Skip to main content
Log in

Glutamatergic neurotransmission in alcoholism

  • Review
  • Published:
Journal of Biomedical Science

Abstract

Substance abuse and dependence is the most common psychiatric problem. Alcohol is the most commonly abused substance and most people who abuse other substance(s) abuse alcohol at the same time. Accumulating evidence suggests that neurophysiological and pathological effects of ethanol are mediated to a considerable extent via the glutamatergic system. Ethanol disrupts glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor and by promoting neuronal toxicity through upregulation of the NMDA receptor density. Therefore, short-term/acute ethanol treatment results in a blockade of NMDA receptor-mediated neurotransmission and apoptotic cell death by inhibiting the trophic effect mediated by the NMDA receptor whereas chronic ethanol treatment and withdrawal results in an enhanced toxic response toward glutamate. The neurobiology of human alcoholism such as ethanol intoxication, dependence, withdrawal seizures, delirium tremens, Wernicke-Korsakoff syndrome, and fetal alcohol syndrome can be better understood as a spectrum of consequences of ethanol's effect on the NMDA glutamatergic system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Abdollah S, Brien JF. Effect of chronic maternal ethanol administration on glutamate and N-methyl-D-aspartate binding sites in the hippocampus of the near-term fetal guinea pig. Alcohol 12:377–382;1995

    Google Scholar 

  2. Andaloro VJ, Monaghan DT, Rosenquist TH. Dextromethorphan and other N-methyl-D-aspartate receptor antagonists are teratogenic in the avian embryo model. Pediatr Res 43:1–7;1998

    Google Scholar 

  3. Balduini W, Reno F, Costa LG, Cattabeni F. Developmental neurotoxicity of ethanol: further evidence for an involvement of muscarinic receptor-stimulated phosphoinositide hydrolysis. Eur J Pharmacol 266:283–289;1994.

    Google Scholar 

  4. Bhave SV, Hoffman PL. Ethanol promotes apoptosis in cerebellar granule cells by inhibiting the trophic effect of NMDA. J Neurochem 68:578–586;1997.

    Google Scholar 

  5. Bhave SV, Snell LD, Tabakoff B, Hoffman PL. Mechanism of ethanol inhibition of NMDA receptor function in primary cultures of cerebral cortical cells. Alcoholism Clin Exp Ther 20:934–941;1996.

    Google Scholar 

  6. Blitzer RD, Gil O, Landau EM. Long-term potentiation in rat hippocampus is inhibited by low concentrations of ethanol. Brain Res 537:203–208;1990.

    Google Scholar 

  7. Bolo N, Nedelec J-F, Muzet M, Witte PD, Dahchour A, Durbin P, Macher J-P. Central effect of acamprosate: acamprosate modifies the brain in vivo proton magnetic resonance spectrum in healthy volunteer. Psychiat Res Submitted:1998.

  8. Brown LM, Leslie SW, Gonzales RA. The effects of chronic ethanol exposure on N-methyl-D-aspartate-stimulated overflow of [3H]catecholamines from rat brain. Brain Res 547:289–294;1991.

    Google Scholar 

  9. Butterworth RF, H'eroux M. Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes. J Neurochem 52:1079–1084;1989.

    Google Scholar 

  10. Candura SM, Manzo L, Costa LG. Inhibition of muscarinic receptor- and G-protein-dependent phosphoinositide metabolism in cerebroncortical membranes form neonatal rats by ethanol. Neurotoxicology 13:281–288;1992.

    Google Scholar 

  11. Carlsson ML, Engberg G. Ethanol behaves as an NMDA antagonist with respect to locomotor stimulation in monoamine-depleted mice. J Neural Transm 87:155–160;1992.

    Google Scholar 

  12. Carmichael FJ, Israel Y. Effects of ethanol on neurotransmitter release by rat brain cortical slices. J Pharmacol Exp Ther 193:824–834;1975.

    Google Scholar 

  13. Chandler LJ, Newsom H, Sumners C, Crews F. Chronic ethanol exposure potentiates NMDA excitotoxicity in cerebral cortical neurons. J Neurochem 60:1578–1581;1993.

    Google Scholar 

  14. Chandler LJ, Sumners C, Crews FT. Ethanol inhibits NMDA receptor-mediated excitotoxicity in rat primary neuronal cultures. Alcohol Clin Exp Res 17:54–60;1993.

    Google Scholar 

  15. Chen X, Michaelis ML, Michaelis EK. Effects of chronic ethanol treatment on the expression of calcium transport carriers and NMDA/glutamate receptor proteins in brain synaptic membranes. J Neurochem 69:1559–69;1997.

    Google Scholar 

  16. Colombo G, Grant KA. NMDA receptor complex antagonists have ethanol-like discrimitive stimulus effects. Ann NY Acad Sci 654:421–423;1992.

    Google Scholar 

  17. Costa LG. Signal transduction mechanisms in developmental neurotoxicity: The phosphoinositide pathway (review). Neurotoxicology 15:19–27;1994.

    Google Scholar 

  18. Cotman CW, Monaghan DT. Chemistry and anatomy of excitatory amino acid systems. In: Meltzer HY, eds. Psychopharmacology: The Third Generation of Progress. New York. Raven Press, 197–210;1987.

    Google Scholar 

  19. Dahchour A, Quertemont E, De WP. Taurine increases in the nucleus accumbens microdialysate after acute ethanol administration to naive and chronically alcoholised rats. Brain Res 735:9–19;1996.

    Google Scholar 

  20. Daniell LC. Effect of volatile general anesthetics and n-alcohols on glutamate-stimulated increases in calcium ion flux in hippocampal membrane vesicles. Pharmacology 50:154–161;1995.

    Google Scholar 

  21. Davidson M, Wilce PA, Shanley BC. Chronic ethanol administration sensitizes hippocampal neurons to neurotoxicity of N-methyl-D-aspartic acid. Alcohol Alcoholism (suppl)2:365–369;1993.

    Google Scholar 

  22. Davidson MD, Wilce P, Shanley BC. Increased sensitivity of the hippocampus in ethanol-dependent rats to toxic effect of N-methyl-D-aspartic acid in vivo. Brain Res 606:5–9;1993.

    Google Scholar 

  23. Diaz GJ, Spuhler PK, Lilliquist MW, Amsel A, Leslie SW. Effects of prenatal and early postnatal ethanol exposure on [3H]MK-801 binding in rat cortex and hippocampus. Alcohol Clin Exp Res 21:874–881;1997.

    Google Scholar 

  24. Dolin SJ, Little HJ. Are changes in neuronal calcium channels involved in ethanol tolerance? J Pharmacol Exp Ther 250:985–991;1989.

    Google Scholar 

  25. Ehlers CL, Kaneko WM, Wall TL, Chaplin RI. Effects of dizocilpine (MK-801) and ethanol on the EEG and event-related potentials (ERPS) in rats. Neuropharmacology 31:369–378;1992.

    Google Scholar 

  26. El-Mas MM, Abdel RA. Role of NMDA and non-NMDA receptors in the nucleus tractus solitarius in the depressant effect of ethanol on baroreflexes. J Pharmacol Exp Ther 266:602–10;1993.

    Google Scholar 

  27. Engberg G, Hajos M. Ethanol attenuates the response of locus coeruleus neurons to excitatory amino acid agonists in vivo. Naunyn-Schmiedebergs Arch Pharmacol 345:222–226;1992.

    Google Scholar 

  28. Faingold CL, Riaz A. Increased responsiveness of pontine reticular formation neurons associated with audiogenic seizure susceptibility during ethanol withdrawal. Brian Res 663:69–76;1994.

    Google Scholar 

  29. Farr KL, Montano CY, Paxton LL, Savage DD. Prenatal ethanol exposure decreases hippocampal3H-glutamate binding in 45-day-old rats. Alcohol 5:125–133;1988.

    Google Scholar 

  30. Favaron M, Manev H, Alho H, Bertolino M, Ferret B, Guidotti A, Costa E. Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex. Proc Natl Acad Sci USA 85:7351–7355;1988.

    Google Scholar 

  31. Freed WJ, Michaelis EK. Glutamic acid and ethanol dependence. Pharmacol Biochem Behav 8:509–514;1978.

    Google Scholar 

  32. Freund G, Anderson KJ. Glutamate receptors in the frontal cortex of alcoholics. Alcohol Clin Exp Res 20:1165–72;1996.

    Google Scholar 

  33. Goldstein DB: Pharmacology of Alcohol. New York, Oxford University Press, 1983.

    Google Scholar 

  34. Gonzales RA: NMDA receptors excite alcohol research. Trends Pharmacol Sci 11:137–139;1990.

    Google Scholar 

  35. Grant KA, Snell LD, Rogawski MA, Thurkauf A, Tabakoff B. Comparison of the effects of the uncompetitive N-methyl-D-aspartate antagonist (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCL) with its structural analogs dizocilpine (MK-801) and carbamazepine on ethanol withdrawal seizures. J Pharmacol Exp Ther 260:1017–1022;1992.

    Google Scholar 

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

    Google Scholar 

  37. Greenberg SS, Xie J, Wang Y, Malinski T, Summer WR, McDonald K.Escherichia coli-induced inhibition of endothelium-dependent relaxation and gene expression and release of nitric oxide is attenuated by chronic alcohol ingestion. Alcohol 11:53–60;1994.

    Google Scholar 

  38. Grimwood S, Gilbert E, Ragan CI, Hutson PH. Modulation of45Ca2+ influx into cells stably expressing recombinant human NMDA receptors by ligands acting at distinct recognition sites. J Neurochem 66:2589–95;1996.

    Google Scholar 

  39. Gruol DL, Parsons KL. Chronic alcohol reduces calcium signaling elicited by glutamate receptor stimulation in developing cerebellar neurons. Brain Res 728:166–174;1996.

    Google Scholar 

  40. Gulya K, Grant KA, Valverius P, Hoffman PL, Tabakoff B. Brain regional specificity and time-course of changes in the NMDA receptor-ionophore complex during ethanol withdrawal. Brain Res 547:129–134;1991.

    Google Scholar 

  41. Halpain S, McEwen B. Corticosteroid decreases3H-glutamate binding in rat hippocampal formation. Neuroendocrinology 48:235–241;1988.

    Google Scholar 

  42. Hazell AS, Butterworth RF, Hakim AM. Cerebral vulnerability is associated with selective increase in extracellular glutamate concentration in experimental thiamine deficiency. J Neurochem 61:1155–1158;1993.

    Google Scholar 

  43. Heaton MB, Bradley DM. Ethanol influences on the chick embryo spinal cord motor system: Analyses of motoneuron cell death, motility, and target trophic factor activity and in vitro analyses of neurotoxicity and trophic factor neuroprotection. J Neurobiol 26:47–61;1995.

    Google Scholar 

  44. Hoffman PL. Glutamate receptors in alcohol withdrawal-induced neurotoxicity. Metab Brain Disease 10:73–79;1995.

    Google Scholar 

  45. Hoffman PL, Bhave SV, Kumar KN, Iorio KR, Snell LD, Tabakoff B, Michaelis EK. The 71 kDa glutamate-binding protein is increased in cerebellar granule cells after chronic ethanol treatment. Mol Brain Res 39:167–176;1996.

    Google Scholar 

  46. Hoffman PL, Grant KA, Snell LD, Reinlib L, Iorio K. NMDA receptors: role in ethanol withdrawal seizures. Ann NY Acad Sci 654:52–69;1992.

    Google Scholar 

  47. Hoffman PL, Iorio KR, Snell LD, Tabakoff B. Attenuation of glutamate-induced neurotoxicity in chronically ethanol-exposed cerebellar granule cells by NMDA receptor antagonist and ganglioside GM1. Alcohol Clin Exp Res 19:721–726;1995.

    Google Scholar 

  48. Hoffman PL, Rabe CS, Moses F, Tabakoff B. N-methyl-D-aspartate receptors and ethanol: Inhibition of calcium flux and cyclic GMP production. J Neurochem 52:1937–1940;1989.

    Google Scholar 

  49. Hoffman PL, Tabakoff B. The role of the NMDA receptor in ethanol withdrawal; in Jomvall JH, Rydberg U, Terenius L, Vallee BL (eds): Toward a Molecular Basis of Alcohol Use and Abuse. Basel, Birkhäuser, 1994, pp 61–70.

    Google Scholar 

  50. Hou YN, Cebers G, Cebere A, Terenius L, Liljequist S. N-methyl-D-aspartate-induced enhancement of activator protein-1 DNA binding activity is blocked by ethanol in cerebellar granule cells. Eur J Pharmacol 309:307–10;1996.

    Google Scholar 

  51. Iorio KR, Reinlib L, Tabakoff B, Hoffman PL. Chronic exposure to cerebellar granule cells to ethanol results in increased N-methyl-D-aspartate receptor function. Mol Pharmacol 41:1142–1148;1992.

    Google Scholar 

  52. Iorio KR, Tabakoff B, Hoffman PL. Glutamate-induced neurotoxicity is increased in cerebellar granule cells exposed chronically to ethanol. Eur J Pharmacol 248:209–212;1993.

    Google Scholar 

  53. Karcz KM, Liljequist S. Effects of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of ethanol tolerance in C57B1 mice. Psychopharmacology 120:49–56;1995.

    Google Scholar 

  54. Keller E, Cummins JT, Hungen KV. Regional effects of ethanol on glutamate level, uptake and release in slice and synaptosome preparations from rat brain. Substance Alcohol Actions/Misuse 4:383–392;1983.

    Google Scholar 

  55. Kemp JA, Leeson PD. The glycine site of the NMDA receptor-five years on. Trends Pharmacol Sci 141:20–25;1993.

    Google Scholar 

  56. Khanna JM, Mihic SJ, Weiner J, Shah G, Wu PH, Kalant H. Differential inhibition by NMDA antagonists of rapid tolerance to, and cross-tolerance between, ethanol and chlordiazepoxide. Brain Res 574:251–256;1992.

    Google Scholar 

  57. Khanna JM, Wu PH, Weiner J, Kalant H. NMDA antagonist inhibits rapid tolerance to ethanol. Brain Res Bull 26:643–645;1991.

    Google Scholar 

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

    Google Scholar 

  59. Kukkarni S, Mehta AK, Ticku MK. Comparison of anticonvulsant effect of ethanol against NMDA-, kainic acid- and picrotoxin-induced convulsions in rats. Life Sci 46:481–487;1990.

    Google Scholar 

  60. Kumari M, Ticku MK. Ethanol and regulation of the NMDA receptor subunits in fetal cortical neurons. J Neurochem 70:1467–1473;1998.

    Google Scholar 

  61. Kuner T, Schoepfer R, Korpi ER. Ethanol inhibits glutamate-induced currents in heterometic NMDA receptor subtypes. Neuroreport 5:297–300;1993.

    Google Scholar 

  62. Langlais PJ, Mair RG. Protective effects of the glutamate antagonist MK-801 on pyrithiamine-induced lesions and amino acid changes in rat brain. J Neurosci 10:1664–1674;1990.

    Google Scholar 

  63. Liljequist S. The competitive NMDA receptor antagonist, CGP 39551, inhibits ethanol withdrawal seizure. Eur J Pharmacol 192:197–198;1991.

    Google Scholar 

  64. Liljequist S. NMDA receptor antagonists inhibit ethanol-produced locomotor stimulation in NMRI mice. Alcohol 8:309–312;1991.

    Google Scholar 

  65. Lima-Landman MTR, Albuquerque EX. Ethanol potentiates and blocks NMDA-activated single-channel currents in rat hippocampal pyramidal cells. FEBS Lett 247:61–67;1989.

    Google Scholar 

  66. Liskow BI, Goodwin DW. Pharmacological treatment of alcohol intoxication, withdrawal and dependence: A critical review. J Stud Alcohol 48:356–370;1987.

    Google Scholar 

  67. Litten RZ, Allen JP. Pharmacotherapies for alcoholism: Promising agents and clinical issues. Alcohol Clin Exp Res 15:620–633;1991.

    Google Scholar 

  68. Lovinger DM. Developmental decrease in ethanol inhibition of N-methyl-D-aspartate receptors in rat neocortical neurons: Relations to the actions of ifenprodil. J Pharmacol Exp Ther 274:164–172;1993.

    Google Scholar 

  69. Lovinger DM. High ethanol sensitivity of recombinant AMPA-type glutamate receptors expressed in mammalian cells. Neurosci Lett 159:82–87;1993.

    Google Scholar 

  70. Lovinger DM. Alcohols and neurotransmitter gated in ion channels: Past, present and future (review). Naunyn Schmiedebergs Arch Pharmacol 356:267–82;1997.

    Google Scholar 

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

    Google Scholar 

  72. Lustig HS, Chan J, Greenberg DA. Ethanol inhibits excitotoxicity in cerebral cortical cultures. Neurosci Lett 135:259–261;1992.

    Google Scholar 

  73. Madamba SG, Schweitzer P, Zieglgansberger W, Siggins GR. Acamprosate (calcium acetyl-homotaurinate) enhances the N-methyl-D-aspartate component of excitatory neurotransmission in rat hippocampal CA1 neurons in vitro. Alcohol Clin Exp Res 20:651–658;1996.

    Google Scholar 

  74. Mao L, Abdel RA. Blockade ofL-glutamate receptors in the rostral ventrolateral medulla contributes to ethanol-evoked impairment of baroreflexes in conscious rats. Brain Res Bull 37:513–521;1995.

    Google Scholar 

  75. Martin D, Savage DD, Swartzwelder HS: Effects of prenatal ethanol exposure on hippocampal ionotropic-quisqualate and kainate receptors. Alcohol Clin Exp Res 16:816–821;1992.

    Google Scholar 

  76. Martin D, Swartzwelder HS. Ethanol inhibits release of excitatory amino acids from slices of hippocampal area CA1. Eur J Pharmacol 219:469–472;1992.

    Google Scholar 

  77. Masood K, Wu C, Brauneis U, Weight FF. Differential ethanol sensitivity of recombinant N-methyl-D-aspartate receptor subunits. J Pharmacol Exp Ther 45:324–329;1993.

    Google Scholar 

  78. McBride WJ, Murphy JM, Lumeng L, Li T-K. Effects of ethanol on monoamine and amino acid release from cerebral cortical slices of the alcohol-preferring P line of rats. Alcohol Clin Exp Res 10:205–208;1986.

    Google Scholar 

  79. McCown TJ, Frye GD, Breese GR. Evidence for site specific ethanol actions in the CNS. Alcohol Drug Res 6:423–429;1986.

    Google Scholar 

  80. McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev 15:41–70;1990.

    Google Scholar 

  81. Menzano E, Carlen PL. Zinc deficiency and corticosteroids in the pathogenesis of alcoholic brain dysfunction: A review. Alcohol Clin Exp Res 18:895–901;1994.

    Google Scholar 

  82. Michaelis EK, Michaelis ML, Freed WJ, Foye J. Glutamate receptor changes in brain synaptic membrane during chronic alcohol intake. Alcohol Alcoholism Suppl 2:377–381;1993.

    Google Scholar 

  83. Michaelis ML, Michaelis EK. Effects of ethanol on NMDA receptors in brain: Possibilities for Mg(2+)-ethanol interactions (review). Alcohol Clin Exp Res 18:1069–1075;1994.

    Google Scholar 

  84. Mirshahi T, Woodward JJ. Ethanol sensitivity of heteromeric NMDA receptors: Effects of subunit assembly, glycine and NMDAR1 Mg2+-insensitive mutants. Neuropharmacology 34:347–355;1995.

    Google Scholar 

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

    Google Scholar 

  86. Morgan PF, Nadi NS, Karanian J, Linnoila M. Mapping rat brain structures activated during ethanol withdrawal: Role of glutamate and NMDA receptors. Eur J Pharmacol 225:217–223;1992.

    Google Scholar 

  87. Morrisett RA, Martin D, Oetting TA, Lewis DV, Wilson WA, Swartzwelder HS. Ethanol and magnesium ions inhibit N-methyl-D-aspartate-mediated synaptic potentials in an interactive manner. Neuropharmacology 30:1173–1178;1991.

    Google Scholar 

  88. Morrisett RA, Rezvani AH, Overstreet D, Janowsky DS, Wilson WA, Swartzwelder HS. MK-801 potently inhibits alcohol withdrawal seizures in rats. Eur J Pharmacol 176:103–105;1990.

    Google Scholar 

  89. Morrisett RA, Swartzwelder HS. Attenuation of hippocampal long-term potentiation by ethanol: A patch-clamp analysis of glutamatergic and GABAergic mechanisms. J Neurosci 13:2264–2272;1993.

    Google Scholar 

  90. Mulkeen D, Anwyl R, Rowan MJ. Enhancement of long-term potentiation by the calcium channel agonist Bayer K8644 in CA1 of the rat hippocampus in vitro. Neurosci Lett 80:351–355;1987

    Google Scholar 

  91. Murphy JM, Cunningham SD, Mcbride WJ. Effects of 250 mg% ethanol on monoamine and amino acid release from rat striatal slices. Brain Res Bull 14:439–442;1985.

    Google Scholar 

  92. Nestler EJ, Hope BT, Widnell KL. Drug addiction: A model for the molecular basis of neural plasticity. Neuron 11:995–1005;1993.

    Google Scholar 

  93. Nestoros JN. Ethanol specifically potentiates GABA-mediated neurotransmission in feline cerebral cortex. Science 209:708–710;1980.

    Google Scholar 

  94. Nevo I, Hamon M. Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism (review). Neurochem International 26:305–336;1995.

    Google Scholar 

  95. Nicoll RA, Kauer JA, Malenka RC. The current excitement in long-term potentiation. Neuron 1:97–103;1988.

    Google Scholar 

  96. Nie Z, Yuan X, Madamba SG, Siggins GR. Ethanol decreases glutamatergic synaptic transmission in rat nucleus accumbens in vitro: Naloxone reversal. J Pharmacol Exp Ther 266:1705–1712;1993.

    Google Scholar 

  97. Noble EP, Ritchie T. Prenatal ethanol exposure reduces the effects of excitatory amino acids in the rat hippocampus. Life Sci 45:803–810;1989.

    Google Scholar 

  98. Ortiz J, Fitzgerald LW, Charlton M, Lane S, Trevisa L, Guitart X, Shoemaker W, Duman RS, Nestler EJ. Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system. Synapse 21:289–298;1995.

    Google Scholar 

  99. Otani S, Ben-Ari Y. Metabotropic receptor-mediated long-term potentiation in rat hippocampus slices. Eur J Pharmacol 205:325–326;1991.

    Google Scholar 

  100. Peoples RW, Weight FF. Ethanol inhibition of N-methyl-D-aspartate-activated ion current in rat hippocampal neurons is no competitive with glycine. Brain Res 571:342–344;1992.

    Google Scholar 

  101. Queen SA, Sanchez CF, Lopez SR, Paxton LL, Savage DD. Dose- and age-dependent effects of prenatal ethanol exposure on hippocampal metabotropic-glutamate receptor-stimulated phophoinositide hydrolysis. Alcohol Clin Exp Res 17:887–893;1993.

    Google Scholar 

  102. Rabe CS, Tabakoff B. Glycine site-directed agonists reverse the actions of ethanol at the N-methyl-D-aspartate receptor. Mol Pharmacol 38:753–757;1990.

    Google Scholar 

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

    Google Scholar 

  104. Reynolds JD, Brien JF. Effects of acute ethanol exposure on glutamate release in the hippocampus of the fetal and adult guinea pig. Alcohol 11:259–267;1994.

    Google Scholar 

  105. Reynolds JD, Penning DH, Dexter F, Atkins B, Hrdy J, Poduska D, Chestnut DH, Brien JF. Dose-dependent effects of acute in vivo ethanol exposure on extracellular glutamate concentration in the cerebral cortex of the near-term fetal sheep. Alcohol Clin Exp Res 19:1447–1453;1995.

    Google Scholar 

  106. Riaz A, Faingold CL. Seizures during ethanol withdrawal are blocked by focal microinjection of excitant amino acid antagonists into the inferior colliculus and pontine reticular formation. Alcohol Clin Exp Res 18:1456–1462;1994.

    Google Scholar 

  107. Robinson JK, Mair RG. MK-801 prevents brain lesions and delayed-nonmatching-to-sample deficits produced by pyrithiamine-induced encephalopathy in rats. Behav Neurosci 106:623–633;1992.

    Google Scholar 

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

    Google Scholar 

  109. Sanna E, Harris RA. Recent developments in alcoholism: Neuronal ion channels (review). Recent Dev Alcohol 11:169–186;1993.

    Google Scholar 

  110. Sapolsky RM, Krey LC, McEwen BS. Prolonged glucocorticoid exposure reduced hippocampal neurons number. J Neurosci 5:1222–1227;1985.

    Google Scholar 

  111. Sass H, Soyka M, Mann K, Zieglgansberger W. Relapse prevention by acamprosate: Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry 53:673–680;1996.

    Google Scholar 

  112. Savage DD, Montano CY, Otero MA, Paxton LL. Prenatal ethanol exposure decreases hippocampal NMDA-sensitive [3H]-glutamate binding site density in 45-day-old rats. Alcohol 8:193–201;1991.

    Google Scholar 

  113. Savage DD, Queen SA, Sanchez CF, Paxton LL, Mahoney JC, Goodlett CR, West JR. Prenatal ethanol exposure during the last third of gestation in rat reduces hippocampal NMDA agonist binding site density in 45-day-old offspring. Alcohol 9:37–41;1991.

    Google Scholar 

  114. Schechter MD, Meehan SM, Gordon TL, McBurney DM. The NMDA receptor antagonist MK-801 produces ethanol-like discrimination in the rat. Alcohol 10:197–201;1993.

    Google Scholar 

  115. Selim M, Bradberry CW. Effect of ethanol on extracellular 5-HT and glutamate in the nucleus accumbens and prefrontal cortex: comparision between the Lewis and Fischer 344 rat strains. Brain Res 716:157–164;1996.

    Google Scholar 

  116. Sharma AC, Thorat SN, Nayar U, Kulkarni SK. Dizocilpine, ketamine and ethanol reverse NMDA-induced EEG changes and convulsions in rats and mice. Indian J Physiol Pharmacol 35;111–116;1991.

    Google Scholar 

  117. Shibata S, Shindou T, Tominaga K, Watanabe S. Calcium channel blockers improve hypoxia/hypoglycemia-induced impairment of rat hippocampal 2-deoxyglucose uptake in vitro after ethanol withdrawal. Brain Res 673:320–324;1995.

    Google Scholar 

  118. Shoemaker WJ, Kosten TA, Muly SM. Ethanol attenuation of morphine dependence: Comparison to dizocilpine. Psychopharmacology 134:83–87;1997.

    Google Scholar 

  119. Simson PEW, Criswell HE, Breese GR. Inhibition of NMDA-evoked electrophysiological activity by ethanol in selected brain regions: Evidence for ethanol-sensitive and ethanol-insensitive NMDA-evoked responses. Brain Res 607:9–16;1993.

    Google Scholar 

  120. Simson PE, Criswell HE, Johnson KB, Hicks RE, Breese GR. Ethanol inhibits NMDA-evoked electrophysiological activity in vivo. J Pharmacol Exp Ther 257:225–231;1991.

    Google Scholar 

  121. Sinclair JG, Lo GF. Ethanol blocks tetanic and calcium-induced long-term potentiation in the hippocampal slice. Gen Pharmacol 17:231–233;1986.

    Google Scholar 

  122. Smith TL. Selective effects of ethanol exposure on metabotropic glutamate receptor and guanine nucleotide stimulated phospholipase C activity in primary cultures of astrocytes. Alcohol 11:405–409;1994.

    Google Scholar 

  123. Smith TL. Regulation of glutamate uptake in astrocytes continuously exposed to ethanol. Life Sci 61:2499–2505;1997.

    Google Scholar 

  124. Smothers CT, Mrotek JJ, Lovinger DM. Chronic ethanol exposure leads to a selective enhancement of N-methyl-D-aspartate receptor function in cultured hippocampal neurons. J Pharmacol Exp Ther 283:1214–1222;1997.

    Google Scholar 

  125. Snell LD, Nunley KR, Lickteig RL, Browning MD, Tabakoff B, Hoffman PL. Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion. Mol Brain Res 40:71–78;1996.

    Google Scholar 

  126. Snell LD, Tabakoff B, Hoffman PL. Radioligand binding to the N-methyl-D-aspartate receptor/ionophore complex: Alternations by ethanol in vitro and by chronic in vivo ethanol ingestion. Brain Res 602:91–98;1993.

    Google Scholar 

  127. Spanagel R, Zieglgansberger W. Anti-craving compounds for ethanol: New pharmacological tools to study addictive processes. Trends Pharmacol Sci 18:54–59;1997.

    Google Scholar 

  128. Spuhler PK, Gonzalez J, Randall PK, Leslie SW. Alteration of [3H]MK-801 binding associated with the N-methyl-D-Aspartate receptor complex by acute ethanol in rat cortex and hippocampus in vitro. Alcohol Clin Exp Res 19:305–313;1995.

    Google Scholar 

  129. Srivastava N, Vernadakis A. Maturation of cerebellar granule cells is delayed in cultures derived from ethanol-treated chick embryos: Survival and proliferation studies. Int J Dev Neurosci 13:529–537;1995.

    Google Scholar 

  130. Swartzwelder HS, Wilson WA, Tayyeb MI. Age-dependent inhibition of long-term potentiation by ethanol in immature versus mature hippocampus. Alcohol Clin Exp Res 19:1480–1485;1995.

    Google Scholar 

  131. Szabo G, Tabakoff B, Hoffman PL. The NMDA receptor antagonist dizocilpine differentially affects environment-dependent and environment-independent ethanol tolerance. Psychopharmacology 113:511–517;1994.

    Google Scholar 

  132. Tan XX, Costa LG. Postnatal development of muscarinic receptor-stimulated phosphoinositide metabolism in mouse cerebral cortex: Sensitivity to ethanol. Dev Brain Res 86:348–353;1995.

    Google Scholar 

  133. Trevisan L, Fitzgerald LW, Brose N, Gasic GP, Heinemann SF, Duman RS, Nestler EJ. Chronic ingestion of ethanol up-regulates NMDAR1 receptor subunit immunoreactivity in rat hippocampus. J Neurochem 62:1635–1638;1994.

    Google Scholar 

  134. Troncoso JC, Johnston MV, Hess KM, Riffin JW, Price DL. Model of Wernicke's encephalopathy. Arch Neurol 38:350–354;1981.

    Google Scholar 

  135. Tsai G, Coyle JT. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Ann Rev Med 49:173–184;1998.

    Google Scholar 

  136. Tsai G, Gastfried DR, Coyle JT. The glutamatergic basis of human alcoholism. Am J Psychiatry 152:332–340;1995.

    Google Scholar 

  137. Ulrichsen J, Bech B, Ebert B, Diemer NH, Allerup P, Hemmingsen R. Glutamate and benzodiazepine receptor autoradiography in rat brain after repetition of alcohol dependence. Psychopharmacology 126:31–41;1996.

    Google Scholar 

  138. Valverius P, Crabbe JC, Hoffman PL, Tabakoff B. NMDA receptors in mice bred to be prone or resistant to ethanol withdrawal seizures. Eur J Pharmacol 184:185–189;1990.

    Google Scholar 

  139. Wang T, O'Connor WT, Ungerstedt U, French ED. N-methyl-D-aspartic acid biphasically regulates the biochemical and electrophysiological response of A10 dopamine neurons in the ventral tegmental area: in vivo microdialysis and in vitro electrophysiological studies. Brain Res 666:255–262;1994.

    Google Scholar 

  140. Wegelius K, Korpi ER. Ethanol inhibits NMDA-induced toxicity and trophism in cultured cerebellar granule cells. Acta Physiol Scand 154:25–34;1995.

    Google Scholar 

  141. Weight FF, Aguayo LG, White G, Lovinger DM, Peoples RW. GABA- and glutamategated ion channels as molecular sites of alcohol and anesthetic action; in Biggion G, Concas A, Costa E (eds): GABAergic Synaptic Transmissions. New York, Raven Press, 1992, pp 335–347.

    Google Scholar 

  142. Weight FF, Peoples RW, Wright JM, Lovinger DM, White G. Ethanol action on excitatory amino acid activated ion channels. Alcohol Alcoholism Suppl 2:353–358;1993.

    Google Scholar 

  143. Whittington MA, Little HJ, A calcium channel antagonist stereoselectively decreases ethanol withdrawal hyperexcitability but not that due to bicuculline, in hippocampal slices. Br J Pharmacol 103:1313–1320;1991.

    Google Scholar 

  144. Woodward JJ. A comparison of the effects of ethanol and the competitive glycine antagonist 7-chlorokynurenic acid on N-methyl-D-aspartic acid-induced neurotransmitter release from hippocampal slices. J Neurochem 62:987–991;1994.

    Google Scholar 

  145. Woodward JJ, Gonzales RA. Ethanol inhibition of N-methyl-D-aspartate-stimulated endogenous dopamine release from rat striatal slices: Reversal by glycine. J Neurochem 54:712–715;1990.

    Google Scholar 

  146. Zieglgansberger W. Acamprosate in relapse prevention of alcoholism; in 1st Campral-Symposium, Stuttgart 1995. Berlin, Springer, 1996, pp 65–70.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsai, G.E. Glutamatergic neurotransmission in alcoholism. J Biomed Sci 5, 309–320 (1998). https://doi.org/10.1007/BF02253441

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02253441

Key Words

Navigation