User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action.

Primary tabs

De Witte, Philippe [UCL] Littleton, John Parot, Philippe Koob, George

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system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn.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.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't, Review
Publication date 2005
Journal information "CNS drugs" - Vol. 19, no. 6, p. 517-37 (2005)
Peer reviewed yes
issn 1172-7047
Publication status Publié
Affiliation UCL - SC/BIOL - Département de biologie
MESH Subject Alcoholism - drug therapy ; Animals ; Drug Interactions ; Ethanol - adverse effects - pharmacology ; Excitatory Amino Acids - pharmacology ; Humans ; Models, Biological ; Neuroprotective Agents - pharmacology - therapeutic use ; Receptors, Glutamate - physiology ; Taurine - analogs & derivatives - pharmacology - therapeutic use
Links
  1. Pelc, Alcohol Clin Exp Res, 26, 1529 (2002)
  2. Mann, Alcohol Clin Exp Res, 28, 51 (2004)
  3. Chick, J Psychopharmacol, 17, 397 (2003)
  4. Morgan, Alcohol Clin Exp Res, 28, 64 (2004)
  5. Boismare, Pharmacol Biochem Behav, 21, 787 (1984)
  6. Heyser, Neuropsychopharmacology, 18, 125 (1998)
  7. Gewiss, Alcohol Alcohol, 26, 129 (1991)
  8. Spanagel, Eur J Pharmacol, 305, 39 (1996)
  9. Ferrer, Neurosci Lett, 69, 115 (1986)
  10. Kril, Prog Neurobiol, 58, 381 (1999)
  11. Jernigan, Alcohol Clin Exp Res, 15, 418 (1991)
  12. Iorio, Mol Pharmacol, 41, 1142 (1992)
  13. Charness, Alcohol Clin Exp Res, 17, 2 (1993)
  14. Dahchour, Prog Neurobiol, 60, 343 (2000)
  15. Wise, Annu Rev Psychol, 40, 191 (1989)
  16. Noble, Addict Biol, 1, 333 (1996)
  17. Dingledine, Pharmacol Rev, 51, 7 (1999)
  18. Williams, Cell Signal, 9, 1 (1997)
  19. Conn, Annu Rev Pharmacol Toxicol, 37, 205 (1997)
  20. Thomas, Neuropharmacology, 39, 1554 (2000)
  21. Allan, Pharmacol Biochem Behav, 27, 665 (1987)
  22. Harris, Alcohol Clin Exp Res, 23, 1563 (1999)
  23. Leidenheimer, Adv Biochem Psychopharmacol, 47, 269 (1992)
  24. Aguayo, Curr Top Med Chem, 2, 869 (2002)
  25. Lovinger, Science, 243, 1721 (1989)
  26. Tsai, Am J Psychiatry, 152, 332 (1995)
  27. Tsai, Annu Rev Med, 49, 173 (1998)
  28. Kumari, Prog Drug Res, 54, 152 (2000)
  29. Allgaier, Neurochem Int, 41, 377 (2002)
  30. De Witte, Addict Behav, 29, 1325 (2004)
  31. White, Brain Res, 507, 332 (1990)
  32. Masood, Mol Pharmacol, 45, 324 (1994)
  33. Blevins, J Neurochem, 69, 2345 (1997)
  34. Simson, J Pharmacol Exp Ther, 257, 225 (1991)
  35. Simson, Brain Res, 607, 9 (1993)
  36. Dildy-Mayfield, J Pharmacol Exp Ther, 262, 487 (1992)
  37. Valenzuela, J Neurochem, 71, 1777 (1998)
  38. Akinshola, Alcohol Clin Exp Res, 27, 1876 (2003)
  39. Agartz, Arch Gen Psychiatry, 56, 356 (1999)
  40. Smothers, J Pharmacol Exp Ther, 283, 1214 (1997)
  41. Floyd, J Pharmacol Exp Ther, 307, 1020 (2003)
  42. Hu, Brain Res Mol Brain Res, 36, 211 (1996)
  43. Snell, Brain Res Mol Brain Res, 40, 71 (1996)
  44. Bao, Neurosci Lett, 315, 5 (2001)
  45. Li, Br J Pharmacol, 139, 73 (2003)
  46. Davidson, Alcohol Clin Exp Res, 22, 1205 (1998)
  47. Mhatre, Alcohol Alcohol Suppl, 2, 331 (1993)
  48. Mhatre, J Neurochem, 61, 1620 (1993)
  49. Devaud, Mol Pharmacol, 48, 861 (1995)
  50. Zeise, Prog Clin Biol Res, 351, 237 (1990)
  51. Zeise, Eur J Pharmacol, 231, 47 (1993)
  52. Madamba, Alcohol Clin Exp Res, 20, 651 (1996)
  53. Berton, Alcohol Clin Exp Res, 22, 183 (1998)
  54. Popp, Eur J Pharmacol, 394, 221 (2000)
  55. Rammes, Neuropharmacology, 40, 749 (2001)
  56. Naassila, Alcohol Clin Exp Res, 22, 802 (1998)
  57. al Qatari, Alcohol Clin Exp Res, 22, 810 (1998)
  58. Harris, Alcohol Clin Exp Res, 26, 1779 (2002)
  59. Harris, Alcohol Clin Exp Res, 27, 1724 (2003)
  60. Fitzjohn, Neurosci Lett, 203, 211 (1996)
  61. Strasser, Eur J Neurosci, 10, 2848 (1998)
  62. McBride, Crit Rev Neurobiol, 12, 339 (1998)
  63. Rogers, Behav Neural Biol, 27, 466 (1979)
  64. Dahchour, Alcohol Clin Exp Res, 23, 1698 (1999)
  65. Rossetti, Eur J Pharmacol, 283, 177 (1995)
  66. Dahchour, Eur J Pharmacol, 459, 171 (2003)
  67. McCown, Alcohol Clin Exp Res, 14, 394 (1990)
  68. Brown, Biol Psychiatry, 23, 507 (1988)
  69. Lechtenberg, Arch Neurol, 47, 535 (1990)
  70. Booth, Alcohol Alcohol, 28, 593 (1993)
  71. Dahchour, ddictologie, 23, 437 (2001)
  72. Dahchour, Psychiatry Res, 82, 107 (1998)
  73. Dahchour, Alcohol Clin Exp Res, 27, 465 (2003)
  74. Dahchour, Alcohol, 18, 77 (1999)
  75. Malenka, Trends Neurosci, 16, 521 (1993)
  76. Schmidt, J Neural Transm Suppl, 43, 63 (1994)
  77. Bowery, Br J Pharmacol, 93, 944 (1988)
  78. Meoni, Neurosci Lett, 249, 45 (1998)
  79. Burgess, Neuron, 35, 625 (2002)
  80. Winocur, Behav Brain Res, 38, 145 (1990)
  81. Mumby, Behav Brain Res, 106, 97 (1999)
  82. Deweer, J Neurol Neurosurg Psychiatry, 58, 590 (1995)
  83. Laakso, J Neural Transm Park Dis Dement Sect, 9, 73 (1995)
  84. Squire, Psychol Rev, 99, 195 (1992)
  85. White, Hippocampus, 10, 88 (2000)
  86. Cooney, J Abnorm Psychol, 106, 243 (1997)
  87. Verheul, Alcohol Alcohol, 34, 197 (1999)
  88. Niaura, J Abnorm Psychol, 97, 133 (1988)
  89. Quertemont, Psychopharmacology, 139, 71 (1998)
  90. Kenny, Trends Pharmacol Sci, 25, 265 (2004)
  91. Duncan, Behav Pharmacol, 11, 395 (2000)
  92. Quertemont, Psychopharmacology, 164, 10 (2002)
  93. Cole, Psychopharmacology, 147, 403 (2000)
  94. Backstrom, Alcohol Clin Exp Res, 28, 558 (2004)
  95. Rothman, Trends Neurosci, 10, 299 (1987)
  96. Hoffman, Metab Brain Dis, 10, 73 (1995)
  97. Prendergast, Alcohol Clin Exp Res, 24, 1855 (2000)
  98. Prendergast, Alcohol Clin Exp Res, 24, 1583 (2000)
  99. Thomas, Neuropharmacology, 39, 218 (2000)
  100. Mayer, Alcohol Clin Exp Res, 26, 655 (2002)
  101. Mayer, Alcohol Clin Exp Res, 26, 1468 (2002)
  102. al Qatari, Alcohol Clin Exp Res, 25, 1276 (2001)
  103. Gibson, Alcohol Clin Exp Res, 27, 1099 (2003)
  104. Bolo, Psychiatry Res Neuroimag, 82, 115 (1998)
  105. Boeijinga, Neuropsychobiology, 50, 71 (2004)
  106. Ballenger, Br J Psychiatry, 133, 1 (1978)
  107. De Soto, Alcohol Clin Exp Res, 9, 505 (1985)
  108. Paille, Alcohol Alcohol, 30, 239 (1995)
  109. Chick, Alcohol Alcohol, 35, 176 (2000)
  110. Sullivan, Alcohol Clin Exp Res, 19, 110 (1995)
Bibliographic reference De Witte, Philippe ; Littleton, John ; Parot, Philippe ; Koob, George. Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action.. In: CNS drugs, Vol. 19, no. 6, p. 517-37 (2005)
Permanent URL http://hdl.handle.net/2078.1/10227