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Glutamatergic targets for new alcohol medications

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Abstract

Rationale

An increasingly compelling literature points to a major role for the glutamate system in mediating the effects of alcohol on behavior and the pathophysiology of alcoholism. Preclinical studies indicate that glutamate signaling mediates certain aspects of ethanol's intoxicating and rewarding effects, and undergoes adaptations following chronic alcohol exposure that may contribute to the withdrawal, craving and compulsive drug-seeking that drive alcohol abuse and alcoholism.

Objectives

We discuss the potential for targeting the glutamate system as a novel pharmacotherapeutic approach to treating alcohol use disorders, focusing on five major components of the glutamate system: the N-methyl-d-aspartate (NMDA) receptor and specific NMDA subunits, the glycineB site on the NMDA receptors (NMDAR), l-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPA) and kainate (KAR) receptors, metabotropic receptors (mGluR), and glutamate transporters.

Results

Chronic alcohol abuse produces a hyperglutamatergic state, characterized by elevated extracellular glutamate and altered glutamate receptors and transporters. Pharmacologically manipulating glutamatergic neurotransmission alters alcohol-related behaviors including intoxication, withdrawal, and alcohol-seeking, in rodents and human subjects. Blocking NMDA and AMPA receptors reduces alcohol consumption in rodents, but side-effects may limit this as a therapeutic approach. Selectively targeting NMDA and AMPA receptor subunits (e.g., GluN2B, GluA3), or the NMDAR glycineB site offers an alternative approach. Blocking mGluR5 potently affects various alcohol-related behaviors in rodents, and mGluR2/3 agonism also suppresses alcohol consumption. Finally, glutamate transporter upregulation may mitigate behavioral and neurotoxic sequelae of excess glutamate caused by alcohol.

Conclusions

Despite the many challenges that remain, targeting the glutamate system offers genuine promise for developing new treatments for alcoholism.

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References

  • Abrahao KP, Ariwodola OJ, Butler TR, Rau AR, Skelly MJ, Carter E, Alexander NP, McCool BA, Souza-Formigoni ML, Weiner JL (2013) Locomotor sensitization to ethanol impairs NMDA receptor-dependent synaptic plasticity in the nucleus accumbens and increases ethanol self-administration. J Neurosci 33:4834–4842

    Article  PubMed  CAS  Google Scholar 

  • Abulseoud OA, Miller JD, Wu J, Choi DS, Holschneider DP (2012) Ceftriaxone upregulates the glutamate transporter in medial prefrontal cortex and blocks reinstatement of methamphetamine seeking in a condition place preference paradigm. Brain Res 1456:14–21

    Article  PubMed  CAS  Google Scholar 

  • Adams CL, Cowen MS, Short JL, Lawrence AJ (2008) Combined antagonism of glutamate mGlu5 and adenosine A2A receptors interact to regulate alcohol-seeking in rats. Int J Neuropsychopharmacol 11:229–241

    Article  PubMed  CAS  Google Scholar 

  • Adermark L, Clarke RB, Olsson T, Hansson E, Soderpalm B, Ericson M (2011) Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens. Addict Biol 16:43–54

    Article  PubMed  CAS  Google Scholar 

  • Alen F, Santos A, Moreno-Sanz G, Gonzalez-Cuevas G, Gine E, Franco-Ruiz L, Navarro M, Lopez-Moreno JA (2009) Cannabinoid-induced increase in relapse-like drinking is prevented by the blockade of the glycine-binding site of N-methyl-d-aspartate receptors. Neuroscience 158:465–473

    Article  PubMed  CAS  Google Scholar 

  • Anton RF, O'Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Zweben A (2006) Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. Jam 295:2003–2017

    Article  CAS  Google Scholar 

  • Ary AW, Cozzoli DK, Finn DA, Crabbe JC, Dehoff MH, Worley PF, Szumlinski KK (2012) Ethanol up-regulates nucleus accumbens neuronal activity dependent pentraxin (Narp): implications for alcohol-induced behavioral plasticity. Alcohol 46:377–387

    Article  PubMed  CAS  Google Scholar 

  • Backstrom P, Bachteler D, Koch S, Hyytia P, Spanagel R (2004) mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology 29:921–928

    Article  PubMed  CAS  Google Scholar 

  • Backstrom P, Hyytia P (2004) Ionotropic glutamate receptor antagonists modulate cue-induced reinstatement of ethanol-seeking behavior. Alcohol Clin Exp Res 28:558–565

    Article  PubMed  CAS  Google Scholar 

  • Backstrom P, Hyytia P (2005) Suppression of alcohol self-administration and cue-induced reinstatement of alcohol seeking by the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG. Eur J Pharmacol 528:110–118

    Article  PubMed  CAS  Google Scholar 

  • Backstrom P, Hyytia P (2006) Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking. Neuropsychopharmacology 31:778–786

    Article  PubMed  CAS  Google Scholar 

  • Backstrom P, Hyytia P (2007) Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 192:571–580

    Article  CAS  Google Scholar 

  • Badanich KA, Doremus-Fitzwater TL, Mulholland PJ, Randall PK, Delpire E, Becker HC (2011) NR2B-deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol. Genes Brain Behav 10:805–816

    Article  PubMed  CAS  Google Scholar 

  • Baltieri DA, Daro FR, Ribeiro PL, de Andrade AG (2008) Comparing topiramate with naltrexone in the treatment of alcohol dependence. Addiction 103:2035–2044

    Article  PubMed  Google Scholar 

  • Barak S, Liu F, Hamida SB, Yowell QV, Neasta J, Kharazia V, Janak PH, Ron D (2013) Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse. Nat Neurosci

  • Bellone C, Luscher C (2012) Drug-evoked plasticity: do addictive drugs reopen a critical period of postnatal synaptic development? Front Mol Neurosci 5:75

    Article  PubMed  CAS  Google Scholar 

  • Besheer J, Faccidomo S, Grondin JJ, Hodge CW (2008) Regulation of motivation to self-administer ethanol by mGluR5 in alcohol-preferring (P) rats. Alcohol Clin Exp Res 32:209–221

    Article  PubMed  CAS  Google Scholar 

  • Besheer J, Grondin JJ, Cannady R, Sharko AC, Faccidomo S, Hodge CW (2010) Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a rat genetic model of high alcohol intake. Biol Psychiatry 67:812–822

    Article  PubMed  CAS  Google Scholar 

  • Biala G, Kotlinska J (1999) Blockade of the acquisition of ethanol-induced conditioned place preference by N-methyl-d-aspartate receptor antagonists. Alcohol Alcohol 34:175–182

    Article  PubMed  CAS  Google Scholar 

  • Bienkowski P, Stefanski R, Kostowski W (1997) Discriminative stimulus effects of ethanol: lack of antagonism with N-methyl-d-aspartate and d-cycloserine. Alcohol 14:345–350

    Article  PubMed  CAS  Google Scholar 

  • Bird MK, Kirchhoff J, Djouma E, Lawrence AJ (2008) Metabotropic glutamate 5 receptors regulate sensitivity to ethanol in mice. Int J Neuropsychopharmacol 11:765–774

    Article  PubMed  CAS  Google Scholar 

  • Bisaga A, Evans SM (2004) Acute effects of memantine in combination with alcohol in moderate drinkers. Psychopharmacology (Berl) 172:16–24

    Article  CAS  Google Scholar 

  • Blednov YA, Harris RA (2008) Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: relationship to acamprosate actions. Int J Neuropsychopharmacol 11:775–793

    Article  PubMed  CAS  Google Scholar 

  • Boyce-Rustay JM, Cunningham CL (2004) The role of NMDA receptor binding sites in ethanol place conditioning. Behav Neurosci 118:822–834

    Article  PubMed  CAS  Google Scholar 

  • Boyce-Rustay JM, Holmes A (2005) Functional roles of NMDA receptor NR2A and NR2B subunits in the acute intoxicating effects of ethanol in mice. Synapse 56:222–225

    Article  PubMed  CAS  Google Scholar 

  • Boyce-Rustay JM, Holmes A (2006a) Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit. Psychopharmacology (Berl) 187:455–466

    Article  CAS  Google Scholar 

  • Boyce-Rustay JM, Holmes A (2006b) Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31:2405–2414

    Article  PubMed  CAS  Google Scholar 

  • Brager AJ, Prosser RA, Glass JD (2011) Circadian and acamprosate modulation of elevated ethanol drinking in mPer2 clock gene mutant mice. Chronobiol Int 28:664–672

    Article  PubMed  CAS  Google Scholar 

  • Brasser SM, McCaul ME, Houtsmuller EJ (2004) Alcohol effects during acamprosate treatment: a dose–response study in humans. Alcohol Clin Exp Res 28:1074–1083

    Article  PubMed  CAS  Google Scholar 

  • Breese CR, Freedman R, Leonard SS (1995) Glutamate receptor subtype expression in human postmortem brain tissue from schizophrenics and alcohol abusers. Brain Res 674:82–90

    Article  PubMed  CAS  Google Scholar 

  • Breslin FJ, Johnson BA, Lynch WJ (2010) Effect of topiramate treatment on ethanol consumption in rats. Psychopharmacology (Berl) 207:529–534

    Article  CAS  Google Scholar 

  • Brigman JL, Daut RA, Wright T, Gunduz-Cinar O, Graybeal C, Davis MI, Jiang Z, Saksida LM, Jinde S, Pease M, Bussey TJ, Lovinger DM, Nakazawa K, Holmes A (2013) GluN2B in corticostriatal circuits governs choice learning and choice shifting. Nat Neurosci

  • Brigman JL, Wright T, Talani G, Prasad-Mulcare S, Jinde S, Seabold GK, Mathur P, Davis MI, Bock R, Gustin RM, Colbran RJ, Alvarez VA, Nakazawa K, Delpire E, Lovinger DM, Holmes A (2010) Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci 30:4590–4600

    Article  PubMed  CAS  Google Scholar 

  • Broadbent J, Kampmueller KM, Koonse SA (2003) Expression of behavioral sensitization to ethanol by DBA/2J mice: the role of NMDA and non-NMDA glutamate receptors. Psychopharmacology (Berl) 167:225–234

    CAS  Google Scholar 

  • Burattini C, McGeehan AJ, Griffin WC 3rd, Gass JT, Kinder JR, Janak PH, Olive MF (2008) A microdialysis study of extracellular levels of acamprosate and naltrexone in the rat brain following acute and repeated administration. Addict Biol 13:70–79

    Article  PubMed  CAS  Google Scholar 

  • Cagetti E, Baicy KJ, Olsen RW (2004) Topiramate attenuates withdrawal signs after chronic intermittent ethanol in rats. Neuroreport 15:207–210

    Article  PubMed  CAS  Google Scholar 

  • Camp MC, Feyder M, Ihne J, Palachick B, Hurd B, Karlsson RM, Noronha B, Chen YC, Coba MP, Grant SG, Holmes A (2011) A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference. Addict Biol 16(3):428–439

    Google Scholar 

  • Cannady R, Fisher KR, Durant B, Besheer J, Hodge CW (2013) Enhanced AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement. Addict Biol 18:54–65

    Article  PubMed  CAS  Google Scholar 

  • Carpenter-Hyland EP, Woodward JJ, Chandler LJ (2004) Chronic ethanol induces synaptic but not extrasynaptic targeting of NMDA receptors. J Neurosci 24:7859–7868

    Article  PubMed  CAS  Google Scholar 

  • Carta M, Ariwodola OJ, Weiner JL, Valenzuela CF (2003) Alcohol potently inhibits the kainate receptor-dependent excitatory drive of hippocampal interneurons. Proc Natl Acad Sci U S A 100:6813–6818

    Article  PubMed  CAS  Google Scholar 

  • Chandler LJ (2003) Ethanol and brain plasticity: receptors and molecular networks of the postsynaptic density as targets of ethanol. Pharmacol Ther 99:311–326

    Article  PubMed  CAS  Google Scholar 

  • Chandler LJ, Norwood D, Sutton G (1999) Chronic ethanol upregulates NMDA and AMPA, but not kainate receptor subunit proteins in rat primary cortical cultures. Alcohol Clin Exp Res 23:363–370

    Article  PubMed  CAS  Google Scholar 

  • Chen F, Jarrott B, Lawrence AJ (1999) Up-regulation of cortical AMPA receptor binding in the fawn-hooded rat following ethanol withdrawal. Eur J Pharmacol 384:139–146

    Article  PubMed  CAS  Google Scholar 

  • Chen YC, Holmes A (2009) Effects of topiramate and other anti-glutamatergic drugs on the acute intoxicating actions of ethanol in mice: modulation by genetic strain and stress. Neuropsychopharmacology 34:1454–1466

    Article  PubMed  CAS  Google Scholar 

  • Christian DT, Alexander NJ, Diaz MR, Robinson S, McCool BA (2012) Chronic intermittent ethanol and withdrawal differentially modulate basolateral amygdala AMPA-type glutamate receptor function and trafficking. Neuropharmacology 62:2430–2439

    Article  PubMed  CAS  Google Scholar 

  • Cippitelli A, Damadzic R, Frankola K, Goldstein A, Thorsell A, Singley E, Eskay RL, Heilig M (2010) Alcohol-induced neurodegeneration, suppression of transforming growth factor-beta, and cognitive impairment in rats: prevention by group II metabotropic glutamate receptor activation. Biol Psychiatry 67(9):823–830

    Google Scholar 

  • Clements JD, Westbrook GL (1991) Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-d-aspartate receptor. Neuron 7:605–613

    Article  PubMed  CAS  Google Scholar 

  • Conn PJ, Jones CK (2009) Promise of mGluR2/3 activators in psychiatry. Neuropsychopharmacology 34:248–249

    Article  PubMed  CAS  Google Scholar 

  • Costa ET, Soto EE, Cardoso RA, Olivera DS, Valenzuela CF (2000) Acute effects of ethanol on kainate receptors in cultured hippocampal neurons. Alcohol Clin Exp Res 24:220–225

    Article  PubMed  CAS  Google Scholar 

  • Cowen MS, Djouma E, Lawrence AJ (2005) The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems. J Pharmacol Exp Ther 315:590–600

    Article  PubMed  CAS  Google Scholar 

  • Cowen MS, Krstew E, Lawrence AJ (2007) Assessing appetitive and consummatory phases of ethanol self-administration in C57BL/6J mice under operant conditions: regulation by mGlu5 receptor antagonism. Psychopharmacology (Berl) 190:21–29

    Article  CAS  Google Scholar 

  • Cowen MS, Schroff KC, Gass P, Sprengel R, Spanagel R (2003) Neurobehavioral effects of alcohol in AMPA receptor subunit (GluR1) deficient mice. Neuropharmacology 45(3):325–333

    Article  PubMed  CAS  Google Scholar 

  • Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384

    Article  PubMed  CAS  Google Scholar 

  • Cozzoli DK, Courson J, Caruana AL, Miller BW, Greentree DI, Thompson AB, Wroten MG, Zhang PW, Xiao B, Hu JH, Klugmann M, Metten P, Worley PF, Crabbe JC, Szumlinski KK (2012) Nucleus accumbens mGluR5-associated signaling regulates binge alcohol drinking under drinking-in-the-dark procedures. Alcohol Clin Exp Res 36:1623–1633

    Article  PubMed  CAS  Google Scholar 

  • Cozzoli DK, Goulding SP, Zhang PW, Xiao B, Hu JH, Ary AW, Obara I, Rahn A, Abou-Ziab H, Tyrrel B, Marini C, Yoneyama N, Metten P, Snelling C, Dehoff MH, Crabbe JC, Finn DA, Klugmann M, Worley PF, Szumlinski KK (2009) Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: functional implications for alcoholism. J Neurosci 29:8655–8668

    Article  PubMed  CAS  Google Scholar 

  • Crews FT, Nixon K (2009) Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol 44:115–127

    Article  PubMed  CAS  Google Scholar 

  • Czachowski CL, Delory MJ, Pope JD (2012) Behavioral and neurotransmitter specific roles for the ventral tegmental area in reinforcer-seeking and intake. Alcohol Clin Exp Res 36:1659–1668

    Article  PubMed  CAS  Google Scholar 

  • Dahchour A, De Witte P (2003) Effects of acamprosate on excitatory amino acids during multiple ethanol withdrawal periods. Alcohol Clin Exp Res 27:465–470

    Article  PubMed  CAS  Google Scholar 

  • Debrouse L, Hurd B, Kiselycznyk C, Plitt A, Todaro A, Mishina M, Grant SG, Camp M, Gunduz-Cinar O, Holmes A (2013) Probing the modulation of acute ethanol intoxication by pharmacological manipulation of the NMDAR glycine co-agonist site. Alcohol Clin Exp Res 37:223–233

    Article  PubMed  CAS  Google Scholar 

  • Dildy-Mayfield JE, Harris RA (1992) Comparison of ethanol sensitivity of rat brain kainate, dl-alpha-amino-3-hydroxy-5-methyl-4-isoxalone proprionic acid and N-methyl-d-aspartate receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 262:487–494

    PubMed  CAS  Google Scholar 

  • Domart MC, Benyamina A, Lemoine A, Bourgain C, Blecha L, Debuire B, Reynaud M, Saffroy R (2012) Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism. Addict Biol 17:783–785

    Article  PubMed  CAS  Google Scholar 

  • Downing C, Marks MJ, Larson C, Johnson TE (2010) The metabotropic glutamate receptor subtype 5 mediates sensitivity to the sedative properties of ethanol. Pharmacogenet Genomics 20:553–564

    Article  PubMed  CAS  Google Scholar 

  • Emmett MR, Mick SJ, Cler JA, Rao TS, Iyengar S, Wood PL (1991) Actions of d-cycloserine at the N-methyl-d-aspartate-associated glycine receptor site in vivo. Neuropharmacology 30:1167–1171

    Article  PubMed  CAS  Google Scholar 

  • Evans SM, Levin FR, Brooks DJ, Garawi F (2007) A pilot double-blind treatment trial of memantine for alcohol dependence. Alcohol Clin Exp Res 31:775–782

    Article  PubMed  CAS  Google Scholar 

  • Fadda E, Danysz W, Wroblewski JT, Costa E (1988) Glycine and d-serine increase the affinity of N-methyl-d-aspartate sensitive glutamate binding sites in rat brain synaptic membranes. Neuropharmacology 27:1183–1185

    Article  PubMed  CAS  Google Scholar 

  • Falco AM, Bergstrom HC, Bachus SE, Smith RF (2009) Persisting changes in basolateral amygdala mRNAs after chronic ethanol consumption. Physiol Behav 96:169–173

    Article  PubMed  CAS  Google Scholar 

  • Farook JM, Morrell DJ, Lewis B, Littleton JM, Barron S (2007) Topiramate (Topamax) reduces conditioned abstinence behaviours and handling-induced convulsions (HIC) after chronic administration of alcohol in Swiss-Webster mice. Alcohol Alcohol 42:296–300

    Article  PubMed  CAS  Google Scholar 

  • Ferreira Seiva FR, Amauchi JF, Ribeiro Rocha KK, Souza GA, Ebaid GX, Burneiko RM, Novelli EL (2009) Effects of N-acetylcysteine on alcohol abstinence and alcohol-induced adverse effects in rats. Alcohol 43:127–135

    Article  PubMed  CAS  Google Scholar 

  • Ferreira VM, Frausto S, Browning MD, Savage DD, Morato And GS, Valenzuela CF (2001) Ionotropic glutamate receptor subunit expression in the rat hippocampus: lack of an effect of a long-term ethanol exposure paradigm. Alcohol Clin Exp Res 25:1536–1541

    Article  PubMed  CAS  Google Scholar 

  • Fliegel S, Brand I, Spanagel R, Noori HR (2013) Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis. In Silicon Pharmacol 1:7

    Article  Google Scholar 

  • Florez G, Garcia-Portilla P, Alvarez S, Saiz PA, Nogueiras L, Bobes J (2008) Using topiramate or naltrexone for the treatment of alcohol-dependent patients. Alcohol Clin Exp Res 32:1251–1259

    Article  PubMed  CAS  Google Scholar 

  • Floyd DW, Jung KY, McCool BA (2003) Chronic ethanol ingestion facilitates N-methyl-d-aspartate receptor function and expression in rat lateral/basolateral amygdala neurons. J Pharmacol Exp Ther 307:1020–1029

    Article  PubMed  CAS  Google Scholar 

  • Freund G, Anderson KJ (1999) Glutamate receptors in the cingulate cortex, hippocampus, and cerebellar vermis of alcoholics. Alcohol Clin Exp Res 23:1–6

    Article  PubMed  CAS  Google Scholar 

  • Fuller RK, Branchey L, Brightwell DR, Derman RM, Emrick CD, Iber FL, James KE, Lacoursiere RB, Lee KK, Lowenstam I et al (1986) Disulfiram treatment of alcoholism. A Veterans Administration cooperative study. Jama 256:1449–1455

    Article  PubMed  CAS  Google Scholar 

  • Garbutt JC, Kranzler HR, O'Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, Loewy JW, Ehrich EW (2005) Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. Jam 293:1617–1625

    Article  CAS  Google Scholar 

  • Garbutt JC, West SL, Carey TS, Lohr KN, Crews FT (1999) Pharmacological treatment of alcohol dependence: a review of the evidence. Jam 281:1318–1325

    Article  CAS  Google Scholar 

  • Gass JT, Olive MF (2008) Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 75:218–265

    Article  PubMed  CAS  Google Scholar 

  • Gass JT, Olive MF (2009) Role of protein kinase C epsilon (PKCvarepsilon) in the reduction of ethanol reinforcement due to mGluR5 antagonism in the nucleus accumbens shell. Psychopharmacology (Berl) 204:587–597

    Article  CAS  Google Scholar 

  • Goulding SP, Obara I, Lominac KD, Gould AT, Miller BW, Klugmann M, Szumlinski KK (2011) Accumbens Homer2-mediated signaling: a factor contributing to mouse strain differences in alcohol drinking? Genes Brain Behav 10:111–126

    Article  PubMed  CAS  Google Scholar 

  • Grant KA, Colombo G (1993) Discriminative stimulus effects of ethanol: effect of training dose on the substitution of N-methyl-d-aspartate antagonists. J Pharmacol Exp Ther 264:1241–1247

    PubMed  CAS  Google Scholar 

  • Grant KA, Valverius P, Hudspith M, Tabakoff B (1990) Ethanol withdrawal seizures and the NMDA receptor complex. Eur J Pharmacol 176:289–296

    Article  PubMed  CAS  Google Scholar 

  • Gremel CM, Gabriel KI, Cunningham CL (2006) Topiramate does not affect the acquisition or expression of ethanol conditioned place preference in DBA/2J or C57BL/6J mice. Alcohol Clin Exp Res 30:783–790

    Article  PubMed  CAS  Google Scholar 

  • Groblewski PA, Lattal KM, Cunningham CL (2009) Effects of d-cycloserine on extinction and reconditioning of ethanol-seeking behavior in mice. Alcohol Clin Exp Res 33:772–782

    Article  PubMed  CAS  Google Scholar 

  • Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, Greene RW (1996) NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 16:2034–2043

    PubMed  CAS  Google Scholar 

  • Gupta T, Syed YM, Revis AA, Miller SA, Martinez M, Cohn KA, Demeyer MR, Patel KY, Brzezinska WJ, Rhodes JS (2008) Acute effects of acamprosate and MPEP on ethanol drinking-in-the-dark in male C57BL/6J mice. Alcohol Clin Exp Res 32:1992–1998

    PubMed  CAS  Google Scholar 

  • Hargreaves GA, McGregor IS (2007) Topiramate moderately reduces the motivation to consume alcohol and has a marked antidepressant effect in rats. Alcohol Clin Exp Res 31:1900–1907

    Article  PubMed  CAS  Google Scholar 

  • Heikkinen AE, Moykkynen TP, Korpi ER (2009) Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. Neuropsychopharmacology 34:290–298

    Article  PubMed  CAS  Google Scholar 

  • Hermann D, Weber-Fahr W, Sartorius A, Hoerst M, Frischknecht U, Tunc-Skarka N, Perreau-Lenz S, Hansson AC, Krumm B, Kiefer F, Spanagel R, Mann K, Ende G, Sommer WH (2012) Translational magnetic resonance spectroscopy reveals excessive central glutamate levels during alcohol withdrawal in humans and rats. Biol Psychiatry 71:1015–1021

    Article  PubMed  CAS  Google Scholar 

  • Herzig V, Capuani EM, Kovar KA, Schmidt WJ (2005) Effects of MPEP on expression of food-, MDMA- or amphetamine-conditioned place preference in rats. Addict Biol 10:243–249

    Article  PubMed  CAS  Google Scholar 

  • Hodge CW, Miles MF, Sharko AC, Stevenson RA, Hillmann JR, Lepoutre V, Besheer J, Schroeder JP (2006) The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice. Psychopharmacology (Berl) 183:429–438

    Article  CAS  Google Scholar 

  • Holmes A, Fitzgerald PJ, Macpherson KP, Debrouse L, Colacicco G, Flynn SM, Masneuf S, Pleil KE, Li C, Marcinkiewcz CA, Kash TL, Gunduz-Cinar O, Camp M (2012) Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat Neurosci 15:1359–1361

    Article  PubMed  CAS  Google Scholar 

  • Hundt W, Danysz W, Holter SM, Spanagel R (1998) Ethanol and N-methyl-d-aspartate receptor complex interactions: a detailed drug discrimination study in the rat. Psychopharmacology (Berl) 135:44–51

    Article  CAS  Google Scholar 

  • Iheanacho T, Issa M, Marienfeld C, Rosenheck R (2013) Use of naltrexone for alcohol use disorders in the Veterans’ Health Administration: A national study. Drug Alcohol Depend

  • Johnson BA, Ait-Daoud N, Akhtar FZ, Ma JZ (2004) Oral topiramate reduces the consequences of drinking and improves the quality of life of alcohol-dependent individuals: a randomized controlled trial. Arch Gen Psychiatry 61:905–912

    Article  PubMed  CAS  Google Scholar 

  • Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Lawson K, Javors MA, Ma JZ (2003a) Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 361:1677–1685

    Article  PubMed  CAS  Google Scholar 

  • Johnson BA, O'Malley SS, Ciraulo DA, Roache JD, Chambers RA, Sarid-Segal O, Couper D (2003b) Dose-ranging kinetics and behavioral pharmacology of naltrexone and acamprosate, both alone and combined, in alcohol-dependent subjects. J Clin Psychopharmacol 23:281–293

    PubMed  CAS  Google Scholar 

  • Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K, McKay A, Ait-Daoud N, Anton RF, Ciraulo DA, Kranzler HR, Mann K, O'Malley SS, Swift RM (2007) Topiramate for treating alcohol dependence: a randomized controlled trial. Jam 298:1641–1651

    Article  CAS  Google Scholar 

  • Jones N, Messenger MJ, O'Neill MJ, Oldershaw A, Gilmour G, Simmons RM, Iyengar S, Libri V, Tricklebank M, Williams SC (2008) AMPA receptor potentiation can prevent ethanol-induced intoxication. Neuropsychopharmacology 33:1713–1723

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW, O'Brien C (2008) Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 33:166–180

    Article  PubMed  CAS  Google Scholar 

  • Karlsson RM, Adermark L, Molander A, Perreau-Lenz S, Singley E, Solomon M, Holmes A, Tanaka K, Lovinger DM, Spanagel R, Heilig M (2012) Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST. Neuropharmacology 63:181–189

    Article  PubMed  CAS  Google Scholar 

  • Karlsson RM, Tanaka K, Heilig M, Holmes A (2008) Loss of glial glutamate and aspartate transporter (excitatory amino acid transporter 1) causes locomotor hyperactivity and exaggerated responses to psychotomimetics: rescue by haloperidol and metabotropic glutamate 2/3 agonist. Biol Psychiatry 64:810–814

    Article  PubMed  CAS  Google Scholar 

  • Kash T, Winder DG (2007) NMDAR LTP and LTD induction: 2B or not 2B…is that the question? Debates Neurosci 1:79–84

    Article  Google Scholar 

  • Kash TL, Matthews RT, Winder DG (2008) Alcohol inhibits NR2B-containing NMDA receptors in the ventral bed nucleus of the stria terminalis. Neuropsychopharmacology 33:1379–1390

    Article  PubMed  CAS  Google Scholar 

  • Khanna JM, Kalant H, Shah G, Chau A (1993) Effect of d-cycloserine on rapid tolerance to ethanol. Pharmacol Biochem Behav 45:983–986

    Article  PubMed  CAS  Google Scholar 

  • Khanna JM, Morato GS, Chau A, Shah G (1995) d-cycloserine enhances rapid tolerance to ethanol motor incoordination. Pharmacol Biochem Behav 52:609–614

    Article  PubMed  CAS  Google Scholar 

  • Knapp CM, Mercado M, Markley TL, Crosby S, Ciraulo DA, Kornetsky C (2007) Zonisamide decreases ethanol intake in rats and mice. Pharmacol Biochem Behav 87:65–72

    Article  PubMed  CAS  Google Scholar 

  • Komanduri R (2003) Two cases of alcohol craving curbed by topiramate. J Clin Psychiatry 64:612

    Article  PubMed  Google Scholar 

  • Kotlinska J, Liljequist S (1997) The NMDA/glycine receptor antagonist, L-701,324, produces discriminative stimuli similar to those of ethanol. Eur J Pharmacol 332:1–8

    Article  PubMed  CAS  Google Scholar 

  • Kotlinska JH, Bochenski M, Danysz W (2011) The role of group I mGlu receptors in the expression of ethanol-induced conditioned place preference and ethanol withdrawal seizures in rats. Eur J Pharmacol 670:154–161

    Article  PubMed  CAS  Google Scholar 

  • Kroener S, Mulholland PJ, New NN, Gass JT, Becker HC, Chandler LJ (2012) Chronic alcohol exposure alters behavioral and synaptic plasticity of the rodent prefrontal cortex. PLoS One 7:e37541

    Article  PubMed  CAS  Google Scholar 

  • Krupitsky EM, Neznanova O, Masalov D, Burakov AM, Didenko T, Romanova T, Tsoy M, Bespalov A, Slavina TY, Grinenko AA, Petrakis IL, Pittman B, Gueorguieva R, Zvartau EE, Krystal JH (2007a) Effect of memantine on cue-induced alcohol craving in recovering alcohol-dependent patients. Am J Psychiatry 164:519–523

    Article  PubMed  Google Scholar 

  • Krupitsky EM, Rudenko AA, Burakov AM, Slavina TY, Grinenko AA, Pittman B, Gueorguieva R, Petrakis IL, Zvartau EE, Krystal JH (2007b) Antiglutamatergic strategies for ethanol detoxification: comparison with placebo and diazepam. Alcohol Clin Exp Res 31:604–611

    PubMed  CAS  Google Scholar 

  • Kryger R, Wilce PA (2010) The effects of alcoholism on the human basolateral amygdala. Neuroscience 167:361–371

    Article  PubMed  CAS  Google Scholar 

  • Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck RA (2001) Naltrexone in the treatment of alcohol dependence. N Engl J Med 345:1734–1739

    Article  PubMed  CAS  Google Scholar 

  • Krystal JH, Petrakis IL, Limoncelli D, Nappi SK, Trevisan L, Pittman B, D’Souza DC, Suckow RF (2011) Characterization of the interactive effects of glycine and d-cycloserine in men: further evidence for enhanced NMDA receptor function associated with human alcohol dependence. Neuropsychopharmacology 36:701–710

    Article  PubMed  CAS  Google Scholar 

  • Krystal JH, Petrakis IL, Mason G, Trevisan L, D’Souza DC (2003) N-methyl-d-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability. Pharmacol Ther 99:79–94

    Article  PubMed  CAS  Google Scholar 

  • Krystal JH, Petrakis IL, Webb E, Cooney NL, Karper LP, Namanworth S, Stetson P, Trevisan LA, Charney DS (1998) Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics. Arch Gen Psychiatry 55:354–360

    Article  PubMed  CAS  Google Scholar 

  • Kufahl PR, Watterson LR, Nemirovsky NE, Hood LE, Villa A, Halstengard C, Zautra N, Foster Olive M (2011) Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration. Neuropharmacology 66:290–301

    Article  CAS  Google Scholar 

  • Kumari M, Ticku MK (2000) Regulation of NMDA receptors by ethanol. Prog Drug Res 54:152–189

    PubMed  CAS  Google Scholar 

  • Kuribara H (1994) Potentiation of the ambulation-increasing effect induced by combined administration of MK-801 with ethanol in mice. Psychopharmacology (Berl) 113:453–456

    Article  CAS  Google Scholar 

  • Lack AK, Ariwodola OJ, Chappell AM, Weiner JL, McCool BA (2008) Ethanol inhibition of kainate receptor-mediated excitatory neurotransmission in the rat basolateral nucleus of the amygdala. Neuropharmacology 55:661–668

    Article  PubMed  CAS  Google Scholar 

  • Lack AK, Diaz MR, Chappell A, DuBois DW, McCool BA (2007) Chronic ethanol and withdrawal differentially modulate pre- and postsynaptic function at glutamatergic synapses in rat basolateral amygdala. J Neurophysiol 98(6):3185–3196

    Google Scholar 

  • Lack AK, Floyd DW, McCool BA (2005) Chronic ethanol ingestion modulates proanxiety factors expressed in rat central amygdala. Alcohol 36:83–90

    Article  PubMed  CAS  Google Scholar 

  • Lee HJ, Kim L, Kang SG, Yoon HK, Choi JE, Park YM, Kim SJ, Kripke DF (2011) PER2 variation is associated with diurnal preference in a Korean young population. Behav Genet 41:273–277

    Article  PubMed  CAS  Google Scholar 

  • Lido HH, Marston H, Ericson M, Soderpalm B (2012) The glycine reuptake inhibitor Org24598 and acamprosate reduce ethanol intake in the rat; tolerance development to acamprosate but not to Org24598. Addict Biol 17:897–907

    Article  PubMed  CAS  Google Scholar 

  • Lieberman R, Levine ES, Kranzler HR, Abreu C, Covault J (2012) Pilot study of iPS-derived neural cells to examine biologic effects of alcohol on human neurons in vitro. Alcohol Clin Exp Res 36:1678–1687

    Article  PubMed  CAS  Google Scholar 

  • Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, Amann M, Anderson HR, Andrews KG, Aryee M, Atkinson C, Bacchus LJ, Bahalim AN, Balakrishnan K, Balmes J, Barker-Collo S, Baxter A, Bell ML, Blore JD, Blyth F, Bonner C, Borges G, Bourne R, Boussinesq M, Brauer M, Brooks P, Bruce NG, Brunekreef B, Bryan-Hancock C, Bucello C, Buchbinder R, Bull F, Burnett RT, Byers TE, Calabria B, Carapetis J, Carnahan E, Chafe Z, Charlson F, Chen H, Chen JS, Cheng AT, Child JC, Cohen A, Colson KE, Cowie BC, Darby S, Darling S, Davis A, Degenhardt L, Dentener F, Des Jarlais DC, Devries K, Dherani M, Ding EL, Dorsey ER, Driscoll T, Edmond K, Ali SE, Engell RE, Erwin PJ, Fahimi S, Falder G, Farzadfar F, Ferrari A, Finucane MM, Flaxman S, Fowkes FG, Freedman G, Freeman MK, Gakidou E, Ghosh S, Giovannucci E, Gmel G, Graham K, Grainger R, Grant B, Gunnell D, Gutierrez HR, Hall W, Hoek HW, Hogan A, Hosgood HD, 3rd, Hoy D, Hu H, Hubbell BJ, Hutchings SJ, Ibeanusi SE, Jacklyn GL, Jasrasaria R, Jonas JB, Kan H, Kanis JA, Kassebaum N, Kawakami N, Khang YH, Khatibzadeh S, Khoo JP, Kok C, Laden F, Lalloo R, Lan Q, Lathlean T, Leasher JL, Leigh J, Li Y, Lin JK, Lipshultz SE, London S, Lozano R, Lu Y, Mak J, Malekzadeh R, Mallinger L, Marcenes W, March L, Marks R, Martin R, McGale P, McGrath J, Mehta S, Mensah GA, Merriman TR, Micha R, Michaud C, Mishra V, Hanafiah KM, Mokdad AA, Morawska L, Mozaffarian D, Murphy T, Naghavi M, Neal B, Nelson PK, Nolla JM, Norman R, Olives C, Omer SB, Orchard J, Osborne R, Ostro B, Page A, Pandey KD, Parry CD, Passmore E, Patra J, Pearce N, Pelizzari PM, Petzold M, Phillips MR, Pope D, Pope CA, 3rd, Powles J, Rao M, Razavi H, Rehfuess EA, Rehm JT, Ritz B, Rivara FP, Roberts T, Robinson C, Rodriguez-Portales JA, Romieu I, Room R, Rosenfeld LC, Roy A, Rushton L, Salomon JA, Sampson U, Sanchez-Riera L, Sanman E, Sapkota A, Seedat S, Shi P, Shield K, Shivakoti R, Singh GM, Sleet DA, Smith E, Smith KR, Stapelberg NJ, Steenland K, Stockl H, Stovner LJ, Straif K, Straney L, Thurston GD, Tran JH, Van Dingenen R, van Donkelaar A, Veerman JL, Vijayakumar L, Weintraub R, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams W, Wilson N, Woolf AD, Yip P, Zielinski JM, Lopez AD, Murray CJ, Ezzati M (2012) A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859): 2224–2260

  • Lockridge A, Romero G, Harrington J, Newland B, Gong Z, Cameron A, Yuan LL (2012) Timing-dependent reduction in ethanol sedation and drinking preference by NMDA receptor co-agonist d-serine. Alcohol 46:389–400

    Article  PubMed  CAS  Google Scholar 

  • Lominac KD, Kapasova Z, Hannun RA, Patterson C, Middaugh LD, Szumlinski KK (2006) Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: potential insight into their anti-addictive properties. Drug Alcohol Depend 85:142–156

    Article  PubMed  CAS  Google Scholar 

  • Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724

    Article  PubMed  CAS  Google Scholar 

  • Lynch WJ, Bond C, Breslin FJ, Johnson BA (2011) Severity of drinking as a predictor of efficacy of the combination of ondansetron and topiramate in rat models of ethanol consumption and relapse. Psychopharmacology (Berl) 217:3–12

    Article  CAS  Google Scholar 

  • Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW (2013) Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction 108:275–293

    Article  PubMed  Google Scholar 

  • Mason BJ, Goodman AM, Chabac S, Lehert P (2006a) Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res 40:383–393

    Article  PubMed  Google Scholar 

  • Mason GF, Petrakis IL, de Graaf RA, Gueorguieva R, Guidone E, Coric V, Epperson CN, Rothman DL, Krystal JH (2006b) Cortical gamma-aminobutyric acid levels and the recovery from ethanol dependence: preliminary evidence of modification by cigarette smoking. Biol Psychiatry 59:85–93

    Article  PubMed  CAS  Google Scholar 

  • Meinhardt MW, Hansson AC, Perreau-Lenz S, Bauder-Wenz C, Stahlin O, Heilig M, Harper C, Drescher KU, Spanagel R, Sommer WH (2013) Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence. J Neurosci 33:2794–2806

    Article  PubMed  CAS  Google Scholar 

  • Meyer PJ, Phillips TJ (2003) Bivalent effects of MK-801 on ethanol-induced sensitization do not parallel its effects on ethanol-induced tolerance. Behav Neurosci 117:641–649

    Article  PubMed  CAS  Google Scholar 

  • Miranda R Jr, MacKillop J, Monti PM, Rohsenow DJ, Tidey J, Gwaltney C, Swift R, Ray L, McGeary J (2008) Effects of topiramate on urge to drink and the subjective effects of alcohol: a preliminary laboratory study. Alcohol Clin Exp Res 32:489–497

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927

    PubMed  CAS  Google Scholar 

  • Moghaddam B, Bolinao ML (1994) Biphasic effect of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus accumbens. Neurosci Lett 178:99–102

    Article  PubMed  CAS  Google Scholar 

  • Molander A, Lido HH, Lof E, Ericson M, Soderpalm B (2007) The glycine reuptake inhibitor Org 25935 decreases ethanol intake and preference in male wistar rats. Alcohol Alcohol 42:11–18

    Article  PubMed  CAS  Google Scholar 

  • Molander A, Soderpalm B (2005) Glycine receptors regulate dopamine release in the rat nucleus accumbens. Alcohol Clin Exp Res 29:17–26

    Article  PubMed  CAS  Google Scholar 

  • Mon A, Durazzo TC, Meyerhoff DJ (2012) Glutamate, GABA, and other cortical metabolite concentrations during early abstinence from alcohol and their associations with neurocognitive changes. Drug Alcohol Depend 125:27–36

    Article  PubMed  CAS  Google Scholar 

  • Moraes Ferreira VM, Morato GS (1997) d-cycloserine blocks the effects of ethanol and HA-966 in rats tested in the elevated plus-maze. Alcohol Clin Exp Res 21:1638–1642

    Article  PubMed  CAS  Google Scholar 

  • Moykkynen T, Korpi ER, Lovinger DM (2003) Ethanol inhibits alpha-amino-3-hydyroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function in central nervous system neurons by stabilizing desensitization. J Pharmacol Exp Ther 306:546–555

    Article  PubMed  CAS  Google Scholar 

  • Mozhui K, Karlsson RM, Kash TL, Ihne J, Norcross M, Patel S, Farrell MR, Hill EE, Graybeal C, Martin KP, Camp M, Fitzgerald PJ, Ciobanu DC, Sprengel R, Mishina M, Wellman CL, Winder DG, Williams RW, Holmes A (2010) Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. J Neurosci 30:5357–5367

    Article  PubMed  CAS  Google Scholar 

  • Mulholland PJ, Chandler LJ (2007) The thorny side of addiction: adaptive plasticity and dendritic spines. Sci World J 7:9–21

    Article  Google Scholar 

  • Neasta J, Ben Hamida S, Yowell Q, Carnicella S, Ron D (2010) Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders. Proc Natl Acad Sci U S A 107:20093–20098

    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 

  • Neyton J, Paoletti P (2006) Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach. J Neurosci 26:1331–1333

    Article  PubMed  CAS  Google Scholar 

  • Nguyen SA, Malcolm R, Middaugh LD (2007) Topiramate reduces ethanol consumption by C57BL/6 mice. Synapse 61:150–156

    Article  PubMed  CAS  Google Scholar 

  • NIAAA NIoAaAA (2000) Tenth Special Report on Alcohol and Health to the U.S. Congress on Alcohol and Health. In: Services HaH (ed)

  • Obara I, Bell RL, Goulding SP, Reyes CM, Larson LA, Ary AW, Truitt WA, Szumlinski KK (2009) Differential effects of chronic ethanol consumption and withdrawal on homer/glutamate receptor expression in subregions of the accumbens and amygdala of P rats. Alcohol Clin Exp Res 33:1924–1934

    Article  PubMed  CAS  Google Scholar 

  • Olive MF, Becker HC (2008) Effects of the mGluR2/3 agonist LY379268 and the mGluR5 antagonist MPEP on handling-induced convulsions during ethanol withdrawal in mice. Alcohol 42:191–197

    Article  PubMed  CAS  Google Scholar 

  • Olive MF, McGeehan AJ, Kinder JR, McMahon T, Hodge CW, Janak PH, Messing RO (2005) The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism. Mol Pharmacol 67:349–355

    Article  PubMed  CAS  Google Scholar 

  • Palachick B, Chen YC, Enoch AJ, Karlsson RM, Mishina M, Holmes A (2008) Role of major NMDA or AMPA receptor subunits in MK-801 potentiation of ethanol intoxication. Alcohol Clin Exp Res 32(8):1479–1492

    Google Scholar 

  • Paparrigopoulos T, Tzavellas E, Karaiskos D, Kourlaba G, Liappas I (2011) Treatment of alcohol dependence with low-dose topiramate: an open-label controlled study. BMC Psychiatry 11:41

    Article  PubMed  CAS  Google Scholar 

  • Parkitna JR, Sikora M, Golda S, Golembiowska K, Bystrowska B, Engblom D, Bilbao A, Przewlocki R (2013) Novelty-seeking behaviors and the escalation of alcohol drinking after abstinence in mice are controlled by metabotropic glutamate receptor 5 on neurons expressing dopamine d1 receptors. Biol Psychiatry 73:263–270

    Article  PubMed  CAS  Google Scholar 

  • Parsons CG, Danysz W, Hesselink M, Hartmann S, Lorenz B, Wollenburg C, Quack G (1998) Modulation of NMDA receptors by glycine—introduction to some basic aspects and recent developments. Amino Acids 14:207–216

    Article  PubMed  CAS  Google Scholar 

  • Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 13:1102–1107

    Article  PubMed  CAS  Google Scholar 

  • Petrakis IL, Limoncelli D, Gueorguieva R, Jatlow P, Boutros NN, Trevisan L, Gelernter J, Krystal JH (2004) Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry 161:1776–1782

    Article  PubMed  Google Scholar 

  • Popp RL, Lovinger DM (2000) Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons. Eur J Pharmacol 394:221–231

    Article  PubMed  CAS  Google Scholar 

  • Qiang M, Denny AD, Ticku MK (2007) Chronic intermittent ethanol treatment selectively alters N-methyl-d-aspartate receptor subunit surface expression in cultured cortical neurons. Mol Pharmacol 72:95–102

    Article  PubMed  CAS  Google Scholar 

  • Rassnick S, Pulvirenti L, Koob GF (1992) Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology (Berl) 109:92–98

    Article  CAS  Google Scholar 

  • Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J (2009) Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373:2223–2233

    Article  PubMed  Google Scholar 

  • Ridge JP, Ho AM, Innes DJ, Dodd PR (2008) The expression of NMDA receptor subunit mRNA in human chronic alcoholics. Ann N Y Acad Sci 1139:10–19

    Article  PubMed  CAS  Google Scholar 

  • Roberto M, Schweitzer P, Madamba SG, Stouffer DG, Parsons LH, Siggins GR (2004) Acute and chronic ethanol alter glutamatergic transmission in rat central amygdala: an in vitro and in vivo analysis. J Neurosci 24:1594–1603

    Article  PubMed  CAS  Google Scholar 

  • Rodd ZA, McKinzie DL, Bell RL, McQueen VK, Murphy JM, Schoepp DD, McBride WJ (2006) The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats. Behav Brain Res 171:207–215

    Article  PubMed  CAS  Google Scholar 

  • Ron D (2004) Signaling cascades regulating NMDA receptor sensitivity to ethanol. Neuroscientist 10:325–336

    Article  PubMed  CAS  Google Scholar 

  • Ronald KM, Mirshahi T, Woodward JJ (2001) Ethanol inhibition of N-methyl-d-aspartate receptors is reduced by site-directed mutagenesis of a transmembrane domain phenylalanine residue. J Biol Chem 276:44729–44735

    Article  PubMed  CAS  Google Scholar 

  • Rossetti ZL, Carboni S (1995) Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum. Eur J Pharmacol 283:177–183

    Article  PubMed  CAS  Google Scholar 

  • Rubio G, Ponce G, Jimenez-Arriero MA, Palomo T, Manzanares J, Ferre F (2004) Effects of topiramate in the treatment of alcohol dependence. Pharmacopsychiatry 37:37–40

    Article  PubMed  CAS  Google Scholar 

  • Rustembegovic A, Sofic E, Kroyer G (2002) A pilot study of topiramate (Topamax) in the treatment of tonic–clonic seizures of alcohol withdrawal syndromes. Med Arh 56:211–212

    PubMed  Google Scholar 

  • Sanchis-Segura C, Borchardt T, Vengeliene V, Zghoul T, Bachteler D, Gass P, Sprengel R, Spanagel R (2006) Involvement of the AMPA receptor GluR-C subunit in alcohol-seeking behavior and relapse. J Neurosci 26:1231–1238

    Article  PubMed  CAS  Google Scholar 

  • Sari Y, Sakai M, Weedman JM, Rebec GV, Bell RL (2011) Ceftriaxone, a beta-lactam antibiotic, reduces ethanol consumption in alcohol-preferring rats. Alcohol Alcohol 46:239–246

    Article  PubMed  CAS  Google Scholar 

  • Sari Y, Sreemantula SN (2012) Neuroimmunophilin GPI-1046 reduces ethanol consumption in part through activation of GLT1 in alcohol-preferring rats. Neuroscience 227:327–335

    Article  PubMed  CAS  Google Scholar 

  • Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299:12–20

    PubMed  CAS  Google Scholar 

  • Schroeder JP, Overstreet DH, Hodge CW (2005) The mGluR5 antagonist MPEP decreases operant ethanol self-administration during maintenance and after repeated alcohol deprivations in alcohol-preferring (P) rats. Psychopharmacology (Berl) 179:262–270

    Article  CAS  Google Scholar 

  • Schroeder JP, Spanos M, Stevenson JR, Besheer J, Salling M, Hodge CW (2008) Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP. Neuropharmacology 55:546–554

    Article  PubMed  CAS  Google Scholar 

  • Schumann G, Johann M, Frank J, Preuss U, Dahmen N, Laucht M, Rietschel M, Rujescu D, Lourdusamy A, Clarke TK, Krause K, Dyer A, Depner M, Wellek S, Treutlein J, Szegedi A, Giegling I, Cichon S, Blomeyer D, Heinz A, Heath S, Lathrop M, Wodarz N, Soyka M, Spanagel R, Mann K (2008) Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior. Arch Gen Psychiatry 65:826–838

    Article  PubMed  CAS  Google Scholar 

  • Sharko AC, Hodge CW (2008) Differential modulation of ethanol-induced sedation and hypnosis by metabotropic glutamate receptor antagonists in C57BL/6J mice. Alcohol Clin Exp Res 32:67–76

    Article  PubMed  CAS  Google Scholar 

  • Shen EH, Phillips TJ (1998) MK-801 potentiates ethanol's effects on locomotor activity in mice. Pharmacol Biochem Behav 59:135–143

    Article  PubMed  CAS  Google Scholar 

  • Sidhpura N, Weiss F, Martin-Fardon R (2010) Effects of the mGlu2/3 agonist LY379268 and the mGlu5 antagonist MTEP on ethanol seeking and reinforcement are differentially altered in rats with a history of ethanol dependence. Biol Psychiatry 67:804–811

    Article  PubMed  CAS  Google Scholar 

  • Simonyi A, Schachtman TR, Christoffersen GR (2010) Metabotropic glutamate receptor subtype 5 antagonism in learning and memory. Eur J Pharmacol 639:17–25

    Article  PubMed  CAS  Google Scholar 

  • Sinclair CM, Cleva RM, Hood LE, Olive MF, Gass JT (2012) mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior. Pharmacol Biochem Behav 101:329–335

    Article  PubMed  CAS  Google Scholar 

  • Skolnick P, Popik P, Trullas R (2009) Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci 30:563–569

    Article  PubMed  CAS  Google Scholar 

  • Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, Lascorz J, Depner M, Holzberg D, Soyka M, Schreiber S, Matsuda F, Lathrop M, Schumann G, Albrecht U (2005) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11:35–42

    Article  PubMed  CAS  Google Scholar 

  • Spanagel R, Vengeliene V (2013) New pharmacological treatment strategies for relapse prevention. Curr Top Behav Neurosci 13:583–609

    Article  PubMed  Google Scholar 

  • Spanagel R, Zieglgansberger W, Hundt W (1996) Acamprosate and alcohol: III. Effects on alcohol discrimination in the rat. Eur J Pharmacol 305:51–56

    Article  PubMed  CAS  Google Scholar 

  • Stepanyan TD, Farook JM, Kowalski A, Kaplan E, Barron S, Littleton JM (2008) Alcohol withdrawal-induced hippocampal neurotoxicity in vitro and seizures in vivo are both reduced by memantine. Alcohol Clin Exp Res 32:2128–2135

    Article  PubMed  CAS  Google Scholar 

  • Stephens DN, Brown G (1999) Disruption of operant oral self-administration of ethanol, sucrose, and saccharin by the AMPA/kainate antagonist, NBQX, but not the AMPA antagonist, GYKI 52466. Alcohol Clin Exp Res 23:1914–1920

    PubMed  CAS  Google Scholar 

  • Stuber GD, Hopf FW, Hahn J, Cho SL, Guillory A, Bonci A (2008) Voluntary ethanol intake enhances excitatory synaptic strength in the ventral tegmental area. Alcohol Clin Exp Res 32:1714–1720

    Article  PubMed  CAS  Google Scholar 

  • Sullivan EV, Pfefferbaum A (2005) Neurocircuitry in alcoholism: a substrate of disruption and repair. Psychopharmacology (Berl) 180:583–594

    Article  CAS  Google Scholar 

  • Thomson AM, West DC, Lodge D (1985) An N-methylaspartate receptor-mediated synapse in rat cerebral cortex: a site of action of ketamine? Nature 313:479–481

    Article  PubMed  CAS  Google Scholar 

  • Trevisan L, Petrakis IL, Pittman B, Gueorguieva R, D’Souza DC, Perry E, Limoncelli D, Krystal JH (2008) Absence of significant interactive effects of high-dose d-cycloserine and ethanol in healthy human subjects: preliminary insights into ethanol actions at the glycine B site of NMDA glutamate receptors. Alcohol Clin Exp Res 32:36–42

    Article  PubMed  CAS  Google Scholar 

  • Tsai G, Coyle JT (1998) The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu Rev Med 49:173–184

    Article  PubMed  CAS  Google Scholar 

  • Tsai GE, Ragan P, Chang R, Chen S, Linnoila VM, Coyle JT (1998) Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. Am J Psychiatry 155:726–732

    PubMed  CAS  Google Scholar 

  • Umhau JC, Momenan R, Schwandt ML, Singley E, Lifshitz M, Doty L, Adams LJ, Vengeliene V, Spanagel R, Zhang Y, Shen J, George DT, Hommer D, Heilig M (2010) Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Arch Gen Psychiatry 67:1069–1077

    Article  PubMed  CAS  Google Scholar 

  • van der Kam EL, De Vry J, Tzschentke TM (2009) The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) supports intravenous self-administration and induces conditioned place preference in the rat. Eur J Pharmacol 607:114–120

    Article  PubMed  CAS  Google Scholar 

  • Vanover KE (1999) Interaction of ethanol with excitatory amino acid receptor antagonists in mice. Eur J Pharmacol 368:137–142

    Article  PubMed  CAS  Google Scholar 

  • Vengeliene V, Bachteler D, Danysz W, Spanagel R (2005) The role of the NMDA receptor in alcohol relapse: a pharmacological mapping study using the alcohol deprivation effect. Neuropharmacology 48:822–829

    Article  PubMed  CAS  Google Scholar 

  • Vengeliene V, Bilbao A, Molander A, Spanagel R (2008a) Neuropharmacology of alcohol addiction. Br J Pharmacol 154:299–315

    Article  PubMed  CAS  Google Scholar 

  • Vengeliene V, Kiefer F, Spanagel R (2008b) d-cycloserine facilitates extinction of conditioned alcohol-seeking behaviour in rats. Alcohol Alcohol 43:626–629

    Article  PubMed  CAS  Google Scholar 

  • Vengeliene V, Leonardi-Essmann F, Sommer WH, Marston HM, Spanagel R (2010) Glycine transporter-1 blockade leads to persistently reduced relapse-like alcohol drinking in rats. Biol Psychiatry 68:704–711

    Article  PubMed  CAS  Google Scholar 

  • Villegas E, Estruch R, Mengod G, Cortes R (2011) NMDA receptors in frontal cortex and hippocampus of alcohol consumers. Addict Biol 16:163–165

    Article  PubMed  CAS  Google Scholar 

  • von der Goltz C, Vengeliene V, Bilbao A, Perreau-Lenz S, Pawlak CR, Kiefer F, Spanagel R (2009) Cue-induced alcohol-seeking behaviour is reduced by disrupting the reconsolidation of alcohol-related memories. Psychopharmacology (Berl) 205:389–397

    Article  CAS  Google Scholar 

  • Vyklicky L Jr, Benveniste M, Mayer ML (1990) Modulation of N-methyl-d-aspartic acid receptor desensitization by glycine in mouse cultured hippocampal neurones. J Physiol 428:313–331

    PubMed  CAS  Google Scholar 

  • Wang J, Ben Hamida S, Darcq E, Zhu W, Gibb SL, Lanfranco MF, Carnicella S, Ron D (2012) Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior. J Neurosci 32:15124–15132

    Article  PubMed  CAS  Google Scholar 

  • Watterson LR, Kufahl PR, Nemirovsky NE, Sewalia K, Hood LE, Olive MF (2013) Attenuation of reinstatement of methamphetamine-, sucrose-, and food-seeking behavior in rats by fenobam, a metabotropic glutamate receptor 5 negative allosteric modulator. Psychopharmacology (Berl) 225:151–159

    Article  CAS  Google Scholar 

  • Weiner JL, Dunwiddie TV, Valenzuela CF (1999) Ethanol inhibition of synaptically evoked kainate responses in rat hippocampal CA3 pyramidal neurons. Mol Pharmacol 56:85–90

    PubMed  CAS  Google Scholar 

  • Wills TA, Klug JR, Silberman Y, Baucum AJ, Weitlauf C, Colbran RJ, Delpire E, Winder DG (2012) GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis. Proc Natl Acad Sci U S A 109:E278–E287

    Article  PubMed  CAS  Google Scholar 

  • Wilson WR, Bosy TZ, Ruth JA (1990) NMDA agonists and antagonists alter the hypnotic response to ethanol in LS and SS mice. Alcohol 7:389–395

    Article  PubMed  CAS  Google Scholar 

  • Wolf ME, Tseng KY (2012) Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: when, how, and why? Front Mol Neurosci 5:72

    Article  PubMed  CAS  Google Scholar 

  • Woodward JJ (2000) Ethanol and NMDA receptor signaling. Crit Rev Neurobiol 14:69–89

    Article  PubMed  CAS  Google Scholar 

  • Zalewska-Kaszubska J, Bajer B, Gorska D, Andrzejczak D, Dyr W, Bienkowski P (2013) Effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in Warsaw alcohol high-preferring rats. Psychopharmacology (Berl) 225:275–281

    Article  CAS  Google Scholar 

  • Zarate CA, Jr., Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, Luckenbaugh DA (2012) A randomized trial of a low-trapping nonselective N-methyl-d-aspartate channel blocker in major depression. Biol Psychiatry

  • Zhao Y, Dayas CV, Aujla H, Baptista MA, Martin-Fardon R, Weiss F (2006) Activation of group II metabotropic glutamate receptors attenuates both stress and cue-induced ethanol-seeking and modulates c-fos expression in the hippocampus and amygdala. J Neurosci 26:9967–9974

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

AH is supported by the NIAAA intramural research program. RS is supported by the Bundesministerium für Bildung und Forschung (NGFN Plus; FKZ: 01GS08152, see under Spanagel et al., 2010 and www.ngfn-alkohol.de), the Deutsche Forschungsgemeinschaft (DFG): SFB 636 (B1) and Reinhart-Koselleck Award SP 383/5-1, and the MWK in Baden-Württemberg. JHK is supported by the U.S. National Institute on Alcohol Abuse and Alcoholism (2P50AA012870), the National Center on Advancing Translational Science (CTSA Grant Number UL1 RR024139), the U.S. Department of Veterans Affairs through its support for the VA National Center for PTSD, and Yale–New Haven Hospital.

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Authors and Affiliations

  1. Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA

    Andrew Holmes

  2. Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

    Rainer Spanagel

  3. NIAAA Center for the Translational Neuroscience of Alcoholism, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    John H. Krystal

  4. 5625 Fishers Lane Room 2N09, Rockville, MD, 20852-9411, USA

    Andrew Holmes

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  1. Andrew Holmes
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  2. Rainer Spanagel
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Correspondence to Andrew Holmes.

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Holmes, A., Spanagel, R. & Krystal, J.H. Glutamatergic targets for new alcohol medications. Psychopharmacology 229, 539–554 (2013). https://doi.org/10.1007/s00213-013-3226-2

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  • DOI: https://doi.org/10.1007/s00213-013-3226-2

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