CNS Drugs

, Volume 19, Issue 6, pp 517–537 | Cite as

Neuroprotective and Abstinence-Promoting Effects of Acamprosate

Elucidating the Mechanism of Action
  • Philippe De Witte
  • John Littleton
  • Philippe Parot
  • George Koob
Review Article


Acamprosate is an abstinence-promoting drug widely used in the treatment of alcohol dependence but which has a mechanism of action that has remained obscure for many years. Recently, evidence has emerged that this drug may interact with excitatory glutamatergic neurotransmission in general and as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular. These findings provide, for the first time, a satisfactory, unifying hypothesis that can bring together and explain the diverse neurochemical effects of acamprosate. Glutamic acid is involved in several aspects of alcohol dependence and withdrawal, many of which can be modified by acamprosate. For example, during chronic exposure to alcohol, the glutamatergic system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn. The surge in glutamic acid release that occurs following alcohol withdrawal can be attenuated by acamprosate. The elevated extracellular levels of glutamic acid observed in withdrawal, together with supersensitivity of NMDA receptors, may expose vulnerable neurons to excitotoxicity, possibly contributing to the neuronal loss sometimes observed in chronic alcohol dependence. In vitro studies suggest that the excitotoxicity produced by ethanol can effectively be blocked by acamprosate. Moreover, glutamatergic neurotransmission plays an important role in the acquisition of cue-elicited drinking behaviours, which again can be modulated by acamprosate. In conclusion, the glutamatergic hypothesis of the mechanism of action of acamprosate helps explain many of its effects in human alcohol dependence and points the way to potential new activities, such as neuroprotection, that merit exploration in the clinic.


NMDA Receptor Alcohol Dependence Excitatory Amino Acid Alcohol Withdrawal Acamprosate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors have all received research funding and honoraria from Merck SA, manufacturers of acamprosate. In addition, Philippe De Witte and Philippe Parot received an educational grant from Merck SA for the preparation of this review. Merck SA, however, were not involved in its content, which is the sole responsibility of the authors. All authors have similarly received funding from many other pharmaceutical companies interested in alcohol research, including Forest (distributors of acamprosate in the US), DuPont (manufacturers of naltrexone), Janssen, Pfizer, GlaxoSmithKline, Sanofi-Aventis, and Lundbeck.


  1. 1.
    Mason BJ. Treatment of alcohol-dependent outpatients with acamprosate: a clinical review. J Clin Psychiatry 2001; 62Suppl. 20: 42–8PubMedGoogle Scholar
  2. 2.
    Pelc I, Ansoms C, Lehert P, et al. The European NEAT Program: an integrated approach using acamprosate and psychosocial support for the prevention of relapse in alcohol-dependent patients with a statistical modeling of therapy success prediction. Alcohol Clin Exp Res 2002; 26(10): 1529–38PubMedCrossRefGoogle Scholar
  3. 3.
    Mann K, Lehert P, Morgan MY. The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: results of a meta-analysis. Alcohol Clin Exp Res 2004; 28(1): 51–63PubMedCrossRefGoogle Scholar
  4. 4.
    Chick J, Lehert P, Landron F. Does acamprosate improve reduction of drinking as well as aiding abstinence? J Psychopharmacol 2003; 17(4): 397–402PubMedCrossRefGoogle Scholar
  5. 5.
    Morgan MY, Landron F, Lehert P, et al. Improvement in quality of life after treatment for alcohol dependence with acamprosate and psychosocial support. Alcohol Clin Exp Res 2004; 28(1): 64–77PubMedCrossRefGoogle Scholar
  6. 6.
    Boismare F, Daoust M, Moore ND, et al. A homotaurine derivative reduces the voluntary intake of ethanol by rats: are cerebral GABA receptors involved? Pharmacol Biochem Behav 1984; 21: 787–9PubMedCrossRefGoogle Scholar
  7. 7.
    Heyser CJ, Schulteis G, Durbin P, et al. Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats. Neuropsychopharmacology 1998; 18(2): 125–33PubMedCrossRefGoogle Scholar
  8. 8.
    Gewiss M, Heidbreder C, Opsomer L, et al. Acamprosate and diazepam differentially modulate alcohol-induced behavioural and cortical alterations in rats following chronic inhalation of ethanol vapour. Alcohol Alcohol 1991; 26(2): 129–37PubMedGoogle Scholar
  9. 9.
    Spanagel R, Holter SM, Allingham K, et al. Acamprosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat. Eur J Pharmacol 1996; 305: 39–44Google Scholar
  10. 10.
    Ferrer I, Fabregues I, Rairiz J, et al. Decreased numbers of dendritic spines on cortical pyramidal neurons in human chronic alcoholism. Neurosci Lett 1986; 69: 115–9PubMedCrossRefGoogle Scholar
  11. 11.
    Kril JJ, Halliday GM. Brain shrinkage in alcoholics: a decade on and what have we learned? Prog Neurobiol 1999; 58: 381–7PubMedCrossRefGoogle Scholar
  12. 12.
    Jernigan TL, Butters N, DiTraglia G, et al. Reduced cerebral grey matter observed in alcoholics using magnetic resonance imaging. Alcohol Clin Exp Res 1991; 15: 418–27PubMedCrossRefGoogle Scholar
  13. 13.
    Iorio KR, Reinlib L, Tabakoff B, et al. Chronic exposure of cerebellar granule cells to ethanol results in increased N-methyl-D-aspartate receptor function. Mol Pharmacol. 1992; 41(6): 1142–8PubMedGoogle Scholar
  14. 14.
    Charness ME. Brain lesions in alcoholics. Alcohol Clin Exp Res 1993; 17: 2–11PubMedCrossRefGoogle Scholar
  15. 15.
    Dahchour A, De Witte P. Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 2000; 60(4): 343–62PubMedCrossRefGoogle Scholar
  16. 16.
    Wise RA, Rompre PP. Brain dopamine and reward. Annu Rev Psychol 1989; 40: 191–225PubMedCrossRefGoogle Scholar
  17. 17.
    Noble EP. Alcoholism and the dopaminergic system: a review. Addict Biol 1996; 1(4): 333–48PubMedCrossRefGoogle Scholar
  18. 18.
    Grace AA. The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving. Addiction 2000; 95Suppl. 2: S119–28PubMedGoogle Scholar
  19. 19.
    Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion channels. Pharmacol Rev 1999; 51: 7–61PubMedGoogle Scholar
  20. 20.
    Hebb DO. The Organization of Behavior. New York (NY): John Wiley and Sons, 1949Google Scholar
  21. 21.
    Williams K. Modulation and block of ion channels: a new biology of polyamines. Cell Signal 1997; 9: 1–13PubMedCrossRefGoogle Scholar
  22. 22.
    Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 1997; 37: 205–37PubMedCrossRefGoogle Scholar
  23. 23.
    Thomas LS, Jane DE, Harris JR, et al. Metabotropic glutamate autoreceptors of the mGlu(5) subtype positively modulate neuronal glutamate release in the rat forebrain in vitro. Neuropharmacology 2000; 39(9): 1554–66PubMedCrossRefGoogle Scholar
  24. 24.
    Allan AM, Harris RA. Acute and chronic ethanol treatments alter GABA receptor-operated chloride channels. Pharmacol Biochem Behav 1987; 27(4): 665–70PubMedCrossRefGoogle Scholar
  25. 25.
    Harris RA. Ethanol actions on multiple ion channels: which are important? Alcohol Clin Exp Res 1999; 23(10): 1563–70PubMedGoogle Scholar
  26. 26.
    Leidenheimer NJ, Harris RA. Acute effects of ethanol on GABAa receptor function: molecular and physiological determinants. Adv Biochem Psychopharmacol 1992; 47: 269–79PubMedGoogle Scholar
  27. 27.
    Aguayo LG, Peoples RW, Yeh HH, et al. GABA(A) receptors as molecular sites of ethanol action. Direct or indirect actions? Curr Top Med Chem 2002; 2(8): 869–85PubMedCrossRefGoogle Scholar
  28. 28.
    Lovinger DM, White G, Weight FF. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 1989; 243: 1721–4PubMedCrossRefGoogle Scholar
  29. 29.
    Tsai G, Gastfriend DR, Coyle JT. The glutamatergic basis of human alcoholism. Am J Psychiatry 1995; 152: 332–40PubMedGoogle Scholar
  30. 30.
    Tsai G, Coyle JT. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu Rev Med 1998; 49: 173–84PubMedCrossRefGoogle Scholar
  31. 31.
    Kumari M, Ticku MK. Regulation of NMDA receptors by ethanol. Prog Drug Res 2000; 54: 152–89PubMedGoogle Scholar
  32. 32.
    Allgaier C. Ethanol sensitivity of NMDA receptors. Neurochem Int 2002; 41(6): 377–82PubMedCrossRefGoogle Scholar
  33. 33.
    De Witte P. Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol. Addict Behav 2004; 29(7): 1325–39PubMedCrossRefGoogle Scholar
  34. 34.
    White G, Lovinger DM, Weight FF. Ethanol inhibits NMDA-activated current but does not alter GABA-activated current in an isolated adult mammalian neuron. Brain Res 1990; 507(2): 332–6PubMedCrossRefGoogle Scholar
  35. 35.
    Hoffman PL, Snell LD, Bhave SV, et al. Ethanol inhibition of NMDA receptor function in primary cultures of rat cerebellar granule cells and cerebral cortical cells. Alcohol Alcohol 1994; 2 Suppl.: 199–204Google Scholar
  36. 36.
    Masood K, Wu C, Brauneis U, et al. Differential ethanol sensitivity of recombinant N-methyl-D-aspartate receptor subunits. Mol Pharmacol 1994; 45: 324–9PubMedGoogle Scholar
  37. 37.
    Blevins T, Mirshahi T, Chandler LJ, et al. Effects of acute and chronic ethanol exposure on heteromeric N-methyl-D-aspartate receptors expressed in HEK 293 cells. J Neurochem 1997; 69(6): 2345–54PubMedCrossRefGoogle Scholar
  38. 38.
    Simson PE, Criswell HE, Johnson KB, et al. Ethanol inhibits NMDA-evoked electrophysiological activity in vivo. J Pharmacol Exp Ther 1991; 257: 225–31PubMedGoogle Scholar
  39. 39.
    Simson PE, 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 1993; 607: 9–16PubMedCrossRefGoogle Scholar
  40. 40.
    Dildy-Mayfield JE, Harris RA. 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 1992; 262: 487–94PubMedGoogle Scholar
  41. 41.
    Valenzuela CF, Bhave S, Hoffman P, et al. Acute effects of ethanol on pharmacologically isolated kainate receptors in cerebellar granule neurons: comparison with NMDA and AMPA receptors. J Neurochem 1998; 71: 1777–80PubMedCrossRefGoogle Scholar
  42. 42.
    Akinshola BE, Yasuda RP, Peoples RW, et al. Ethanol sensitivity of recombinant homomeric and heteromeric AMPA receptor subunits expressed in Xenopus oocytes. Alcohol Clin Exp Res 2003; 27(12): 1876–83PubMedCrossRefGoogle Scholar
  43. 43.
    Agartz I, Momenan R, Rawlings RR, et al. Hippocampal volume in patients with alcohol dependence. Arch Gen Psychiatry 1999; 56(4): 356–63PubMedCrossRefGoogle Scholar
  44. 44.
    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 1997; 283(3): 1214–22PubMedGoogle Scholar
  45. 45.
    Floyd DW, Jung KY, McCool BA. Chronic ethanol ingestion facilitates N-methyl-D-aspartate receptor function and expression in rat lateral/basolateral amygdala neurons. J Pharmacol Exp Ther 2003; 307(3): 1020–9PubMedCrossRefGoogle Scholar
  46. 46.
    Hu XJ, Follesa P, Ticku MK. Chronic ethanol treatment produces a selective upregulation of the NMDA receptor subunit gene expression in mammalian cultured cortical neurons. Brain Res Mol Brain Res 1996; 36(2): 211–8PubMedCrossRefGoogle Scholar
  47. 47.
    Snell LD, Nunley KR, Lickteig RL, et al. Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion. Brain Res Mol Brain Res 1996; 40: 71–8PubMedCrossRefGoogle Scholar
  48. 48.
    Bao X, Hui D, Naassila M, et al. Chronic ethanol exposure increases gene transcription of subunits of an N-methyl-D-aspartate receptor-like complex in cortical neurons in culture. Neurosci Lett 2001; 315: 5–8PubMedCrossRefGoogle Scholar
  49. 49.
    Li HF, Kendig JJ. Ethanol withdrawal hyper-responsiveness mediated by NMDA receptors in spinal cord motor neurons. Br J Pharmacol 2003; 139(1): 73–80PubMedCrossRefGoogle Scholar
  50. 50.
    Davidson M, Wilce P. Chronic ethanol treatment leads to increased ornithine decarboxylase activity: implications for a role of polyamines in ethanol dependence and withdrawal. Alcohol Clin Exp Res 1998; 22(6): 1205–11PubMedGoogle Scholar
  51. 51.
    Mhatre MC, Ticku MK. Alcohol: effects on GABAa receptor function and gene expression. Alcohol Alcohol Suppl 1993; 2: 331–5PubMedGoogle Scholar
  52. 52.
    Mhatre MC, Pena G, Sieghart W, et al. Antibodies specific for GABAa receptor alpha subunits reveal that chronic alcohol treatment down-regulates alpha-subunit expression in rat brain regions. J Neurochem 1993; 61: 1620–5PubMedCrossRefGoogle Scholar
  53. 53.
    Devaud LL, Smith FD, Grayson DR, et al. Chronic ethanol consumption differentially alters the expression of gamma-aminobutyric acidA receptor subunit mRNAs in rat cerebral cortex: competitive, quantitative reverse transcriptase-polymerase chain reaction analysis. Mol Pharmacol 1995; 48: 861–8PubMedGoogle Scholar
  54. 54.
    Zeise ML, Kasparow S, Capogna M, et al. Calcium diacetylhomotaurinate (CA-AOTA) decreases the action of excitatory amino acids in the rat neocortex in vitro. Prog Clin Biol Res 1990; 351: 237–42PubMedGoogle Scholar
  55. 55.
    Zeise ML, Kasparov S, Capogna M, et al. Acamprosate (calcium acetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors. Eur J Pharmacol 1993; 231: 47–52PubMedCrossRefGoogle Scholar
  56. 56.
    Madamba SG, Schweitzer P, Zieglgänsberger W, et al. Acamprosate (calcium acetylhomotaurinate) enhances the N-methyl-D-aspartate component of excitatory neurotransmission in rat hippocampal CA1 neurons in vitro. Alcohol Clin Exp Res 1996; 20: 651–8PubMedCrossRefGoogle Scholar
  57. 57.
    Berton F, Francesconi WG, Madamba SG, et al. Acamprosate enhances N-methyl-D-aspartate receptor-mediated neurotransmission but inhibits presynaptic GABA(B) receptors in nucleus accumbens neurons. Alcohol Clin Exp Res 1998; 22(1): 183–91PubMedCrossRefGoogle Scholar
  58. 58.
    Popp RL, Lovinger DM. Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons. Eur J Pharmacol 2000; 394(2–3): 221–31PubMedCrossRefGoogle Scholar
  59. 59.
    Rammes G, Mahal B, Putzke J, et al. The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801. Neuropharmacology 2001; 40: 749–60PubMedCrossRefGoogle Scholar
  60. 60.
    Naassila M, Hammoumi S, Legrand E, et al. Mechanism of action of acamprosate Pt I: characterization of spermidine-sensitive acamprosate binding site in rat brain. Alcohol Clin Exp Res 1998; 22(4): 802–9PubMedCrossRefGoogle Scholar
  61. 61.
    al Qatari M, Bouchenafa O, Littleton J. Mechanism of action of acamprosate Pt II: ethanol dependence modifies effects of acamprosate on NMDA receptor binding in membranes from rat cerebral cortex. Alcohol Clin Exp Res 1998; 22(4): 810–4PubMedCrossRefGoogle Scholar
  62. 62.
    Harris BR, Prendergast MA, Gibson DA, et al. Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. Alcohol Clin Exp Res 2002; 26(12): 1779–93PubMedCrossRefGoogle Scholar
  63. 63.
    Harris BR, Gibson DA, Prendergast MA, et al. The neurotoxicity induced by ethanol withdrawal in mature organotypic hippocampal slices might involve cross-talk between metabotropic glutamate type 5 receptors and N-methyl-D-aspartate receptors. Alcohol Clin Exp Res 2003; 27(11): 1724–35PubMedCrossRefGoogle Scholar
  64. 64.
    Fitzjohn SM, Irving AJ, Palmer MJ, et al. Activation of group I mGluRs potentiates NMDA responses in rat hippocampal slices. Neurosci Lett 1996; 203: 211–3PubMedCrossRefGoogle Scholar
  65. 65.
    Strasser U, Lobner D, Behrens MM, et al. Antagonists for group I mGluRs attenuate excitotoxic neuronal death in cortical cultures. Eur J Neurosci 1998; 10: 2848–55PubMedCrossRefGoogle Scholar
  66. 66.
    McBride WJ, Li TK. Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. Crit Rev Neurobiol 1998; 12(4): 339–69PubMedCrossRefGoogle Scholar
  67. 67.
    Weiss F, Koob GF. The neuropharmacology of ethanol self administration. In: Meyer RE, Koob GF, Lewis MJ, et al., editors. Neuropharmacology of ethanol: new approaches. Boston (MA): Birkhäuser, 1991: 125–62CrossRefGoogle Scholar
  68. 68.
    Rogers J, Wiener SG, Bloom FE. Long-term ethanol administration methods for rats: advantages of inhalation over intubation or liquid diets. Behav Neural Biol 1979; 27(4): 466–86PubMedCrossRefGoogle Scholar
  69. 69.
    Dahchour A, De Witte P. Effect of repeated ethanol withdrawal on glutamate microdialysate in the hippocampus. Alcohol Clin Exp Res 1999; 23(10): 1698–703PubMedCrossRefGoogle Scholar
  70. 70.
    Rossetti ZL, Carboni S. Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum. Eur J Pharmacol 1995; 283(1–3): 177–83PubMedCrossRefGoogle Scholar
  71. 71.
    Dahchour A, De Witte P. Excitatory and inhibitory amino acid changes during repeated episodes of ethanol withdrawal: an in vivo microdialysis study. Eur J Pharmacol 2003; 459(2–3): 171–8PubMedCrossRefGoogle Scholar
  72. 72.
    McCown TJ, Breese GR. Multiple withdrawals from chronic ethanol “kindles” inferior collicular seizure activity: evidence for kindling of seizures associated with alcoholism. Alcohol Clin Exp Res 1990; 14(3): 394–9PubMedCrossRefGoogle Scholar
  73. 73.
    Brown ME, Anton RF, Malcolm R, et al. Alcohol detoxification and withdrawal seizures: clinical support for a kindling hypothesis. Biol Psychiatry 1988; 23(5): 507–14PubMedCrossRefGoogle Scholar
  74. 74.
    Lechtenberg R, Worner TM. Seizure risk with recurrent alcohol detoxification. Arch Neurol 1990; 47(5): 535–8PubMedCrossRefGoogle Scholar
  75. 75.
    Booth BM, Blow FC. The kindling hypothesis: further evidence from a US national study of alcoholic men. Alcohol Alcohol 1993; 28(5): 593–8PubMedGoogle Scholar
  76. 76.
    Dahchour A, Landron F, De Witte P. Acamprosate reduces mortality during repeated experimental withdrawal in rats, Alcoologie et Addictologie 2001; 23: 437–40Google Scholar
  77. 77.
    Dahchour A, De Witte P, Bolo N, et al. Central effects of acamprosate Pt I: acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats. Psychiatry Res 1998; 82(2): 107–14PubMedCrossRefGoogle Scholar
  78. 78.
    Dahchour A, De Witte P. Effects of acamprosate on excitatory amino acids during multiple ethanol withdrawal periods. Alcohol Clin Exp Res 2003; 27(3): 465–70PubMedCrossRefGoogle Scholar
  79. 79.
    Dahchour A, De Witte P. Acamprosate decreases the hypermotility during repeated ethanol withdrawal. Alcohol 1999; 18(1): 77–81PubMedCrossRefGoogle Scholar
  80. 80.
    Malenka RC, Nicoll RA. NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci 1993; 16(12): 521–7PubMedCrossRefGoogle Scholar
  81. 81.
    Schmidt WJ. Behavioural effects of NMDA-receptor antagonists. J Neural Transm Suppl 1994; 43: 63–9PubMedGoogle Scholar
  82. 82.
    Bowery NG, Wong EH, Hudson AL. Quantitative autoradiography of [3H]-MK-801 binding sites in mammalian brain. Br J Pharmacol 1988; 93: 944–54PubMedCrossRefGoogle Scholar
  83. 83.
    Meoni P, Bunnemann BH, Trist DG, et al. N-terminal splice variants of the NMDARl glutamate receptor subunit: differential expression in human and monkey brain. Neurosci Lett 1998; 249(1): 45–8PubMedCrossRefGoogle Scholar
  84. 84.
    Burgess N, Maguire EA, O’Keefe J. The human hippocampus and spatial and episodic memory. Neuron 2002; 35(4): 625–41PubMedCrossRefGoogle Scholar
  85. 85.
    Winocur G. Anterograde and retrograde amnesia in rats with dorsal hippocampal or dorsomedial thalamic lesions. Behav Brain Res 1990; 38: 145–54PubMedCrossRefGoogle Scholar
  86. 86.
    Mumby DG, Astur RS, Weisend MP, et al. Retrograde amnesia and selective damage to the hippocampal formation: memory for places and object discriminations. Behav Brain Res 1999; 106: 97–107PubMedCrossRefGoogle Scholar
  87. 87.
    Deweer B, Lehéricy S, Pillon B, et al. Memory disorders in probable Alzheimer’s disease: the role of hippocampal atrophy as shown with MRI. J Neurol Neurosurg Psychiatry 1995; 58: 590–7PubMedCrossRefGoogle Scholar
  88. 88.
    Laakso MP, Soininen H, Partanen K, et al. Volumes of hippocampus, amygdala and frontal lobes in the MRI-based diagnosis of early Alzheimer’s disease: correlation with memory functions. J Neural Transm Park Dis Dement Sect 1995; 9: 73–86PubMedCrossRefGoogle Scholar
  89. 89.
    Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 1992; 99: 195–231PubMedCrossRefGoogle Scholar
  90. 90.
    White AM, Matthews DB, Best PJ. Ethanol, memory, and hippocampal function: a review of recent findings. Hippocampus 2000; 10(1): 88–93PubMedCrossRefGoogle Scholar
  91. 91.
    Cooney NL, Litt MD, Morse PA, et al. Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men. J Abnorm Psychol 1997; 106: 243–50PubMedCrossRefGoogle Scholar
  92. 92.
    Verheul R, van den Brink W, Geerlings PJ. A three-pathway psychobiological model of craving for alcohol. Alcohol Alcohol 1999; 34: 197–222PubMedGoogle Scholar
  93. 93.
    Niaura RS, Rohsenow DJ, Binkoff JA, et al. Relevance of cue reactivity to understanding alcohol and smoking relapse. J Abnorm Psychol 1988; 97(2): 133–52PubMedCrossRefGoogle Scholar
  94. 94.
    Drummond DC. What does cue-reactivity have to offer clinical research? Addiction 2000; 95Suppl. 2: S129–44PubMedGoogle Scholar
  95. 95.
    Quertemont E, de Neuville J, De Witte P. Changes in the amygdala amino acid microdialysate after conditioning with a cue associated with ethanol. Psychopharmacology 1998; 139(1–2): 71–8PubMedCrossRefGoogle Scholar
  96. 96.
    Kenny PJ, Markou A. The ups and downs of addiction: role of metabotropic glutamate receptors. Trends Pharmacol Sci 2004; 25(5): 265–72PubMedCrossRefGoogle Scholar
  97. 97.
    Duncan PM, Alici T, Woodward JD. Conditioned compensatory response to ethanol as indicated by locomotor activity in rats. Behav Pharmacol. 2000; 11(5): 395–402PubMedCrossRefGoogle Scholar
  98. 98.
    Quertemont E, Brabant C, De Witte P. Acamprosate reduces context-dependent ethanol effects. Psychopharmacology 2002; 164(1): 10–8PubMedCrossRefGoogle Scholar
  99. 99.
    Bachteler D, Economidou D, Danysz W, et al. The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat. Neuropsychopharmacology. Epub 2005 Jan 19Google Scholar
  100. 100.
    Cole JC, Littleton JM, Little HJ. Acamprosate, but not naltrex-one, inhibits conditioned abstinence behaviour associated with repeated ethanol administration and exposure to a plus-maze. Psychopharmacology 2000; 147(4): 403–11PubMedCrossRefGoogle Scholar
  101. 101.
    Morse AC, Koob GF. Intra-BNST acamprosate attenuates withdrawal-induced increases in ethanol consumption in dependent rats. Washington, DC: Abstract Society for Neuroscience, 2002Google Scholar
  102. 102.
    Backstrom P, Hyytia P. Ionotropic glutamate receptor antagonists modulate cue-induced reinstatement of ethanol-seeking behavior. Alcohol Clin Exp Res 2004; 28(4): 558–65PubMedCrossRefGoogle Scholar
  103. 103.
    Olney JW. Neurotoxicity of excitatory amino acids. In: McGeer EG, Olney JW, McGeer PL, editors. Kainic acid as a tool in neurobiology. New York: Raven Press, 1978: 95–112Google Scholar
  104. 104.
    Rothman SM, Olney JW. Excitotoxicity and the NMDA receptor. Trends Neurosci 1987; 10(7): 299–302CrossRefGoogle Scholar
  105. 105.
    Hoffman PL. Glutamate receptors in alcohol withdrawal-induced neurotoxicity. Metab Brain Dis 1995; 10(1): 73–9PubMedCrossRefGoogle Scholar
  106. 106.
    Prendergast MA, Harris BR, Blanchard II JA, et al. In vitro effects of ethanol withdrawal and spermidine on viability of hippocampus from male and female rat. Alcohol Clin Exp Res 2000; 24(12): 1855–61PubMedCrossRefGoogle Scholar
  107. 107.
    Prendergast MA, Harris BR, Mayer S, et al. Chronic, but not acute, nicotine exposure attenuates ethanol withdrawal-induced hippocampal damage in vitro. Alcohol Clin Exp Res 2000; 24(12): 1583–92PubMedCrossRefGoogle Scholar
  108. 108.
    Thomas MP, Morrisett RA. Dynamics of NMDAR-mediated neurotoxicity during chronic ethanol exposure and withdrawal. Neuropharmacology 2000; 39(2): 218–26PubMedCrossRefGoogle Scholar
  109. 109.
    Mayer S, Harris B, Gibson DA, et al. Acamprosate has no effect on NMDA-induced toxicity but reduces toxicity induced by spermidine or by changing the medium in organotypic hippo-campal slice cultures from rat. Alcohol Clin Exp Res 2002; 26(5): 655–62PubMedCrossRefGoogle Scholar
  110. 110.
    Mayer S, Harris BR, Gibson DA, et al. Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus. Alcohol Clin Exp Res 2002; 26(10): 1468–78PubMedCrossRefGoogle Scholar
  111. 111.
    al Qatari M, Khan S, Harris B, et al. Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain. Alcohol Clin Exp Res 2001; 25(9): 1276–83PubMedCrossRefGoogle Scholar
  112. 112.
    Gibson DA, Harris BR, Prendergast MA, et al. Polyamines contribute to ethanol withdrawal-induced neurotoxicity in rat hippocampal slice cultures through interactions with the NMDA receptor. Alcohol Clin Exp Res 2003; 27: 1099–106PubMedCrossRefGoogle Scholar
  113. 113.
    Bolo N, Nedelec JF, Muzet M, et al. Central effects of acamprosate Pt II: acamprosate modifies the brain in-vivo proton magnetic resonance spectrum in healthy young male volunteers. Psychiatry Res Neuroimag 1998; 82: 115–27CrossRefGoogle Scholar
  114. 114.
    Matejcek M. Vigilance and the EEG: psychological, physiological and pharmacological aspects. In: WM Herrmann, editor. Electroencephalography in drug research. Stuttgart: Fischer, 1982: 508Google Scholar
  115. 115.
    Boeijinga PH, Parot P, Soufflet L, et al. Pharmacodynamic effects of acamprosate on markers of cerebral function in alcohol dependent subjects administered as pre-treatment and during alcohol abstinence. Neuropsychobiology 2004; 50(1): 71–7PubMedCrossRefGoogle Scholar
  116. 116.
    Ballenger JC, Post RM. Kindling as a model for alcohol withdrawal syndromes. Br J Psychiatry 1978; 133: 1–14PubMedCrossRefGoogle Scholar
  117. 117.
    De Soto CB, O’Donnell WE, Allred LJ, et al. Symptomatology in alcoholics at various stages of abstinence. Alcohol Clin Exp Res 1985; 9: 505–12PubMedCrossRefGoogle Scholar
  118. 118.
    Rueff B. Alcoologie clinique. Médecine-Sciences. Paris: Flammarion, 1989: 113Google Scholar
  119. 119.
    Paille F, Guelfi JD, Perkins A, et al. Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol Alcohol 1995; 30: 239–47PubMedGoogle Scholar
  120. 120.
    Chick J, Howlett H, Morgan MY, et al. United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol 2000; 35: 176–87PubMedGoogle Scholar
  121. 121.
    Sullivan EV, Marsh L, Mathalon DH, et al. Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics. Alcohol Clin Exp Res 1995; 19(1): 110–22PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Philippe De Witte
    • 1
  • John Littleton
    • 2
  • Philippe Parot
    • 3
  • George Koob
    • 4
  1. 1.Biologie Du ComportementUniversité Catholique de LouvainLouvain-la-NeuveBelgium
  2. 2.Department of PharmacologyUniversity of KentuckyLexingtonUSA
  3. 3.Conseil en Pharmacologie CliniqueMassyFrance
  4. 4.Department of NeuropharmacologyThe Scripps Research InstituteLa JollaUSA

Personalised recommendations