actions. Adv Pharmacol 54:171–203

    Article  PubMed  CAS  Google Scholar 

  • Borghese CM, Storustovu SI, Ebert B, Herd MB, Belelli D, Lambert JJ, Marshall G, Wafford KA, Harris RA (2006a) The δ subunit of γ-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol. J Pharmacol Exp Ther 316:1360–1368

    Article  PubMed  CAS  Google Scholar 

  • Borghese CM, Werner DF, Topf N, Baron NV, Henderson LA, Boehm SL 2nd, Blednov YA, Saad A, Dai S, Pearce RA, Harris RA, Homanics GE, Harrison NL (2006b) An isoflurane- and alcohol-insensitive mutant GABAA receptor α1 subunit with near-normal apparent affinity for GABA: characterization in heterologous systems and production of knockin mice. J Pharmacol Exp Ther 319:208–218

    Article  PubMed  CAS  Google Scholar 

  • Borlikova GG, Le Merrer J, Stephens DN (2006) Previous experience of ethanol withdrawal increases withdrawal-induced c-fos expression in limbic areas, but not withdrawal-induced anxiety and prevents withdrawal-induced elevations in plasma corticosterone. Psychopharmacology (Berl) 185:188–200

    Article  CAS  Google Scholar 

  • Botta P, Mameli M, Floyd KL, Radcliffe RA, Valenzuela CF (2007a) Ethanol sensitivity of GABAergic currents in cerebellar granule neurons is not increased by a single amino acid change (R100Q) in the alpha6 GABAA receptor subunit. J Pharmacol Exp Ther 323:684–691

    Article  PubMed  CAS  Google Scholar 

  • Botta P, Radcliffe RA, Carta M, Mameli M, Daly E, Floyd KL, Deitrich RA, Valenzuela CF (2007b) Modulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies. Alcohol 41:187–199

    Article  PubMed  CAS  Google Scholar 

  • Bowers BJ, Owen EH, Collins AC, Abeliovich A, Tonegawa S, Wehner JM (1999) Decreased ethanol sensitivity and tolerance development in gamma-protein kinase C null mutant mice is dependent on genetic background. Alcohol Clin Exp Res 23:387–397

    PubMed  CAS  Google Scholar 

  • Bowers BJ, Elliott KJ, Wehner JM (2001) Differential sensitivity to the anxiolytic effects of ethanol and flunitrazepam in PKCgamma null mutant mice. Pharmacol Biochem Behav 69:99–110

    Article  PubMed  CAS  Google Scholar 

  • Brandon NJ, Delmas P, Kittler JT, McDonald BJ, Sieghart W, Brown DA, Smart TG, Moss SJ (2000) GABAA receptor phosphorylation and functional modulation in cortical neurons by a protein kinase C-dependent pathway. J Biol Chem 275:38856–38862

    Article  PubMed  CAS  Google Scholar 

  • Brasser SM, Spear NE (2002) Physiological and behavioral effects of acute ethanol hangover in juvenile, adolescent, and adult rats. Behav Neurosci 116:305–320

    Article  PubMed  Google Scholar 

  • Brickley SG, Revilla V, Cull-Candy SG, Wisden W, Farrant M (2001) Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature 409:88–92

    Article  PubMed  CAS  Google Scholar 

  • Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA (2002) Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors. Br J Pharmacol 136:965–974

    Article  PubMed  CAS  Google Scholar 

  • Brünig I, Penschuck S, Berninger B, Benson J, Fritschy JM (2001) BDNF reduces miniature inhibitory postsynaptic currents by rapid downregulation of GABAA receptor surface expression. Eur J Neurosci 13:1320–1328

    Article  PubMed  Google Scholar 

  • Buchner K, Adamec E, Beermann ML, Nixon RA (1999) Isoform-specific translocation of protein kinase C following glutamate administration in primary hippocampal neurons. Brain Res Mol Brain Res 64:222–235

    Article  PubMed  CAS  Google Scholar 

  • Buck KJ, Harris RA (1990) Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol. J Pharmacol Exp Ther 253:713–719

    PubMed  CAS  Google Scholar 

  • Buck KJ, Hahner L, Sikela J, Harris RA (1991a) Chronic ethanol treatment alters brain levels of gamma-aminobutyric acidA receptor subunit mRNAs: relationship to genetic differences in ethanol withdrawal seizure severity. J Neurochem 57:1452–1455

    Article  PubMed  CAS  Google Scholar 

  • Buck KJ, Heim H, Harris RA (1991b) Reversal of alcohol dependence and tolerance by a single administration of flumazenil. J Pharmacol Exp Ther 257:984–989

    PubMed  CAS  Google Scholar 

  • Buckley ST, Dodd PR (2004) GABAA receptor β subunit mRNA expression in the human alcoholic brain. Neurochem Int 45:1011–1020

    Article  PubMed  CAS  Google Scholar 

  • Buckley ST, Foley PF, Innes DJ, el Loh W, Shen Y, Williams SM, Harper CG, Tannenberg AE, Dodd PR (2006) GABAA receptor β isoform protein expression in human alcoholic brain: interaction with genotype. Neurochem Int 49:557–567

    Article  PubMed  CAS  Google Scholar 

  • Cagetti E, Liang J, Spigelman I, Olsen RW (2003) Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors. Mol Pharmacol 63:53–64

    Article  PubMed  CAS  Google Scholar 

  • Cagetti E, Pinna G, Guidotti A, Baicy K, Olsen RW (2004) Chronic intermittent ethanol (CIE) administration in rats decreases levels of neurosteroids in hippocampus, accompanied by altered behavioral responses to neurosteroids and memory function. Neuropharmacology 46:570–579

    Article  PubMed  CAS  Google Scholar 

  • Calkin PA, Barnes EM Jr (1994) Gamma-aminobutyric acid-A (GABAA) agonists down-regulate GABAA/benzodiazepine receptor polypeptides from the surface of chick cortical neurons. J Biol Chem 269:1548–1553

    PubMed  CAS  Google Scholar 

  • Carta M, Mameli M, Valenzuela CF (2004) Alcohol enhances GABAergic transmission to cerebellar granule cells via an increase in Golgi cell excitability. J Neurosci 24:3746–3751

    Article  PubMed  CAS  Google Scholar 

  • Casagrande S, Cupello A, Pellistri F, Robello M (2007) Only high concentrations of ethanol affect GABAA receptors of rat cerebellum granule cells in culture. Neurosci Lett 414:273–276

    Article  PubMed  CAS  Google Scholar 

  • Chandra D, Jia F, Liang J, Peng Z, Suryanarayanan A, Werner DF, Spigelman I, Houser CR, Olsen RW, Harrison NL, Homanics GE (2006) GABAA receptor α4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol. Proc Natl Acad Sci U S A 103:15230–15235

    Article  PubMed  CAS  Google Scholar 

  • Chandra D, Werner DF, Liang J, Suryanarayanan A, Harrison NL, Spigelman I, Olsen RW, Homanics GE (2008) Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor alpha 4 subunit knockout mice. Alcohol Clin Exp Res 32:10–18

    Article  PubMed  CAS  Google Scholar 

  • Charlton ME, Sweetnam PM, Fitzgerald LW, Terwilliger RZ, Nestler EJ, Duman RS (1997) Chronic ethanol administration regulates the expression of GABAA receptor α1 and α5 subunits in the ventral tegmental area and hippocampus. J Neurochem 68:121–127

    Article  PubMed  CAS  Google Scholar 

  • Chen ZW, Olsen RW (2007) GABAA receptor associated proteins: a key factor regulating GABAA receptor function. J Neurochem 100:279–294

    Article  PubMed  CAS  Google Scholar 

  • Chester JA, Cunningham CL (1999) GABAA receptors modulate ethanol induced conditioned place preference and taste aversion in mice. Psychopharmacology 144:363–372

    Article  PubMed  CAS  Google Scholar 

  • Chester JA, Risinger FO, Cunningham CL (1998) Ethanol reward and aversion in mice bred for sensitivity to ethanol withdrawal. Alcohol Clin Exp Res 22:468–473

    PubMed  CAS  Google Scholar 

  • Choi DS, Wei W, Deitchman JK, Kharazia VN, Lesscher HM, McMahon T, Wang D, Qi ZH, Sieghart W, Zhang C, Shokat KM, Mody I, Messing RO (2008) Protein kinase Cdelta regulates ethanol intoxication and enhancement of GABA-stimulated tonic current. J Neurosci 28:11890–11899

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Agabio R, Lobina C, Loche A, Reali R, Gessa GL (1998) High sensitivity to gamma-hydroxybutyric acid in ethanol-preferring sP rats. Alcohol Alcohol 33:121–125

    PubMed  CAS  Google Scholar 

  • Colombo G, Agabio R, Carai MA, Lobina C, Pani M, Reali R, Vacca G, Gessa GL (2000) Different sensitivity to ethanol in alcohol-preferring sP and -nonpreferring sNP rats. Alcohol Clin Exp Res 24:1603–1608

    Article  PubMed  CAS  Google Scholar 

  • Connolly CN, Kittler JT, Thomas P, Uren JM, Brandon NJ, Smart TG, Moss SJ (1999) Cell surface stability of gamma-aminobutyric acid type A receptors: dependence on protein kinase C activity and subunit composition. J Biol Chem 274:36565–36572

    Article  PubMed  CAS  Google Scholar 

  • Cook JB, Foster KL, Eiler WJ 2nd, McKay PF, Woods J 2nd, Harvey SC, Garcia M, Grey C, McCane S, Mason D, Cummings R, Li X, Cook JM, June HL (2005) Selective GABAA α5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol. Alcohol Clin Exp Res 29:1390–1401

    Article  PubMed  CAS  Google Scholar 

  • Costa L, Bauer L (1997) Quantitative electroencephalographic differences associated with alcohol, cocaine, heroin and dual-substance dependence. Drug Alcohol Depend 46:87–93

    Article  PubMed  CAS  Google Scholar 

  • Covault J, Gelernter J, Hesselbrock V, Nellissery M, Kranzler HR (2004) Allelic and haplotypic association of GABRA2 with alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 129:104–109

    Article  Google Scholar 

  • Covault J, Gelernter J, Jensen K, Anton R, Kranzler HR (2008) Markers in the 5′-region of GABRG1 associate to alcohol dependence and are in linkage disequilibrium with markers in the adjacent GABRA2 gene. Neuropsychopharmacology 33:837–848

    Article  PubMed  CAS  Google Scholar 

  • Cowley DS, Roy-Byrne PP, Radant A, Hommer DW, Greenblatt DJ, Vitaliano PP, Godon C (1994) Eye movement effects of diazepam in sons of alcoholic fathers and male control subjects. Alcohol Clin Exp Res 18:324–332

    Article  PubMed  CAS  Google Scholar 

  • Crabbe JC, Kosobud A (1986) Sensitivity and tolerance to ethanol in mice bred to be genetically prone or resistant to ethanol withdrawal seizures. J Pharmacol Exp Ther 239:327–333

    PubMed  CAS  Google Scholar 

  • Crabbe JC, Phillips TJ, Harris RA, Arends MA, Koob GF (2006) Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol 11:195–269

    Article  PubMed  CAS  Google Scholar 

  • Crews F, Morrow AL, Criswell H, Breese G (1996) Effects of ethanol on ion channels. In: Bradley RJ, Harris RA (eds) International review of neurobiology, vol 39. Academic, New York, pp 283–367

    Google Scholar 

  • Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, Qin L, Szabo G, Wheeler M, Zou JY (2006) Cytokines and alcohol. Alcohol Clin Exp Res 30:720–730

    Article  PubMed  CAS  Google Scholar 

  • Criswell HE, Breese GR (2005) A conceptualization of integrated actions of ethanol contributing to its GABAmimetic profile: a commentary. Neuropsychopharmacology 30:1407–1425

    Article  PubMed  CAS  Google Scholar 

  • Criswell HE, Ming Z, Kelm MK, Breese GR (2008) Brain regional differences in the effect of ethanol on GABA release from presynaptic terminals. J Pharmacol Exp Ther 326:596–603

    Article  PubMed  CAS  Google Scholar 

  • Davidson M, Chen W, Wilce PA (1999) Behavioral analysis of PTZ-kindled rats after acute and chronic ethanol treatments. Pharmacol Biochem Behav 64:7–13

    Article  PubMed  CAS  Google Scholar 

  • de Almeida RM, Rowlett JK, Cook JM, Yin W, Miczek KA (2004) GABAA/α1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice. Psychopharmacology (Berl) 172:255–263

    Article  CAS  Google Scholar 

  • De Witte P, Dahchour A, Quertemont E (1994) Acute and chronic alcohol injections increase taurine in the nucleus accumbens. Alcohol Alcohol Suppl 2:229–233

    PubMed  Google Scholar 

  • Devaud LL, Smith FD, Grayson DR, Morrow AL (1995) Chronic ethanol consumption differentially alters the expression of γ-aminobutyric acid type A receptor subunit mRNAs in rat cerebral cortex: competitive, quantitative reverse transcriptase-polymerase chain reaction analysis. Mol Pharmacol 48:861–868

    PubMed  CAS  Google Scholar 

  • Devaud LL, Purdy RH, Finn DA, Morrow AL (1996) Sensitization of γ-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal. J Pharmacol Exp Ther 278:510–517

    PubMed  CAS  Google Scholar 

  • Devaud LL, Fritschy J-M, Sieghart W, Morrow AL (1997) Bidirectional alterations of GABAA receptor subunit peptide levels in rat cortex during chronic ethanol consumption and withdrawal. J Neurochem 69:126–130

    Article  PubMed  CAS  Google Scholar 

  • Devaud LL, Fritschy J-M, Morrow AL (1998) Influence of gender on chronic ethanol-induced alternations of GABAA receptors in rats. Brain Res 796:222–230

    Article  PubMed  CAS  Google Scholar 

  • Diamond I, Gordon AS (1994) The role of adenosine in mediating cellular and molecular responses to ethanol. EXS 71:175–183

    PubMed  CAS  Google Scholar 

  • Diaz-Granados JL, Graham DL (2007) The effects of continuous and intermittent ethanol exposure in adolescence on the aversive properties of ethanol during adulthood. Alcohol Clin Exp Res 12:2020–2027

    Article  Google Scholar 

  • Dick DM, Edenberg HJ, Xuei X, Goate A, Kuperman S, Schuckit M, Crowe R, Smith TL, Porjesz B, Begleiter H, Foroud T (2004) Association of GABRG3 with alcohol dependence. Alcohol Clin Exp Res 28:4–9

    Article  PubMed  CAS  Google Scholar 

  • Dick DM, Edenberg HJ, Xuei X, Goate A, Hesselbrock V, Schuckit M, Crowe R, Foroud T (2005) No association of the GABAA receptor genes on chromosome 5 with alcoholism in the collaborative study on the genetics of alcoholism sample. Am J Med Genet B Neuropsychiatr Genet 132B:24–28

    Article  PubMed  Google Scholar 

  • Dick DM, Plunkett J, Wetherill LF, Xuei X, Goate A, Hesselbrock V, Schuckit M, Crowe R, Edenberg HJ, Foroud T (2006) Association between GABRA1 and drinking behaviors in the collaborative study on the genetics of alcoholism sample. Alcohol Clin Exp Res 30:1101–1110

    Article  PubMed  CAS  Google Scholar 

  • Dixon CI, Rosahl TW, Stephens DN (2008) Targeted deletion of the GABRA2 gene encoding α2-subunits of GABAA receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiazepines and barbiturates. Pharmacol Biochem Behav 90:1–8

    Article  PubMed  CAS  Google Scholar 

  • Dodd PR, Thomas GJ, Harper CG, Kril JJ (1992) Amino acid neurotransmitter receptor changes in cerebral cortex in alcoholism: effect of cirrhosis of the liver. J Neurochem 59:1506–1515

    Article  PubMed  CAS  Google Scholar 

  • Dodd PR (1995) Benzodiazepine binding sites in alcoholic cirrhotics: evidence for gender differences. Metab Brain Dis 10:93–104

    Article  PubMed  CAS  Google Scholar 

  • Dodd PR, Foley PF, Buckley ST, Eckert AL, Innes DJ (2004) Genes and gene expression in the brain of the alcoholic. Addict Behav 29:1295–1309

    Article  PubMed  Google Scholar 

  • Dodd PR, Buckley ST, Eckert AL, Foley PF, Innes DJ (2006) Genes and gene expression in the brains of human alcoholics. Ann N Y Acad Sci 1074:104–115

    Article  PubMed  CAS  Google Scholar 

  • Doremus TL, Brunell SC, Varlinskaya EI, Spear LP (2003) Anxiogenic effects during withdrawal from acute ethanol in adolescent and adult rats. Pharmacol Biochem Behav 75:411–418

    Article  PubMed  CAS  Google Scholar 

  • Doremus TL, Brunell SC, Rajendran P, Spear LP (2005) Factors influencing elevated ethanol consumption in adolescent relative to adult rats. Alcohol Clin Exp Res 29:1796–1808

    Article  PubMed  Google Scholar 

  • Drgon T, D'Addario C, Uhl GR (2006) Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions. Am J Med Genet B Neuropsychiatr Genet 141B:854–860

    Article  PubMed  CAS  Google Scholar 

  • Edenberg HJ, Dick DM, Xuei X, Tian H, Almasy L, Bauer LO, Crowe RR, Goate A, Hesselbrock V, Jones K, Kwon J, Li TK, Nurnberger JI Jr, O'Connor SJ, Reich T, Rice J, Schuckit MA, Porjesz B, Foroud T, Begleiter H (2004) Variations in GABRA2, encoding the α 2 subunit of the GABAA receptor, are associated with alcohol dependence and with brain oscillations. Am J Hum Genet 74:705–714

    Article  PubMed  CAS  Google Scholar 

  • Enoch MA (2008) The role of GABAA receptors in the development of alcoholism. Pharmacol Biochem Behav 90:95–104

    Article  PubMed  CAS  Google Scholar 

  • Enoch MA, Schwartz L, Albaugh B, Virkkunen M, Goldman D (2006) Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism. Am J Med Genet B Neuropsychiatr Genet 141B:599–607

    Article  PubMed  Google Scholar 

  • Ericson M, Haythornthwaite AR, Yeh PW, Yeh HH (2003) Brain-derived neurotrophic factor mitigates chronic ethanol-induced attenuation of gamma-aminobutyric acid responses in cultured cerebellar granule cells. J Neurosci Res 73:722–730

    Article  PubMed  CAS  Google Scholar 

  • Etoh S, Baba A, Iwata H (1991) NMDA induces protein kinase C translocation in hippocampal slices of immature rat brain. Neurosci Lett 126:119–122

    Article  PubMed  CAS  Google Scholar 

  • Farrant M, Nusser Z (2005) Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat Rev Neurosci 6:215–229

    Article  PubMed  CAS  Google Scholar 

  • Fehr C, Sander T, Tadic A, Lenzen KP, Anghelescu I, Klawe C, Dahmen N, Schmidt LG, Szegedi A (2006) Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis. Psychiatr Genet 16:9–17

    Article  PubMed  Google Scholar 

  • Feng J, Cai X, Zhao J, Yan Z (2001) Serotonin receptors modulate GABAA receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J Neurosci 21:6502–6511

    PubMed  CAS  Google Scholar 

  • File SE, Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology (Berl) 88:1–11

    Article  CAS  Google Scholar 

  • Fish EW, Faccidomo S, DeBold JF, Miczek KA (2001) Alcohol, allopregnanolone and aggression in mice. Psychopharmacology 153:473–483

    Article  PubMed  CAS  Google Scholar 

  • Fleming RL, Wilson WA, Swartzwelder HS (2007) Magnitude and ethanol sensitivity of tonic GABAA receptor-mediated inhibition in dentate gyrus changes from adolescence to adulthood. J Neurophysiol 97:3806–3811

    Article  PubMed  CAS  Google Scholar 

  • Flores-Hernandez J, Hernandez S, Snyder GL, Yan Z, Fienberg AA, Moss SJ, Greengard P, Surmeier DJ (2000) D(1) dopamine receptor activation reduces GABAA receptor currents in neostriatal neurons through a PKA/DARPP-32/PP1 signaling cascade. J Neurophysiol 83:2996–3004

    PubMed  CAS  Google Scholar 

  • Floyd DW, Friedman DP, Daunais JB, Pierre PJ, Grant KA, McCool BA (2004) Long-term ethanol self-administration by cynomolgus macaques alters the pharmacology and expression of GABAA receptors in basolateral amygdala. J Pharmacol Exp Ther 311:1071–1079

    Article  PubMed  CAS  Google Scholar 

  • Follesa P, Biggio F, Talani G, Murru L, Serra M, Sanna E, Biggio G (2006) Neurosteroids, GABAA receptors, and ethanol dependence. Psychopharmacology 186:267–280

    Article  PubMed  CAS  Google Scholar 

  • Freund G, Ballinger WEJ (1988) Decrease of benzodiazepine receptors in frontal cortex of alcoholics. Alcohol 5:275–282

    Article  PubMed  CAS  Google Scholar 

  • Fritschy J-M, Paysan J, Enna A, Möhler H (1994) Switch in the expression of rat GABAA receptor subtypes during postnatal development: an immunohistochemical study. J Neurosci 14:5302–5324

    PubMed  CAS  Google Scholar 

  • Frye CA, Van Keuren KR, Erskine MS (1996) Behavioral effects of 3α-androstanediol 1. Modulation of sexual receptivity and promotion of GABA-stimulated chloride flux. Behav Brain Res 79:109–118

    Article  PubMed  CAS  Google Scholar 

  • Gabriel KI, Cunningham CL, Finn DA (2004) Allopregnanolone does not influence ethanol-induced conditioned place preference in DBA/2J mice. Psychopharmacology (Berl) 176:50–56

    Article  CAS  Google Scholar 

  • Galindo R, Valenzuela CF (2006) Immature hippocampal neuronal networks do not develop tolerance to the excitatory actions of ethanol. Alcohol 40:111–118

    Article  PubMed  CAS  Google Scholar 

  • Gallaher EJ, Gionet SE (1988) Initial sensitivity and tolerance to ethanol in mice genetically selected for diazepam sensitivity. Alcohol Clin Exp Res 12:77–80

    Article  PubMed  CAS  Google Scholar 

  • Gallaher EJ, Jones GE, Belknap JK, Crabbe JC (1996) Identification of genetic markers for initial sensitivity and rapid tolerance to ethanol-induced ataxia using quantitative trait locus analysis in BXD recombinant inbred mice. J Pharmacol Exp Ther 277:604–612

    PubMed  CAS  Google Scholar 

  • Gatch MB (1999) Effects of benzodiazepines on acute and chronic ethanol-induced nociception in rats. Alcohol Clin Exp Res 23:1736–1743

    PubMed  CAS  Google Scholar 

  • Gilman S, Koeppe RA, Adams K, Johnson-Greene D, Junck L, Kluin KJ, Brunberg J, Martorello S, Lohman M (1996) Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics. Ann Neurol 40:163–171

    Article  PubMed  CAS  Google Scholar 

  • Glykys J, Peng Z, Chandra D, Homanics GE, Houser CR, Mody I (2007) A new naturally occurring GABAA receptor subunit partnership with high sensitivity to ethanol. Nat Neurosci 10:40–48

    Article  PubMed  CAS  Google Scholar 

  • Graham DL, Diaz-Granados JL (2006) Periadolescent exposure to ethanol and diazepam alters the aversive properties of ethanol in adult mice. Pharmacol Biochem Behav 84:406–414

    Article  PubMed  CAS  Google Scholar 

  • Grant KA (1999) Strategies for understanding the pharmacological effects of ethanol with drug discrimination procedures. Pharmacol Biochem Behav 64:261–267

    Article  PubMed  CAS  Google Scholar 

  • Grant KA, Azarov A, Bowen CA, Mirkis S, Purdy RH (1996) Ethanol-like discriminative stimulus effects of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in female Macaca fascicularis monkeys. Psychopharmacology 124:340–346

    Article  PubMed  CAS  Google Scholar 

  • Grant KA, Helms CM, Rogers LS, Purdy RH (2008a) Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys. J. Pharmacol. Exp. Ther. 326:354–361

    Article  PubMed  CAS  Google Scholar 

  • Grant KA, Leng X, Green HL, Szeliga KT, Rogers LS, Gonzales SW (2008b) Drinking typography established by scheduled induction predicts chronic heavy drinking in a monkey model of ethanol self-administration. Alcohol Clin Exp Res 32:1824–1838

    Article  PubMed  CAS  Google Scholar 

  • Grobin AC, Matthews DB, Devaud LL, Morrow AL (1998) The role of GABAA receptors in the acute and chronic effects of ethanol. Psychopharmacology 139:2–19

    Article  PubMed  CAS  Google Scholar 

  • Grobin AC, Fritschy J-M, Morrow AL (2000) Chronic ethanol administration alters immunoreactivity for GABAA receptor subunits in rat cortex in a region-specific manner. Alcohol Clin Exp Res 24:1137–1144

    Article  PubMed  CAS  Google Scholar 

  • Grobin AC, Matthews DB, Montoya D, Wilson WA, Morrow AL, Swartzwelder HS (2001) Age-related differences in neurosteroid potentiation of muscimol-stimulated 36Cl-flux following chronic ethanol treatment. Neuroscience 105:547–552

    Article  PubMed  CAS  Google Scholar 

  • Gutiérrez A, Khan ZU, Miralles CP, Mehta AK, Ruano D, Araujo F, Vitorica J, De Blas AL (1997) GABAA receptor subunit expression changes in the rat cerebellum and cerebral cortex during aging. Brain Res 45:59–70

    Article  Google Scholar 

  • Hanchar HJ, Dodson PD, Olsen RW, Otis TS, Wallner M (2005) Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity. Nat Neurosci 8:339–345

    Article  PubMed  CAS  Google Scholar 

  • Hanchar HJ, Chutsrinopkun P, Meera P, Supavilai P, Sieghart W, Wallner M, Olsen RW (2006) Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to alpha4/6beta3delta GABAA receptors. Proc Natl Acad Sci U S A 103:8546–8551

    Article  PubMed  CAS  Google Scholar 

  • Harris RA, McQuilkin SJ, Paylor R, Abeliovich A, Tonegawa S, Wehner JM (1995) 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. Proc Natl Acad Sci U S A 92:3658–3662

    Article  PubMed  CAS  Google Scholar 

  • Harvey SC, Foster KL, McKay PF, Carroll MR, Seyoum R, Woods JE 2nd, Grey C, Jones CM, McCane S, Cummings R, Mason D, Ma C, Cook JM, June HL (2002) The GABAA receptor α1 subtype in the ventral pallidum regulates alcohol-seeking behaviors. J Neurosci 22:3765–3775

    PubMed  CAS  Google Scholar 

  • Haughey HM, Ray LA, Finan P, Villanueva R, Niculescu M, Hutchison KE (2008) Human γ-aminobutyric acid A receptor α2 gene moderates the acute effects of alcohol and brain mRNA expression. Genes Brain Behav 7:447–454

    Article  PubMed  CAS  Google Scholar 

  • Hefner K, Holmes A (2007) Ontogeny of fear-, anxiety- and depression-related behavior across adolescence in C57BL/6J mice. Behav Brain Res 176:210–215

    Article  PubMed  Google Scholar 

  • Helms CM, Rogers LS, Waters CA, Grant KA (2008) Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol. Alcohol Clin Exp Res 32:1197–1206

    Article  PubMed  CAS  Google Scholar 

  • Hemby SE, O'Connor JA, Acosta G, Floyd D, Anderson N, McCool BA, Friedman D, Grant KA (2006) Ethanol-induced regulation of GABAA subunit mRNAs in prefrontal fields of cynomolgus monkeys. Alcohol Clin Exp Res 30:1978–1985

    Article  PubMed  CAS  Google Scholar 

  • Henschel O, Gipson KE, Bordey A (2008) GABAA receptors, anesthetics and anticonvulsants in brain development. CNS Neurol Disord Drug Targets 7:211–224

    Article  PubMed  CAS  Google Scholar 

  • Herring D, Huang R, Singh M, Robinson LC, Dillon GH, Leidenheimer NJ (2003) Constitutive GABAA receptor endocytosis is dynamin-mediated and dependent on a dileucine AP2 adaptin-binding motif within the β2 subunit of the receptor. J Biol Chem 278:24046–24052

    Article  PubMed  CAS  Google Scholar 

  • Hirani K, Khisti RT, Chopde CT (2002) Behavioral action of ethanol in Porsolt’s forced swim test: modulation by 3α-hydroxy-5α-pregnan-20-one. Neuropharmacology 43:1339–1350

    Article  PubMed  CAS  Google Scholar 

  • Hirani K, Sharma AN, Jain NS, Ugale RR, Chopde CT (2005) Evaluation of GABAergic neuroactive steroid 3α-hydroxy-5α-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats. Psychopharmacology 180:267–278

    Article  PubMed  CAS  Google Scholar 

  • Hodge CW, Cox AA (1998) The discriminative stimulus effects of ethanol are mediated by NMDA and GABAA receptors in specific limbic brain regions. Psychopharmacology 139:95–107

    Article  PubMed  CAS  Google Scholar 

  • Hodge CW, Mehmert KK, Kelley SP, McMahon T, Haywood A, Olive MF, Wang D, Sanchez-Perez AM, Messing RO (1999) Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKCε. Nat Neurosci 2:997–1002

    Article  PubMed  CAS  Google Scholar 

  • Hoffpauir B, Gleason E (2002) Activation of mGluR5 modulates GABAA receptor function in retinal amacrine cells. J Neurophysiol 88:1766–1776

    PubMed  CAS  Google Scholar 

  • Hollstedt C, Olsson O, Rydberg U (1977) The effect of alcohol on the developing organism. Genetical, teratological and physiological aspects. Med Biol 55:1–14

    PubMed  CAS  Google Scholar 

  • Holtzman SG (1990) Discriminative stimulus effects of drugs: relationship to potential for abuse. In: Adler MW, Cowan A (eds) Modern methods in pharmacology. Testing and evaluation of drugs of abuse, vol 6. Wiley-Liss, New York, pp 193–210

    Google Scholar 

  • Homanics GE, Ferguson C, Quinlan JJ, Daggett J, Snyder K, Lagenaur C, Mi ZP, WAng XH, Grayson DR, Firestone LL (1997) Gene knockout of the α6 subunit of the γ-aminobutyric acid type A receptor: lack of effect of responses to ethanol, pentobarbital, and general anesthetics. Mol Pharmacol 51:588–596

    PubMed  CAS  Google Scholar 

  • Homanics GE, Le NQ, Kist F, Mihalek R, Hart AR, Quinlan JJ (1998) Ethanol tolerance and withdrawal responses in GABAA receptor alpha 6 subunit null allele mice and in inbred C57BL/6J and strain 129/SvJ mice. Alcohol Clin Exp Res 22:259–265

    PubMed  CAS  Google Scholar 

  • Homanics GE, Harrison NL, Quinlan JJ, Krasowski MD, Rick CEM, de Blas AL, Mehta AK, Kist F, Mihalek RM, Aul JJ, Firestone LL (1999a) Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the γ2 subunit of the γ-aminobutyrate type A receptor. Neuropharmacology 38:253–265

    Article  PubMed  CAS  Google Scholar 

  • Homanics GE, Quinlan JJ, Firestone LL (1999b) Pharmacologic and behavioral responses of inbred C57BL/6J and strain 129/SvJ mouse lines. Pharmacol Biochem Behav 63:21–26

    Article  PubMed  CAS  Google Scholar 

  • Homanics GE, Elsen FP, Ying S-W, Jenkins AE, Ferguson C, Sloat B, Yuditskaya S, Goldstein PA, Kralic JE, Morrow AL, Harrison NL (2005) A gain-of-function mutation in the GABAA receptor produces synaptic and behavorial abnormalities in the mouse. Genes Brain Behav 4:10–19

    Article  PubMed  CAS  Google Scholar 

  • Hood HM, Buck KJ (2000) Allelic variation in the GABAA receptor γ2 subunit is associated with genetic susceptibility to ethanol-induced motor incoordination and hypothermia, conditioned taste aversion, and withdrawal in BXD/Ty recombinant inbred mice. Alcohol Clin Exp Res 24:1327–1334

    PubMed  CAS  Google Scholar 

  • Hsu FC, Waldeck R, Faber DS, Smith SS (2003) Neurosteroid effects on GABAergic synaptic plasticity in hippocampus. J Neurophysiol 89:1929–1940

    Article  PubMed  CAS  Google Scholar 

  • Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 29:8–16

    Article  PubMed  CAS  Google Scholar 

  • Huang RQ, Dillon GH (1998) Maintenance of recombinant type A gamma-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin. J Pharmacol Exp Ther 286:243–255

    PubMed  CAS  Google Scholar 

  • Ittiwut C, Listman J, Mutirangura A, Malison R, Covault J, Kranzler HR, Sughondhabirom A, Thavichachart N, Gelernter J (2008) Interpopulation linkage disequilibrium patterns of GABRA2 and GABRG1 genes at the GABA cluster locus on human chromosome 4. Genomics 91:61–69

    Article  PubMed  CAS  Google Scholar 

  • Ives JH, Drewery DL, Thompson CL (2002) Differential cell surface expression of GABAA receptor α1, α6, β2 and β3 subunits in cultured mouse cerebellar granule cells influence of cAMP-activated signalling. J Neurochem 80:317–327

    Article  PubMed  CAS  Google Scholar 

  • Iwata N, Cowley DS, Radel M, Roy-Byrne PP, Goldman D (1999) Relationship between a GABAA α6 Pro385Ser substitution and benzodiazepine sensitivity. Am J Psychiatry 156:1447–1449

    PubMed  CAS  Google Scholar 

  • Jenkins SA, Simmons DD (2006) GABAergic neurons in the lateral superior olive of the hamster are distinguished by differential expression of gad isoforms during development. Brain Res 1111:12–25

    Article  PubMed  CAS  Google Scholar 

  • Jia F, Chandra D, Homanics GE, Harrison NL (2008a) Ethanol modulates synaptic and extrasynaptic GABAA receptors in the thalamus. J Pharmacol Exp Ther 326:475–482

    Article  PubMed  CAS  Google Scholar 

  • Jia F, Yue M, Chandra D, Keramidas A, Goldstein PA, Homanics GE, Harrison NL (2008b) Taurine is a potent activator of extrasynaptic GABAA receptors in the thalamus. J Neurosci 28:106–115

    Article  PubMed  CAS  Google Scholar 

  • Jones A, Korpi ER, McKernan RM, Pelz R, Nusser Z, Mäkelä R, Mellor JR, Pollard S, Bahn S, Stephenson FA, Randall AD, Sieghart W, Somogyi P, Smith AJH, Wisden W (1997) Ligand-gated ion channel subunit partnerships: GABAA receptor α6 subunit gene inactivation inhibits δ subunit expression. J Neurosci 17:1350–1362

    PubMed  CAS  Google Scholar 

  • June HL Sr, Foster KL, Eiler WJ 2nd, Goergen J, Cook JB, Johnson N, Mensah-Zoe B, Simmons JO, June HL Jr, Yin W, Cook JM, Homanics GE (2007) Dopamine and benzodiazepine-dependent mechanisms regulate the EtOH-enhanced locomotor stimulation in the GABAA alpha1 subunit null mutant mice. Neuropsychopharmacology 32:137–152

    Article  PubMed  CAS  Google Scholar 

  • Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M, Vogt KE, Ledermann B, Antkowiak B, Rudolph U (2003) General anesthetic actions in vivo strongly attenuated by a point mutation in the GABAA receptor β3 subunit. FASEB J 17:250–252

    PubMed  CAS  Google Scholar 

  • Kalant H, LeBlanc AE, Gibbins RJ (1971) Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev 23:135–191

    PubMed  CAS  Google Scholar 

  • Kaminski RM, Marini H, Kim W, Rogawski MA (2005) Anticonvulsant activity of androsterone and etiocholanolone. Epilepsia 46:819–827

    Article  PubMed  CAS  Google Scholar 

  • Kaminski RM, Marini H, Ortinski PI, Vicini S, Rogawski MA (2006) The pheromone androstenol (5 alpha-androst-16-en-3 alpha-ol) is a neurosteroid positive modulator of GABAA receptors. J Pharmacol Exp Ther 317:694–703

    Article  PubMed  CAS  Google Scholar 

  • Kanaumi T, Takashima S, Iwasaki H, Mitsudome A, Hirose S (2006) Developmental changes in the expression of GABAA receptor alpha 1 and gamma 2 subunits in human temporal lobe, hippocampus and basal ganglia: an implication for consideration on age-related epilepsy. Epilepsy Res 71:47–53

    Article  PubMed  CAS  Google Scholar 

  • Kang M, Spigelman I, Sapp DW, Olsen RW (1996) Persistent reduction of GABAA receptor-mediated inhibition in rat hippocampus after chronic intermittent ethanol treatment. Brain Res 709:221–228

    Article  PubMed  CAS  Google Scholar 

  • Kaur KH, Baur R, Sigel E (2009) Unanticipated structural and functional properties of delta subunit containing GABAA receptors. J Biol Chem 284:7889–7896

    Google Scholar 

  • Keir WJ, Morrow AL (1994) Differential expression of GABAA receptor subunit mRNAs in ethanol-naive withdrawal seizure resistant (WSR) vs. withdrawal seizure prone (WSP) mouse brain. Brain Res Mol Brain Res 25:200–208

    Article  PubMed  CAS  Google Scholar 

  • Kellenberger S, Malherbe P, Sigel E (1992) Function of the α1ß2γ2s γ-aminobutyric acid typeA receptor is modulated by protein kinase C via multiple phosphorylation sites. J Biol Chem 267:25660–25663

    PubMed  CAS  Google Scholar 

  • Kelly SJ, Bonthius DJ, West JR (1987) Developmental changes in alcohol pharmacokinetics in rats. Alcohol Clin Exp Res 11:281–286

    Article  PubMed  CAS  Google Scholar 

  • Khisti RT, VanDoren MJ, O'Buckley TK, Morrow AL (2003) Neuroactive steroid 3α-hydroxy-5α-pregnan-20-one modulates ethanol-induced loss of righting reflex in rats. Brain Res 980:255–265

    Article  PubMed  CAS  Google Scholar 

  • Khisti RT, VanDoren MJ, Matthews DB, Morrow AL (2004) Ethanol-induced elevation of 3alpha-hydroxy-5alpha-pregnan-20-one does not modulate motor incoordination in rats. Alcohol Clin Exp Res 28:1249–1256

    Article  PubMed  CAS  Google Scholar 

  • Khisti RT, Boyd KN, Kumar S, Morrow AL (2005) Systemic ethanol administration elevates deoxycorticosterone levels and chronic ethanol exposure attenuates this response. Brain Res. 1049:104–111

    Article  PubMed  CAS  Google Scholar 

  • Kiefer F, Jahn H, Schick M, Wiedemann K (2002) Alcohol intake, tumour necrosis, factor-α, leptin and craving: factors of a possibly vicious circle? Alcohol Alcohol 37:401–404

    PubMed  CAS  Google Scholar 

  • Kim JH, Lee S, Chow J, Lau J, Tsang A, Choi J, Griffiths SM (2008) Prevalence and the factors associated with binge drinking, alcohol abuse, and alcohol dependence: a population-based study of Chinese adults in Hong Kong. Alcohol Alcohol 43:360–370

    PubMed  Google Scholar 

  • Kittler JT, Chen G, Honing S, Bogdanov Y, McAinsh K, Arancibia-Carcamo IL, Jovanovic JN, Pangalos MN, Haucke V, Yan Z, Moss SJ (2005) Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission. Proc Natl Acad Sci U S A 102:14871–14876

    Article  PubMed  CAS  Google Scholar 

  • Kittler JT, Chen G, Kukhtina V, Vahedi-Faridi A, Gu Z, Tretter V, Smith KR, McAinsh K, Arancibia-Carcamo IL, Saenger W, Haucke V, Yan Z, Moss SJ (2008) Regulation of synaptic inhibition by phospho-dependent binding of the AP2 complex to a YECL motif in the GABAA receptor γ2 subunit. Proc Natl Acad Sci U S A 105:3616–3621

    Article  PubMed  CAS  Google Scholar 

  • Korneyev AY, Costa E, Guidotti A (1993) During anesthetic-induced activation of hypothalamic pituitary adrenal axis, blood borne steroids fail to contribute to the anesthetic effect. Neuroendocrinology 57:559–565

    Article  PubMed  CAS  Google Scholar 

  • Korpi ER, Debus F, Linden AM, Malecot C, Leppa E, Vekovischeva O, Rabe H, Bohme I, Aller MI, Wisden W, Luddens H (2007) Does ethanol act preferentially via selected brain GABAA receptor subtypes? The current evidence is ambiguous. Alcohol 41:163–176

    Article  PubMed  CAS  Google Scholar 

  • Kralic JE, Korpi ER, O'Buckley TK, Homanics GE, Morrow AL (2002a) Molecular and pharmacological characterization of GABAA receptor α1 subunit knockout mice. J Pharmacol Exp Ther 302:1037–1045

    Article  PubMed  CAS  Google Scholar 

  • Kralic JE, O'Buckley TK, Khisti RT, Hodge CW, Homanics GE, Morrow AL (2002b) GABAA receptor α1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43:685–694

    Article  PubMed  CAS  Google Scholar 

  • Kralic JE, Wheeler M, Renzi K, Ferguson C, O'Buckley TK, Grobin AC, Morrow AL, Homanics GE (2003) Deletion of GABAA receptor α1 subunit-containing receptors alters responses to ethanol and other anesthetics. J Pharmacol Exp Ther 305:600–607

    Article  PubMed  CAS  Google Scholar 

  • Krishek BJ, Xie X, Blackstone C, Huganir RL, Moss SJ, Smart TG (1994) Regulation of GABAA receptor function by protein kinase C phosphorylation. Neuron 12:1081–1095

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Sieghart W, Morrow AL (2002) Association of protein kinase C with GABAA receptors containing α1 and α4 subunits in the cerebral cortex: selective effects of chronic ethanol consumption. J Neurochem 82:110–117

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Kralic JE, O'Buckley TK, Grobin AC, Morrow AL (2003) Chronic ethanol consumption enhances internalization of α1 subunit-containing GABAA receptors in cerebral cortex. J Neurochem 86:700–708

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Fleming R, Morrow AL (2004) Ethanol regulation of γ-aminobutyric acidA receptors: genomic and nongenomic mechanisms. Pharmacol Ther 101:211–226

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Khisti RT, Morrow AL (2005) Regulation of native GABAA receptors by PKC and protein phosphatase activity. Psychopharmacology 183:241–247

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Lane BM, Morrow AL (2006) Differential effects of systemic ethanol administration on PKCε, γ and β isoform expression, translocation to membranes and target phosphorylation: reversal by chronic ethanol exposure. J Pharmacol Exp Ther 319:1366–1375

    Article  PubMed  CAS  Google Scholar 

  • Kumar S, Ren Q, Beckley JH, Morrow AL (2008) Effects of ethanol on PKC and PKA expression in rat cerebral cortex contribute to the regulation of GABAA α1 subunit receptor surface expression. Alcohol Clin Exp Res 32:21A Supplement to vol. 32

    Google Scholar 

  • Kurtz DL, Stewart RB, Zweifel M, Li TK, Froehlich JC (1996) Genetic differences in tolerance and sensitization to the sedative/hypnotic effects of alcohol. Pharmacol Biochem Behav 53:585–591

    Article  PubMed  CAS  Google Scholar 

  • Lai CC, Kuo TI, Lin HH (2007) The role of protein kinase A in acute ethanol-induced neurobehavioral actions in rats. Anesth Analg 105:89–96

    Article  PubMed  CAS  Google Scholar 

  • Lancaster FE, Brown TD, Coker KL, Elliott JA, Wren SB (1996) Sex differences in alcohol preference and drinking patterns emerge during early postpubertal period in Sprague-Dawley rats. Alcohol Clin Exp Res 20:1043–1049

    Article  PubMed  CAS  Google Scholar 

  • Land C, Spear NE (2004) Ethanol impairs memory of a single discrimination in adolescent rats at doses that leave adult memory unaffected. Neurobiol Learn Mem 81:75–81

    Article  PubMed  CAS  Google Scholar 

  • Lappalainen J, Krupitsky E, Remizov M, Pchelina S, Taraskina A, Zvartau E, Somberg LK, Covault J, Kranzler HR, Krystal JH, Gelernter J (2005) Association between alcoholism and γ-amino butyric acid α2 receptor subtype in a Russian population. Alcohol Clin Exp Res 29:493–498

    Article  PubMed  CAS  Google Scholar 

  • Laurie DJ, Wisden W, Seeburg PH (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci 12:4151–4172

    PubMed  CAS  Google Scholar 

  • Laviola G, Macri S, Morley-Fletcher S, Adriani W (2003) Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev 27:19–31

    Article  PubMed  Google Scholar 

  • Le AD, Khanna JM, Kalant H, Grossi F (1986) Tolerance to and cross-tolerance among ethanol, pentobarbital and chlordiazepoxide. Pharmacol Biochem Behav 24:93–98

    Article  PubMed  CAS  Google Scholar 

  • Lee S, Schmidt ED, Tilders FJ, Rivier C (2001) Effect of repeated exposure to alcohol on the response of the hypothalamic–pituitary–adrenal axis of the rat: I. Role of changes in hypothalamic neuronal activity. Alcohol Clin Exp Res 25:98–105

    Article  PubMed  CAS  Google Scholar 

  • Leidenheimer NJ, McQuiklin SJ, Hahner LD, Whiting P, Harris RA (1992) Activation of protein kinase C selectively inhibits the γ-aminobutyric acidA receptor: role of desensitization. Mol Pharmacol 41:1116–1123

    PubMed  CAS  Google Scholar 

  • Lewohl JM, Crane DI, Dodd PR (1997) Expression of the α1, α2, and α3 isoforms of the GABAA receptor in human alcoholic brain. Brain Res 751:102–112

    Article  PubMed  CAS  Google Scholar 

  • Lewohl JM, Huygens F, Crane DI, Dodd PR (2001) GABAA receptor alpha-subunit proteins in human chronic alcoholics. J Neurochem 78:424–434

    Article  PubMed  CAS  Google Scholar 

  • Liang J, Cagetti E, Olsen RW, Spigelman I (2004) Altered pharmacology of synaptic and extrasynaptic GABAA receptors on CA1 hippocampal neurons is consistent with subunit changes in a model of alcohol withdrawal and dependence. J Pharmacol Exp Ther 310:1234–1245

    Article  PubMed  CAS  Google Scholar 

  • Liang J, Zhang N, Cagetti E, Houser CR, Olsen RW, Spigelman I (2006) Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors. J Neurosci 26:1749–1758

    Article  PubMed  CAS  Google Scholar 

  • Liang J, Suryanarayanan A, Abriam A, Snyder B, Olsen RW, Spigelman I (2007) Mechanisms of reversible GABAA receptor plasticity after ethanol intoxication. J Neurosci 27:12367–12377

    Article  PubMed  CAS  Google Scholar 

  • Liang J, Suryanarayanan A, Chandra D, Homanics GE, Olsen RW, Spigelman I (2008) Functional consequences of GABAA receptor α4 subunit deletion on synaptic and extrasynaptic currents in mouse dentate granule cells. Alcohol Clin Exp Res 32:19–26

    Article  PubMed  CAS  Google Scholar 

  • Lim WY, Fong CW, Chan JM, Heng D, Bhalla V, Chew SK (2007) Trends in alcohol consumption in Singapore 1992–2004. Alcohol Alcohol 42:354–361

    PubMed  Google Scholar 

  • Lingford-Hughes AR, Acton PD, Gacinovic S, Suckling J, Busatto GF, Boddington SJ, Bullmore E, Woodruff PW, Costa DC, Pilowsky LS, Ell PJ, Marshall EJ, Kerwin RW (1998) Reduced levels of GABA-benzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy. Br J Psychiatry 173:116–122

    Article  PubMed  CAS  Google Scholar 

  • Lingford-Hughes AR, Acton PD, Gacinovic S, Boddington SJ, Costa DC, Pilowsky LS, Ell PJ, Marshall EJ, Kerwin RW (2000) Levels of gamma-aminobutyric acid-benzodiazepine receptors in abstinent, alcohol-dependent women: preliminary findings from an 123I-iomazenil single photon emission tomography study. Alcohol Clin Exp Res 24:1449–1455

    PubMed  CAS  Google Scholar 

  • Lingford-Hughes AR, Wilson SJ, Cunningham VJ, Feeney A, Stevenson B, Brooks DJ, Nutt DJ (2005) GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study. Psychopharmacology (Berl) 180:595–606

    Article  CAS  Google Scholar 

  • Lodish H, Baltimore D, Berk A, Zipursky SL, Matsuaira P, Darnell J (1996) Synthesis and sorting of plasma membrane, secretory, and lysosomal proteins. Molecular Cell Biology (Scientific American Books). Freeman, New York, pp 711–715

    Google Scholar 

  • Loh EW, Smith I, Murray R, McLaughlin M, McNulty S, Ball D (1999) Association between variants at the GABAAβ2, GABAAα6 and GABAAγ2 gene cluster and alcohol dependence in a Scottish population. Mol Psychiatry 4:539–544

    Article  PubMed  CAS  Google Scholar 

  • Loh EW, Higuchi S, Matsushita S, Murray R, Chen CK, Ball D (2000) Association analysis of the GABAA receptor subunit genes cluster on 5q33–34 and alcohol dependence in a Japanese population. Mol Psychiatry 5:301–307

    Article  PubMed  CAS  Google Scholar 

  • Long JC, Knowler WC, Hanson RL, Robin RW, Urbanek M, Moore E, Bennett PH, Goldman D (1998) Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population. Am J Med Genet 81:216–221

    Article  PubMed  CAS  Google Scholar 

  • Lovinger DM (1999) 5-HT3 receptors and the neural actions of alcohols: an increasingly exciting topic. Neurochem Int 35:125–130

    Article  PubMed  CAS  Google Scholar 

  • Maas JW Jr, Vogt SK, Chan GC, Pineda VV, Storm DR, Muglia LJ (2005) Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity. J Neurosci 25:4118–4126

    Article  PubMed  CAS  Google Scholar 

  • Macdonald RL (1995) Ethanol, γ-aminobutyrate type A receptors, and protein kinase C phosphorylation. Proc Natl Acad Sci U S A 92:3633–3635

    Article  PubMed  CAS  Google Scholar 

  • MacLennan AJ, Lee N, Walker DW (1995) Chronic ethanol administration decreases brain-derived neurotrophic factor gene expression in the rat hippocampus. Neurosci Lett 197:105–108

    Article  PubMed  CAS  Google Scholar 

  • Mahmoudi M, Kang MH, Tillakarartne N, Tobin AJ, Olsen RW (1997) Chronic intermittent ethanol treatment in rats increases GABAA receptor α4-subunit expression: possible relevance to alcohol dependence. J Neurochem 68:2485–2492

    Article  PubMed  CAS  Google Scholar 

  • Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986) Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232:1004–1007

    Article  PubMed  CAS  Google Scholar 

  • Markwiese BJ, Acheson SK, Levin ED, Wilson WA, Swartzwelder HS (1998) Differential effects of ethanol on memory in adolescent and adult rats. Alcohol Clin Exp Res 22:416–421

    PubMed  CAS  Google Scholar 

  • Marutha Ravindran CR, Ticku MK (2006) Tyrosine kinase phosphorylation of GABAA receptor subunits following chronic ethanol exposure of cultured cortical neurons of mice. Brain Res 1086:35–41

    Article  PubMed  CAS  Google Scholar 

  • Marutha Ravindran CR, Mehta AK, Ticku MK (2007) Effect of chronic administration of ethanol on the regulation of tyrosine kinase phosphorylation of the GABAA receptor subunits in the rat brain. Neurochem Res 32:1179–1187

    Article  PubMed  CAS  Google Scholar 

  • Matthews DB, Silvers JR (2004) The use of acute ethanol administration as a tool to investigate multiple memory systems. Neurobiol Learn Mem 82:299–308

    Article  PubMed  CAS  Google Scholar 

  • Matthews DB, Devaud LL, Fritschy J-M, Sieghart W, Morrow AL (1998) Differential regulation of GABAA receptor gene expression by ethanol in the rat hippocampus vs. cerebral cortex. J Neurochem 70:1160–1166

    Article  PubMed  CAS  Google Scholar 

  • Matthews DB, Criswell HE, Grobin AC, Morrow AL (2000a) Chronic ethanol consumption alters recovery of spontaneously active medial septal/diagonal band of Broca neurons from GABA-microiontophoresis. Alcohol Clin Exp Res 24:1427–1432

    Article  PubMed  CAS  Google Scholar 

  • Matthews DB, Kralic JE, Devaud LL, Fritschy J-M, Morrow AL (2000b) Chronic blockade of N-methyl-D-aspartate receptors alters γ-aminobutyric acid type A receptor gene expression and function in the rat. J Neurochem 74:1522–1528

    Article  PubMed  CAS  Google Scholar 

  • Matthews DB, Morrow AL, Tokunaga S, McDaniel JR (2002) Acute ethanol administration and acute allopregnanolone administration impair spatial memory in the Morris water task. Alcohol Clin Exp Res 26:1747–1751

    PubMed  CAS  Google Scholar 

  • McCown TJ, Breese GR (1990) Multiple withdrawals from chronic ethanol “kindle” inferior collicular seizure activity: evidence for kindling of seizures associated with alcoholism. Alcohol Clin Exp Res 14:394–399

    Article  PubMed  CAS  Google Scholar 

  • McDonald BJ, Moss SJ (1997) Conserved phosphorylation of the intracellular domains of GABAA receptor β2 and β3 subunits by cAMP-dependent protein kinase, cGMP-dependent protein kinase, protein kinase C and Ca2+/calmodulin type II-dependent protein kinase. Neuropharmacology 36:1377–1385

    Article  PubMed  CAS  Google Scholar 

  • McKernan RM, Whiting PJ (1996) Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 19:139–143

    Article  PubMed  CAS  Google Scholar 

  • Mehta AK, Marutha Ravindran CR, Ticku MK (2007) Low concentrations of ethanol do not affect radioligand binding to the delta-subunit-containing GABAA receptors in the rat brain. Brain Res 1165:15–20

    Article  PubMed  CAS  Google Scholar 

  • Mhatre MC, Mehta AK, Ticku MK (1988) Chronic ethanol administration increases the binding of the benzodiazepine inverse agonist and alcohol antagonist [3H]Ro15-4513 in rat brain. Eur J Pharmacol 153:141–145

    Google Scholar 

  • Mhatre MC, Ticku MK (1992) Chronic ethanol administration alters γ-aminobutyric acid A receptor gene expression. Mol Pharmacol 42:415–422

    PubMed  CAS  Google Scholar 

  • Mhatre MC, Ticku MK (1994a) Chronic ethanol treatment upregulates GABAA receptor β subunit expression. Brain Res Mol Brain Res 23:246–252

    Article  PubMed  CAS  Google Scholar 

  • Mhatre MC, Ticku MK (1994b) Chronic GABA treatment downregulates the GABAA receptor α2 and α3 subunit mRNAs as well as polypeptide expression in primary cultured cerebral cortical neurons. Brain Res Mol Brain Res 24:159–165

    Article  PubMed  CAS  Google Scholar 

  • Mhatre MC, Pena G, Sieghart W, Ticku MK (1993) Antibodies specific for GABAA receptor alpha subunits reveal that chronic alcohol treatment down-regulates alpha-subunit expression in rat brain regions. J Neurochem 61:1620–1625

    Article  PubMed  CAS  Google Scholar 

  • Mihalek RM, Bowers BJ, Wehner JM, Kralic JE, VanDoren MJ, Morrow AL, Homanics GE (2001) GABAA-receptor δ subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin Exp Res 25:1708–1718

    PubMed  CAS  Google Scholar 

  • Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MA, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA, Harrison NL (1997) Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors. Nature 389:385–389

    Article  PubMed  CAS  Google Scholar 

  • Mitsuyama H, Little KY, Sieghart W, Devaud LL, Morrow AL (1998) GABAA receptor α1, α4 and β3 subunit mRNA and protein expression in frontal cortex of human alcoholics. Alcohol Clin Exp Res 22(4):815–822

    PubMed  CAS  Google Scholar 

  • Mody I (2001) Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem Res 26:907–913

    Article  PubMed  CAS  Google Scholar 

  • Mohler H, Fritschy J-M, Lüscher B, Rudolph U, Benson J, Benke D (1996) The GABAA receptors: from subunits to diverse functions. In: Narahashi T (ed) Ion channels, vol 4. Plenum, New York, pp 89–111

    Google Scholar 

  • Montpied P, Ginns EI, Martin BM, Roca D, Farb DH, Paul SM (1991a) Gamma-aminobutyric acid (GABA) induces a receptor-mediated reduction in GABAA receptor α subunit messenger RNAs in embryonic chick neurons in culture. J Biol Chem 266:6011–6014

    PubMed  CAS  Google Scholar 

  • Montpied P, Morrow AL, Karanian JW, Ginns EI, Martin BM, Paul SM (1991b) Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor α subunit mRNAs in the rat cerebral cortex. Mol Pharmacol 39:157–163

    PubMed  CAS  Google Scholar 

  • Moran MH, Goldberg N, Smith SS (1998) Progesterone withdrawal II: Insensitivity to the sedative effects of a benzodiazepine. Brain Res 807:91–100

    Article  PubMed  CAS  Google Scholar 

  • Morrow AL, Suzdak PD, Paul SM (1987) Steroid hormone metabolites potentiate GABA receptor-mediated chloride ion flux with nanomolar potency. Eur J Pharmacol 142:483–485

    Article  PubMed  CAS  Google Scholar 

  • Morrow AL, Suzdak PD, Karanian JW, Paul SM (1988) Chronic ethanol administration alters γ-aminobutyric acid, pentobarbital and ethanol-mediated 36Cl- uptake in cerebral cortical synaptoneurosomes. J Pharmacol Exp Ther 246:158–164

    PubMed  CAS  Google Scholar 

  • Morrow AL, Herbert JS, Montpied P (1992) Differential effects of chronic ethanol administration on GABAA receptor α1 and α6 subunit mRNA levels in rat cerebellum. Mol Cell Neurosci 3:251–258

    Article  CAS  PubMed  Google Scholar 

  • Morrow AL, VanDoren MJ, Devaud LL (1998) Effects of progesterone or neuroactive steroid? Nature 395:652–653

    Article  PubMed  CAS  Google Scholar 

  • Morrow AL, Janis GC, VanDoren MJ, Matthews DB, Samson HH, Janak PH, Grant KA (1999) Neurosteroids mediate pharmacological effects of ethanol: a new mechanism of ethanol action? Alcohol Clin Exp Res 23:1933–1940

    Article  PubMed  CAS  Google Scholar 

  • Morrow AL, VanDoren MJ, Penland SN, Matthews DB (2001) The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence. Brain Res Rev 37:98–109

    Article  PubMed  CAS  Google Scholar 

  • Morrow AL, Porcu P, Boyd KN, Grant KA (2006) Hypothalamic–pituitary–adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior. Dialogues Clin Neurosci 8:463–477

    PubMed  Google Scholar 

  • Moss SJ, Smart TG (2001) Constructing inhibitory synapses. Nat Rev Neurosci 2:240–250

    Article  PubMed  CAS  Google Scholar 

  • Moss SJ, Smart TG, Blackstone CD, Huganir RL (1992) Functional modulation of GABAA receptors by cAMP-dependent protein phosphorylation. Science 257:661–665

    Article  PubMed  CAS  Google Scholar 

  • Moy SS, Knapp DJ, Criswell HE, Breese GR (1997) Flumazenil blockade of anxiety following ethanol withdrawal in rats. Psychopharmacology 131:354–360

    Article  PubMed  CAS  Google Scholar 

  • Moy SS, Knapp DJ, Duncan GE, Breese GR (2000) Enhanced ultrasonic vocalization and Fos protein expression following ethanol withdrawal: effects of flumazenil. Psychopharmacology 152:208–215

    Article  PubMed  CAS  Google Scholar 

  • Nance DM (1983) The developmental and neural determinants of the effects of estrogen on feeding behavior in the rat: a theoretical perspective. Neurosci Biobehav Rev 7:189–211

    Article  PubMed  CAS  Google Scholar 

  • Newton PM, Messing RO (2006) Intracellular signaling pathways that regulate behavioral responses to ethanol. Pharmacol Ther 109:227–237

    Article  PubMed  CAS  Google Scholar 

  • Niimura M, Moussa R, Bissoon N, Ikeda-Douglas C, Milgram NW, Gurd JW (2005) Changes in phosphorylation of the NMDA receptor in the rat hippocampus induced by status epilepticus. J Neurochem 92:1377–1385

    Article  PubMed  CAS  Google Scholar 

  • O'Dell LE, Alomary AA, Vallee M, Koob GF, Fitzgerald RL, Purdy RH (2004) Ethanol-induced increases in neuroactive steroids in the rat brain and plasma are absent in adrenalectomized and gonadectomized rats. Eur J Pharmacol 484:241–247

    Article  PubMed  CAS  Google Scholar 

  • Obrietan K, Gao XB, Van Den Pol AN (2002) Excitatory actions of GABA increase BDNF expression via a MAPK-CREB-dependent mechanism—a positive feedback circuit in developing neurons. J Neurophysiol 88:1005–1015

    PubMed  CAS  Google Scholar 

  • Oh S, Jang CG, Ma T, Ho IK (1999) Activation of protein kinase C by phorbol dibutyrate modulates GABAA receptor binding in rat brain slices. Brain Res 850:158–165

    Article  PubMed  CAS  Google Scholar 

  • Olive MF, Hodge CW (2000) Co-localization of PKCε with various GABAA receptor subunits in the mouse limbic system. Neuroreport 11:683–687

    Article  PubMed  CAS  Google Scholar 

  • Olsen RW, Sieghart W (2008) International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev 60:243–260

    Article  PubMed  CAS  Google Scholar 

  • Olsen RW, Sieghart W (2009) GABAA receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 56:141–148

    Article  PubMed  CAS  Google Scholar 

  • Pandey SC (1998) Neuronal signaling systems and ethanol dependence. Mol Neurobiol 17:1–15

    Article  PubMed  CAS  Google Scholar 

  • Pandey SC, Roy A, Zhang H (2003) The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats. Alcohol Clin Exp Res 27:396–409

    Article  PubMed  CAS  Google Scholar 

  • Papadeas S, Grobin AC, Morrow AL (2001) Chronic ethanol consumption differentially alters GABAA receptor α1 and α4 subunit peptide expressions and GABAA receptor-mediated 36CL- uptake in mesocorticolimbic regions of rat brain. Alcohol Clin Exp Res 25:1270–1275

    PubMed  CAS  Google Scholar 

  • Park-Chung M, Malayev A, Purdy RH, Gibbs TT, Farb DH (1999) Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites. Brain Research 830:72–87

    Article  PubMed  CAS  Google Scholar 

  • Park SK, Sedore SA, Cronmiller C, Hirsh J (2000) Type II cAMP-dependent protein kinase-deficient Drosophila are viable but show developmental, circadian, and drug response phenotypes. J Biol Chem 275:20588–20596

    Article  PubMed  CAS  Google Scholar 

  • Parsian A, Zhang ZH (1999) Human chromosomes 11p15 and 4p12 and alcohol dependence: possible association with the GABRB1 gene. Am J Med Genet 88:533–538

    Article  PubMed  CAS  Google Scholar 

  • Petrie J, Sapp DW, Tyndale RF, Park MK, Fanselow M, Olsen RW (2001) Altered GABAA receptor subunit and splice variant expression in rats treated with chronic intermittent ethanol. Alcohol Clin Exp Res 25:819–828

    Article  PubMed  CAS  Google Scholar 

  • Pierucci-Lagha A, Covault J, Feinn R, Nellissery M, Hernandez-Avila C, Oncken C, Morrow AL, Kranzler HR (2005) GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride. Neuropsychopharmacology 30:1193–1203

    Article  PubMed  CAS  Google Scholar 

  • Pignataro L, Miller AN, Ma L, Midha S, Protiva P, Herrera DG, Harrison NL (2007) Alcohol regulates gene expression in neurons via activation of heat shock factor 1. J Neurosci 27:12957–12966

    Article  PubMed  CAS  Google Scholar 

  • Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815–850

    Article  PubMed  CAS  Google Scholar 

  • Platt DM, Duggan A, Spealman RD, Cook JM, Li X, Yin W, Rowlett JK (2005) Contribution of α1 GABAA and α5 GABAA receptor subtypes to the discriminative stimulus effects of ethanol in squirrel monkeys. J Pharmacol Exp Ther 313:658–667

    Article  PubMed  CAS  Google Scholar 

  • Poisbeau P, Cheney MC, Browning MD, Mody I (1999) Modulation of synaptic GABAA receptor function by PKA and PKC in adult hippocampal neurons. J Neurosci 19:674–683

    PubMed  CAS  Google Scholar 

  • Porcu P, Sogliano C, Ibba C, Piredda M, Tocco S, Marra C, Purdy RH, Biggio G, Concas A (2004) Failure of γ-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized-orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals. Brain Res 1012:160–168

    Article  PubMed  CAS  Google Scholar 

  • Porter NM, Twyman RE, Uhler MD, Macdonald RL (1990) Cyclic AMP-dependent protein kinase decreases GABAA receptor current in mouse spinal neurons. Neuron 5:789–796

    Article  PubMed  CAS  Google Scholar 

  • Powell K (2006) How does the teenage brain work? Nature 442:865–867

    Article  PubMed  CAS  Google Scholar 

  • Proctor WR, Poelchen W, Bowers BJ, Wehner JM, Messing RO, Dunwiddie TV (2003) Ethanol differentially enhances hippocampal GABA A receptor-mediated responses in protein kinase C gamma (PKC gamma) and PKC epsilon null mice. J Pharmacol Exp Ther 305:264–270

    Article  PubMed  CAS  Google Scholar 

  • Proctor WR, Wu PH, Bennett B, Johnson TE (2004) Differential effects of ethanol on gamma-aminobutyric acid-A receptor-mediated synaptic currents in congenic strains of inbred long and short-sleep mice. Alcohol Clin Exp Res 28:1277–1283

    Article  PubMed  CAS  Google Scholar 

  • Puia G, Ducic I, Vicini S, Costa E (1993) Does neurosteroid modulatory efficacy depend on GABAA receptor subunit composition? Receptors Channels 1:135–142

    PubMed  CAS  Google Scholar 

  • Pyapali GK, Turner DA, Wilson WA, Swartzwelder HS (1999) Age and dose-dependent effects of ethanol on the induction of hippocampal long-term potentiation. Alcohol 19:107–111

    Article  PubMed  CAS  Google Scholar 

  • Qi ZH, Song M, Wallace MJ, Wang D, Newton PM, McMahon T, Chou WH, Zhang C, Shokat KM, Messing RO (2007) Protein kinase Cε regulates γ-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of γ2 subunits. J Biol Chem 282:33052–33063

    Article  PubMed  CAS  Google Scholar 

  • Quertemont E, Lallemand F, Colombo G, De Witte P (2000) Taurine and ethanol preference: a microdialysis study using Sardinian alcohol-preferring and non-preferring rats. Eur Neuropsychopharmacol 10:377–383

    Article  PubMed  CAS  Google Scholar 

  • Radcliffe RA, Floyd KL, Drahnak JA, Deitrich RA (2005) Genetic dissociation between ethanol sensitivity and rapid tolerance in mouse and rat strains selectively bred for differential ethanol sensitivity. Alcohol Clin Exp Res 29:1580–1589

    Article  PubMed  Google Scholar 

  • Radel M, Vallejo RL, Iwata N, Aragon R, Long JC, Virkkunen M, Goldman D (2005) Haplotype-based localization of an alcohol dependence gene to the 5q34 γ-aminobutyric acid type A gene cluster. Arch Gen Psychiatry 62:47–55

    Article  PubMed  CAS  Google Scholar 

  • Rajendran P, Spear LP (2004) The effects of ethanol on spatial and nonspatial memory in adolescent and adult rats studied using an appetitive paradigm. Ann NY Acad Sci 1021:441–444

    Article  PubMed  CAS  Google Scholar 

  • Rakhade SN, Zhou C, Aujla PK, Fishman R, Sucher NJ, Jensen FE (2008) Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures. J Neurosci 28:7979–7990

    Article  PubMed  CAS  Google Scholar 

  • Reich T (1996) A genomic survey of alcohol dependence and related phenotypes: results from the Collaborative Study on the Genetics of Alcoholism (COGA). Alcohol Clin Exp Res 20:133A–137A

    Article  PubMed  CAS  Google Scholar 

  • Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, Van Eerdewegh P, Foroud T, Hesselbrock V, Schuckit MA, Bucholz K, Porjesz B, Li TK, Conneally PM, Nurnberger JI Jr, Tischfield JA, Crowe RR, Cloninger CR, Wu W, Shears S, Carr K, Crose C, Willig C, Begleiter H (1998) Genome-wide search for genes affecting the risk for alcohol dependence. Am J Med Genet 81:207–215

    Article  PubMed  CAS  Google Scholar 

  • Rewal M, Jurd R, Gill TM, He DY, Ron D, Janak PH (2009) Alpha4-containing GABAA receptors in the nucleus accumbens mediate moderate intake of alcohol. J Neurosci 29:543–549

    Article  PubMed  CAS  Google Scholar 

  • Ripley TL, Dunworth SJ, Stephens DN (2002) Consequences of amygdala kindling and repeated withdrawal from ethanol on amphetamine-induced behaviours. Eur J Neurosci 16:1129–1138

    Article  PubMed  Google Scholar 

  • Robello M, Amico C, Cupello A (1993) Regulation of GABAA receptor in cerebellar granule cells in culture: differential involvement of kinase activities. Neuroscience 53:131–138

    Article  PubMed  CAS  Google Scholar 

  • Robello M, Amico C, Cupello A (1997) A dual mechanism for impairment of GABAA receptor activity by NMDA receptor activation in rat cerebellum granule cells. Eur Biophys J 25:181–187

    Article  PubMed  CAS  Google Scholar 

  • Roberto M, Madamba SG, Moore SD, Tallent MK, Siggins GR (2003) Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proc Natl Acad Sci U S A 100:2053–2058

    Article  PubMed  CAS  Google Scholar 

  • Roberto M, Madamba SG, Stouffer DG, Parsons LH, Siggins GR (2004) Increased GABA release in the central amygdala of ethanol-dependent rats. J Neurosci 24:10159–10166

    Article  PubMed  CAS  Google Scholar 

  • Roca DJ, Rozenberg I, Farrant M, Farb DH (1990) Chronic agonist exposure induces down-regulation and allosteric uncoupling of the gamma-aminobutyric acid/benzodiazepine receptor complex. Mol Pharmacol 37:37–43

    PubMed  CAS  Google Scholar 

  • Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H (1999) Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 401:796–800

    Article  PubMed  CAS  Google Scholar 

  • Salimov RM, McBride WJ, McKinzie DL, Lumeng L, Li TK (1996) Effects of ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests. Alcohol 13:297–300

    Article  PubMed  CAS  Google Scholar 

  • Sanchis-Segura C, Cline B, Jurd R, Rudolph U, Spanagel R (2007) Etomidate and propofol-hyposensitive GABAA receptor β3(N265M) mice show little changes in acute alcohol sensitivity but enhanced tolerance and withdrawal. Neurosci Lett 416:275–278

    Article  PubMed  CAS  Google Scholar 

  • Sander T, Ball D, Murray R, Patel J, Samochowiec J, Winterer G, Rommelspacher H, Schmidt LG, Loh EW (1999) Association analysis of sequence variants of GABAA α6, β2, and γ2 gene cluster and alcohol dependence. Alcohol Clin Exp Res 23:427–431

    PubMed  CAS  Google Scholar 

  • Sanna E, Serra M, Cossu A, Colombo G, Follesa P, Cuccheddu T, Concas A, Biggio G (1993) Chronic ethanol intoxication induces differential effects on GABAA and NMDA receptor function in the rat brain. Alcohol Clin Exp Res 17:115–123

    Article  PubMed  CAS  Google Scholar 

  • Sanna E, Talani G, Busonero F, Pisu MG, Purdy RH, Serra M, Biggio G (2004) Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus. J Neurosci 24:6521–6530

    Article  PubMed  CAS  Google Scholar 

  • Santhakumar V, Hanchar HJ, Wallner M, Olsen RW, Otis TS (2006) Contributions of the GABAA receptor α6 subunit to phasic and tonic inhibition revealed by a naturally occurring polymorphism in the α6 gene. J Neurosci 26:3357–3364

    Article  PubMed  CAS  Google Scholar 

  • Schuckit MA, Mazzanti C, Smith TL, Ahmed U, Radel M, Iwata N, Goldman D (1999) Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABAα6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study. Biol Psychiatry 45:647–651

    Article  PubMed  CAS  Google Scholar 

  • Serra M, Pisu MG, Floris I, Cara V, Purdy RH, Biggio G (2003) Social isolation-induced increase in the sensitivity of rats to the steroidogenic effect of ethanol. J Neurochem 85:257–263

    Article  PubMed  CAS  Google Scholar 

  • Shannon EE, Shelton KL, Vivian JA, Yount I, Morgan AR, Homanics GE, Grant KA (2004) Discriminative stimulus effects of ethanol in mice lacking the γ-aminobutyric acid type A receptor δ subunit. Alcohol Clin Exp Res 28:906–913

    PubMed  CAS  Google Scholar 

  • Shelton KL, Grant KA (2002) Discriminative stimulus effects of ethanol in C57BL/6J and DBA/2J inbred mice. Alcohol Clin Exp Res 26:747–757

    PubMed  CAS  Google Scholar 

  • Shen EH, Dorow J, Harland R, Burkhart-Kasch S, Phillips TJ (1998) Seizure sensitivity and GABAergic modulation of ethanol sensitivity in selectively bred FAST and SLOW mouse lines. J Pharmacol Exp Ther 287:606–615

    PubMed  CAS  Google Scholar 

  • Sieghart W, Sperk G (2002) Subunit composition, distribution and function of GABA(A) receptor subtypes. Curr Top Med Chem 2:795–816

    Article  PubMed  CAS  Google Scholar 

  • Sieghart W, Fuchs K, Tretter V, Ebert V, Jechlinger M, Hoger H, Adamiker D (1999) Structure and subunit composition of GABAA receptors. Neurochem Int 34:379–385

    Article  PubMed  CAS  Google Scholar 

  • Silveri MM, Spear LP (1998) Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny. Alcohol Clin Exp Res 22(3):670–676

    Article  PubMed  CAS  Google Scholar 

  • Silveri MM, Spear LP (2000) Ontogeny of ethanol elimination and ethanol-induced hypothermia. Alcohol 20:45–53

    Article  PubMed  CAS  Google Scholar 

  • Silvers JM, Tokunaga S, Berry RB, White AM, Matthews DB (2003a) Impairments in spatial learning and memory: ethanol, allopregnanolone, and the hippocampus. Brain Res Rev 43:275–284

    Article  PubMed  CAS  Google Scholar 

  • Silvers JM, Tokunaga S, Mittleman G, Matthews DB (2003b) Chronic intermittent injections of high-dose ethanol during adolescence produce metabolic, hypnotic, and cognitive tolerance in rats. Alcohol Clin Exp Res 27:1606–1612

    Article  PubMed  CAS  Google Scholar 

  • Silvers JM, Tokunaga S, Mittleman G, Matthews DB (2003c) Chronic intermittent injections of high-dose ethanol during adolescence produce metabolic, hypnotic, and cognitive tolerance in rats. Alcohol Clin Exp Res 27:1606–1612

    Article  PubMed  CAS  Google Scholar 

  • Silvers JM, Tokunaga S, Mittleman G, O'Buckley T, Morrow AL, Matthews DB (2006) Chronic intermittent ethanol exposure during adolescence reduces the effect of ethanol challenge on hippocampal allopregnanolone levels and Morris water maze task performance. Alcohol 39:151–158

    Article  PubMed  CAS  Google Scholar 

  • Simpson CA, Rush CR (2002) Acute performance-impairing and subject-rated effects of triazolam and temazepam, alone and in combination with ethanol, in humans. J Psychopharmacol 16:23–34

    Article  PubMed  CAS  Google Scholar 

  • Sisk CL, Foster DL (2004) The neural basis of puberty and adolescence. Nat Neurosci 7:1040–1047

    Article  PubMed  CAS  Google Scholar 

  • Smith SS (1989) Progesterone enhances inhibitory responses of cerebellar Purkinje cells mediated by the GABAA receptor subtype. Brain Res Bull 23:317–322

    Article  PubMed  CAS  Google Scholar 

  • Smith RF (2003) Animal models of periadolescent substance abuse. Neurotoxicol Teratol 25:291–301

    Article  PubMed  CAS  Google Scholar 

  • Smith SS, Gong QH, Hsu F-C, Markowitz RS, Ffrench-Mullen JMH, Li X (1998) GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392:926–930

    Article  PubMed  CAS  Google Scholar 

  • Smith SS, Ruderman Y, Hua Gong Q, Gulinello M (2004) Effects of a low dose of ethanol in an animal model of premenstrual anxiety. Alcohol 33:41–49

    PubMed  CAS  Google Scholar 

  • Song J, Koller DL, Foroud T, Carr K, Zhao J, Rice J, Nurnberger JI Jr, Begleiter H, Porjesz B, Smith TL, Schuckit MA, Edenberg HJ (2003) Association of GABAA receptors and alcohol dependence and the effects of genetic imprinting. Am J Med Genet B Neuropsychiatr Genet 117B:39–45

    Article  PubMed  Google Scholar 

  • Soyka M, Preuss UW, Hesselbrock V, Zill P, Koller G, Bondy B (2008) GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence. J Psychiatr Res 42:184–191

    Article  PubMed  CAS  Google Scholar 

  • Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463

    Article  PubMed  CAS  Google Scholar 

  • Spear LP (2007) Assessment of adolescent neurotoxicity: rationale and methodological considerations. Neurotoxicol Teratol 29:1–9

    Article  PubMed  CAS  Google Scholar 

  • Spear LP, Varlinskaya EI (2005) Adolescence. Alcohol sensitivity, tolerance, and intake. Recent Dev Alcohol 17:143–159

    Article  PubMed  Google Scholar 

  • Spencer RL, McEwen BS (1990) Adaptation of the hypothalamic–pituitary–adrenal axis to chronic ethanol stress. Neuroendocrinology 52:481–489

    Article  PubMed  CAS  Google Scholar 

  • Staley JK, Gottschalk C, Petrakis IL, Gueorguieva R, O'Malley S, Baldwin R, Jatlow P, Verhoeff NP, Perry E, Weinzimmer D, Frohlich E, Ruff E, van Dyck CH, Seibyl JP, Innis RB, Krystal JH (2005) Cortical gamma-aminobutyric acid type A-benzodiazepine receptors in recovery from alcohol dependence: relationship to features of alcohol dependence and cigarette smoking. Arch Gen Psychiatry 62:877–888

    Article  PubMed  CAS  Google Scholar 

  • Stell BM, Brickley SG, Tang CY, Farrant M, Mody I (2003) Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors. Proc Natl Acad Sci U S A 100:14439–14444

    Article  PubMed  CAS  Google Scholar 

  • Stellwagen D, Beattie EC, Seo JY, Malenka RC (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 25:3219–3228

    Article  PubMed  CAS  Google Scholar 

  • Stephens DN, Pistovcakova J, Worthing L, Atack JR, Dawson GR (2005) Role of GABAA alpha5-containing receptors in ethanol reward: the effects of targeted gene deletion, and a selective inverse agonist. Eur J Pharmacol 526:240–250

    Article  PubMed  CAS  Google Scholar 

  • Sullivan EV, Sable HJ, Strother WN, Friedman DP, Davenport A, Tillman-Smith H, Kraft RA, Wyatt C, Szeliga KT, Buchheimer NC, Daunais JB, Adalsteinsson E, Pfefferbaum A, Grant KA (2005) Neuroimaging of rodent and primate models of alcoholism: initial reports from the integrative neuroscience initiative on alcoholism. Alcohol Clin Exp Res 29:287–294

    Article  PubMed  Google Scholar 

  • Sundstrom-Poromaa I, Smith DH, Gong QH, Sabado TN, Li X, Light A, Wiedmann M, Williams K, Smith S (2002) Hormonally regulated α4β2δ GABAA receptors are a target for alcohol. Nat Neurosci 5:721–722

    PubMed  CAS  Google Scholar 

  • Sur C, Farrar SJ, Kerby J, Whiting PJ, Atack JR, McKernan RM (1999) Preferential coassembly of α4 and δ subunits of the γ-aminobutyric acidA receptor in rat thalamus. Mol Pharmacol 56:110–115

    PubMed  CAS  Google Scholar 

  • Takiguchi A, Masuoka T, Yamamoto Y, Mikami A, Kamei C (2006) Potentiation of ethanol in spatial memory deficits induced by some benzodiazepines. J Pharmacol Sci 101:325–328

    Article  PubMed  CAS  Google Scholar 

  • Tapia-Arancibia L, Rage F, Givalois L, Dingeon P, Arancibia S, Beauge F (2001) Effects of alcohol on brain-derived neurotrophic factor mRNA expression in discrete regions of the rat hippocampus and hypothalamus. J Neurosci Res 63:200–208

    Article  PubMed  CAS  Google Scholar 

  • Tauber M, Calame-Droz E, Prut L, Rudolph U, Crestani F (2003) α2-γ-Aminobutyric acid (GABA) A receptors are the molecular substrates mediating precipitation of narcosis but not of sedation by the combined use of diazepam and alcohol in vivo. Eur J Neurosci 18:2599–2604

    Article  PubMed  Google Scholar 

  • Taylor C, Nash J, Rich A, Lingford-Hughes A, Nutt D, Potokar J (2008) Assessment of GABAA benzodiazepine receptor (GBzR) sensitivity in patients with alcohol dependence. Alcohol Alcohol 43:614–618

    PubMed  CAS  Google Scholar 

  • Tehrani MHJ, Barnes EM Jr (1997) Sequestration of gamma-aminobutyric acidA receptors on clathrin-coated vesicles during chronic benzodiazepine administration in vivo. J Pharmacol Exp Ther 283:384–390

    PubMed  CAS  Google Scholar 

  • Terunuma M, Xu J, Vithlani M, Sieghart W, Kittler J, Pangalos M, Haydon PG, Coulter DA, Moss SJ (2008) Deficits in phosphorylation of GABAA receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus. J Neurosci 28:376–384

    Article  PubMed  CAS  Google Scholar 

  • Thiele TE, Willis B, Stadler J, Reynolds JG, Bernstein IL, McKnight GS (2000) High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice. J Neurosci 20:RC75

    PubMed  CAS  Google Scholar 

  • Thomas P, Mortensen M, Hosie AM, Smart TG (2005) Dynamic mobility of functional GABAA receptors at inhibitory synapses. Nat Neurosci 8:889–897

    PubMed  CAS  Google Scholar 

  • Ticku MK, Burch T (1980) Alterations in γ-aminobutyric acid receptor sensitivity following acute and chronic ethanol treatments. J Neurochem 34:417–423

    Article  PubMed  CAS  Google Scholar 

  • Tokunaga S, Silvers JM, Matthews DB (2006) Chronic intermittent ethanol exposure during adolescence blocks ethanol-induced inhibition of spontaneously active hippocampal pyramidal neurons. Alcohol Clin Exp Res 30:1–6

    Article  PubMed  CAS  Google Scholar 

  • Tossman U, Jonsson G, Ungerstedt U (1986) Regional distribution and extracellular levels of amino acids in rat central nervous system. Acta Physiol Scand 127:533–545

    Article  PubMed  CAS  Google Scholar 

  • Tran VT, Snyder SH, Major LF, Hawley RJ (1981) GABA receptors are increased in brains of alcoholics. Ann Neurol 9:289–292

    Article  PubMed  CAS  Google Scholar 

  • Tremwel MF, Hunter BE, Peris J (1994) Chronic ethanol exposure enhances [3H]GABA release and does not affect GABAA receptor mediated 36Cl uptake. Synapse 17:149–154

    Article  PubMed  CAS  Google Scholar 

  • Tretter V, Ehya N, Fuchs K, Sieghart W (1997) Stoichiometry and assembly of a recombinant GABAA receptor subtype. J Neurosci 17:2728–2737

    PubMed  CAS  Google Scholar 

  • Truxell E, Molina JC, Spear NE (2007) Ethanol intake in the juvenile, adolescent, and adult rat: effects of age and prior exposure to ethanol. Alcohol Clin Exp Res 31:755–765

    Article  PubMed  CAS  Google Scholar 

  • Ueno S, Lin A, Nikolaeva N, Trudell JR, Mihic SJ, Harris RA, Harrison NL (2000) Tryptophan scanning mutagenesis in TM2 of the GABAA receptor α subunit: effects on channel gating and regulation by ethanol. Br J Pharmacol 131:296–302

    Article  PubMed  CAS  Google Scholar 

  • Valenzuela CF, Mameli M, Carta M (2005) Single-amino-acid difference in the sequence of alpha6 subunit dramatically increases the ethanol sensitivity of recombinant GABAA receptors. Alcohol Clin Exp Res 29:1356–1357 Author reply 1358

    Article  PubMed  Google Scholar 

  • VanDoren MJ, Matthews DB, Janis GC, Grobin AC, Devaud LL, Morrow AL (2000) Neuroactive steroid 3α-hydroxy-5α-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol. J Neurosci 20:1982–1989

    PubMed  CAS  Google Scholar 

  • Varlinskaya EI, Spear LP (2002) Acute effects of ethanol on social behavior of adolescent and adult rats: role of familiarity of the test situation. Alcohol Clin Exp Res 26:1502–1511

    PubMed  Google Scholar 

  • Varlinskaya EI, Spear LP (2004) Acute ethanol withdrawal (hangover) and social behavior in adolescent and adult male and female Sprague-Dawley rats. Alcohol Clin Exp Res 28:40–50

    Article  PubMed  Google Scholar 

  • Vetter CS, Doremus-Fitzwater TL, Spear LP (2007) Time course of elevated ethanol intake in adolescent relative to adult rats under continuous, voluntary-access conditions. Alcohol Clin Exp Res 31:1159–1168

    Article  PubMed  CAS  Google Scholar 

  • Vivian JA, Green HL, Young JE, Majerksy LS, Thomas BW, Shively CA, Tobin JR, Nader MA, Grant KA (2001) Induction and maintenance of ethanol self-administration in cynomolgus monkeys (Macaca fascicularis): long-term characterization of sex and individual differences. Alcohol Clin Exp Res 25:1087–1097

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Wang GJ, Hitzemann R, Fowler JS, Wolf AP, Pappas N, Biegon A, Dewey SL (1993) Decreased cerebral response to inhibitory neurotransmission in alcoholics. Am J Psychiatr 150:417–422

    PubMed  CAS  Google Scholar 

  • Volkow ND, Wang GJ, Overall JE, Hitzemann R, Fowler JS, Pappas N, Frecska E, Piscani K (1997) Regional brain metabolic response to lorazepam in alcoholics during early and late alcohol detoxification. Alcohol Clin Exp Res 21:1278–1284

    PubMed  CAS  Google Scholar 

  • Wallner M, Hanchar HJ, Olsen RW (2003) Ethanol enhances α4β3δ and α6β3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Natl Acad Sci U S A 100:15218–15223

    Article  PubMed  CAS  Google Scholar 

  • Wallace MJ, Newton PM, Oyasu M, McMahon T, Chou WH, Connolly J, Messing RO (2007) Acute functional tolerance to ethanol mediated by protein kinase Cepsilon. Neuropsychopharmacology 32:127–136

    Article  PubMed  CAS  Google Scholar 

  • Wallner M, Hanchar HJ, Olsen RW (2006) Low-dose alcohol actions on α4β3δ GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513. Proc Natl Acad Sci USA 103:8540–8545

    Article  PubMed  CAS  Google Scholar 

  • Wei W, Zhang N, Peng Z, Houser CR, Mody I (2003) Perisynaptic localization of δsubunit-containing GABAA receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci 23:10650–10661

    PubMed  CAS  Google Scholar 

  • Wei W, Faria LC, Mody I (2004) Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J Neurosci 24:8379–8382

    Article  PubMed  CAS  Google Scholar 

  • 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. J Pharmacol Exp Ther 319:219–227

    Article  PubMed  CAS  Google Scholar 

  • Werner DF, Swihart AR, Ferguson C, Lariviere WR, Harrison NL, Homanics GE (2009) Alcohol-induced tolerance and physical dependence in mice with ethanol insensitive alpha1 GABAA receptors. Alcohol Clin Exp Res 33:289–299

    Article  PubMed  CAS  Google Scholar 

  • White AM, Ghia AJ, Levin ED, Swartzwelder HS (2000) Binge pattern ethanol exposure in adolescent and adult rats: differential impact on subsequent responsiveness to ethanol. Alcohol Clin Exp Res 24:1251–1256

    Article  PubMed  CAS  Google Scholar 

  • White AM, Bae JG, Truesdale MC, Ahmad S, Wilson WA, Swartzwelder HS (2002a) Chronic-intermittent ethanol exposure during adolescence prevents normal developmental changes in sensitivity to ethanol-induced motor impairments. Alcohol Clin Exp Res 26:960–968

    Article  PubMed  CAS  Google Scholar 

  • White AM, Truesdale MC, Bae JG, Ahmad S, Wilson WA, Best PJ, Swartzwelder HS (2002b) Differential effects of ethanol on motor coordination in adolescent and adult rats. Pharmacol Biochem Behav 73:673–677

    Article  PubMed  CAS  Google Scholar 

  • Whittemore ER, Yang W, Drewe JA, Woodward RM (1996) Pharmacology of the human γ-aminobutyric acidA α4 subunit expressed in Xenopus laevis oocytes. Mol Pharmacol 50:1365–1375

    Google Scholar 

  • Wick MJ, Mihic SJ, Ueno S, Mascia MP, Trudell JR, Brozowski SJ, Ye Q, Harrison NL, Harris RA (1998) Mutations of γ-aminobutyric acid and glycine receptors change alcohol cutoff: evidence for an alcohol receptor? Proc Natl Acad Sci U S A 95:6504–6509

    Article  PubMed  CAS  Google Scholar 

  • Wick MJ, Radcliffe RA, Bowers BJ, Mascia MP, Luscher B, Harris RA, Wehner JM (2000) Behavioural changes produced by transgenic overexpression of γ2L and γ2S subunits of the GABAA receptor. Eur J Neurosci 12:2634–2638

    Article  PubMed  CAS  Google Scholar 

  • Wills TA, Knapp DJ, Overstreet DH, Breese GR (2008) Differential dietary ethanol intake and blood ethanol levels in adolescent and adult rats: effects on anxiety-like behavior and seizure thresholds. Alcohol Clin Exp Res 32:1350–1360

    Article  PubMed  Google Scholar 

  • Wisden W, Herb A, Wieland H, Keinänen K, Lüddens H, Seeburg PH (1991) Cloning, pharmacological characteristics and expression pattern of the rat GABAA receptor α4 subunit. FEBS Lett 289:227–230

    Article  PubMed  CAS  Google Scholar 

  • Wisden W, Laurie DH, Monyer H, Seeburg PH (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci 12:1040–1062

    PubMed  CAS  Google Scholar 

  • Woo E, Greenblatt DJ (1979) Massive benzodiazepine requirements during acute alcohol withdrawal. Am J Psychiatry 136:821–823

    PubMed  CAS  Google Scholar 

  • Yamashita M, Marszalec W, Yeh JZ, Narahashi T (2006) Effects of ethanol on tonic GABA currents in cerebellar granule cells and mammalian cells recombinantly expressing GABAA receptors. J Pharmacol Exp Ther 319:431–438

    Article  PubMed  CAS  Google Scholar 

  • Ye Q, Koltchine VV, Mihic SJ, Mascia MP, Wick MJ, Finn SE, Harrison NL, Harris RA (1998) Enhancement of glycine receptor function by ethanol is inversely correlated with molecular volume at position α267. J Biol Chem 273:3314–3319

    Article  PubMed  CAS  Google Scholar 

  • Yu Z-Y, Wang W, Fritschy J-M, Witte OW, Redecker C (2006) Changes in neocortical and hippocampal GABAA receptor subunit distribution during brain maturation and aging. Brain Res 1099:73–81

    Article  PubMed  CAS  Google Scholar 

  • Zafra F, Castren E, Thoenen H, Lindholm D (1991) Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci USA 88:10037–10041

    Article  PubMed  CAS  Google Scholar 

  • Ziskind-Conhaim L, Gao BX, Hinckley C (2003) Ethanol dual modulatory actions on spontaneous postsynaptic currents in spinal motoneurons. J Neurophysiol 89:806–813

    Article  PubMed  CAS  Google Scholar 

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Correspondence to A. Leslie Morrow.

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Kumar, S., Porcu, P., Werner, D.F. et al. The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology 205, 529–564 (2009). https://doi.org/10.1007/s00213-009-1562-z

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