, Volume 195, Issue 3, pp 397–406 | Cite as

Acamprosate attenuates cocaine- and cue-induced reinstatement of cocaine-seeking behavior in rats

  • M. Scott Bowers
  • Billy T. Chen
  • Jonathan K. Chou
  • Megan P. H. Osborne
  • Justin T. Gass
  • Ronald E. See
  • Antonello Bonci
  • Patricia H. Janak
  • M. Foster Olive
Original Investigation



Acamprosate (calcium acetylhomotaurinate) is a glutamatergic neuromodulator used for the treatment of alcoholism, but its potential efficacy in the treatment of psychostimulant addiction has not been explored.


The purpose of this study was to assess the effects of acamprosate on cocaine-stimulated locomotor activity, cocaine self-administration, and cue- and cocaine-induced reinstatement of cocaine-seeking behavior.

Materials and methods

All experiments utilized once-daily treatment for 5 consecutive days. First, the effects of saline or acamprosate (100, 300, or 500 mg/kg intraperitoneally) on body weight were examined. On the last day of treatment, locomotor activity was assessed before and after drug treatment, after which all animals received an acute challenge of cocaine (10 mg/kg). Next, a separate group of rats were trained to intravenously (IV) self-administer cocaine (0.6 mg/kg per infusion), subjected to extinction procedures, and then tested for effects of acamprosate on cue- or cocaine-induced reinstatement. A third group of rats was trained to self-administer cocaine as described above and were treated with saline or acamprosate before daily IV self-administration sessions.


Repeated administration of 500 mg/kg acamprosate but not lower doses produced reductions in both body weight and spontaneous locomotor activity, and thus this dose was not tested further. Acamprosate at 300 mg/kg but not 100 mg/kg attenuated both cocaine- and cue-induced reinstatement without altering baseline patterns of cocaine self-administration or cocaine-stimulated hyperlocomotion.


Acamprosate attenuates both drug- and cue-induced reinstatement of cocaine-seeking behavior, suggesting that this compound may serve as a potential treatment for preventing relapse in cocaine-addicted humans.


Cocaine Self-administration Reinstatement Relapse Cues Drug priming Acamprosate Glutamate Locomotor activity Body weight 



This work was supported by the Neurobiology of Addiction Research Center (DA015369) and funds provided by the State of California for medical research on alcohol and substance abuse through the University of California at San Francisco. The authors wish to thank Shannon Ghee and Brian Wheeler for technical assistance.


  1. Backstrom P, Hyytia P (2006) Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking. Neuropsychopharmacology 31:778–786PubMedCrossRefGoogle Scholar
  2. 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 192:571–580PubMedCrossRefGoogle Scholar
  3. Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW (2003) Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 6:743–749PubMedCrossRefGoogle Scholar
  4. Bardo MT, Bevins RA (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology 153:31–43PubMedCrossRefGoogle Scholar
  5. Bell K, Duffy P, Kalivas PW (2000) Context-specific enhancement of glutamate transmission by cocaine. Neuropsychopharmacology 23:335–344PubMedCrossRefGoogle Scholar
  6. Berton F, Francesconi WG, Madamba SG, Zieglgänsberger W, Siggins GR (1998) Acamprosate enhances N-methyl-D-aspartate receptor-mediated neurotransmission but inhibits presynaptic GABAB receptors in nucleus accumbens neurons. Alcohol Clin Exp Res 22:183–191PubMedGoogle Scholar
  7. Calcagnetti DJ, Keck BJ, Quatrella LA, Schechter MD (1995) Blockade of cocaine-induced conditioned place preference: relevance to cocaine abuse therapeutics. Life Sci 56:475–483PubMedCrossRefGoogle Scholar
  8. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 4:873–874PubMedCrossRefGoogle Scholar
  9. Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20: RC89 (1–5)Google Scholar
  10. Cornish JL, Duffy P, Kalivas PW (1999) A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior. Neuroscience 92:1359–1367CrossRefGoogle Scholar
  11. Czachowski CL, Legg BH, Samson HH (2001) Effects of acamprosate on ethanol-seeking and self-administration in the rat. Alcohol Clin Exp Res 25:344–350PubMedCrossRefGoogle Scholar
  12. Dahchour A, De Witte P (2000) Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 60:343–362PubMedCrossRefGoogle Scholar
  13. Dahchour A, De Witte P (2003) Effects of acamprosate on excitatory amino acids during multiple ethanol withdrawal periods. Alcohol Clin Exp Res 27:465–470PubMedCrossRefGoogle Scholar
  14. Dahchour A, De Witte P, Bolo N, Nédélec JF, Muzet M, Durbin P, Macher JP (1998) Central effects of acamprosate: part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats. Psychiatry Res 82:107–114PubMedCrossRefGoogle Scholar
  15. De Witte P, Littleton J, Parot P, Koob G (2005) Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 19:517–37PubMedCrossRefGoogle Scholar
  16. Durbin P, Hulot T, Chabac S (1996) Pharmacodynamics and pharmacokinetics of acamprosate: an overview. In: Soyka M (ed) Acamprosate in relapse prevention of alcoholism. Springer, Berlin, pp 47–64Google Scholar
  17. Escher T, Mittleman G (2006) Schedule-induced alcohol drinking: non-selective effects of acamprosate and naltrexone. Addict Biol 11:55–63PubMedCrossRefGoogle Scholar
  18. Famous KR, Schmidt HD, Pierce RC (2007) When administered into the nucleus accumbens core or shell, the NMDA receptor antagonist AP-5 reinstates cocaine-seeking behavior in the rat. Neurosci Lett 420:169–173PubMedCrossRefGoogle Scholar
  19. Gewiss M, Heidbreder C, Opsomer L, Durbin P, De Witte P (1991) Acamprosate and diazepam differentially modulate alcohol-induced behavioural and cortical alterations in rats following chronic inhalation of ethanol vapour. Alcohol Alcohol 26:129–137PubMedGoogle Scholar
  20. Grant KA, Woolverton WL (1989) Reinforcing and discriminative stimulus effects of Ca-acetyl homotaurine in animals. Pharmacol Biochem Behav 32:607–611PubMedCrossRefGoogle Scholar
  21. Harris BR, Prendergast MA, Gibson DA, Rogers DT, Blanchard JA, Holley RC, Fu MC, Hart SR, Pedigo NW, Littleton JM (2002) Acamprosate inhibits the binding of neurotoxic effects on trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. Alcohol Clin Exp Res 26:1779–1793PubMedGoogle Scholar
  22. Harris BR, Gibson DA, Prendergast MA, Blanchard JA, Holley RC, Hart SR, Scotland RL, Foster TC, Pedigo NW, Littleton JM (2003) 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 27:1724–1735PubMedCrossRefGoogle Scholar
  23. Heilig M, Egli M (2006) Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther 111:855–876PubMedCrossRefGoogle Scholar
  24. Heyser CJ, Schulteis G, Durbin P, Koob GF (1998) Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats. Neuropsychopharmacology 18:125–133PubMedCrossRefGoogle Scholar
  25. Hotsenpiller G, Giorgetti M, Wolf ME (2001) Alterations in behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposure. Eur J Neurosci 14:1843–1855PubMedCrossRefGoogle Scholar
  26. Hölter SM, Landgraf R, Zieglgansberger W, Spanagel R (1997) Time course of acamprosate action on operant ethanol self-administration after ethanol deprivation. Alcohol Clin Exp Res 21:862–868PubMedCrossRefGoogle Scholar
  27. Hyytia P, Backstrom P, Liljequist S (1999) Site-specific NMDA receptor antagonists produce differential effects on cocaine self-administration in rats. Eur J Pharmacol 378:9–16PubMedCrossRefGoogle Scholar
  28. Iso Y, Grajkowska E, Wroblewski JT, Davis J, Goeders NE, Johnson KM, Sanker S, Roth BL, Tueckmantel W, Kozikowski AP (2006) Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications. J Med Chem 49:1080–1100PubMedCrossRefGoogle Scholar
  29. Kalivas PW, McFarland K, Bowers S, Szumlinski K, Xi ZX, Baker D (2003) Glutamate transmission and addiction to cocaine. Ann N Y Acad Sci 1003:169–175PubMedCrossRefGoogle Scholar
  30. Kenny PJ, Paterson NE, Boutrel B, Semenova S, Harrison AA, Gasparini F, Koob GF, Skoubis PD, Markou A (2003) Metabotropic glutamate 5 receptor antagonist MPEP decreased nicotine and cocaine self-administration but not nicotine and cocaine-induced facilitation of brain reward function in rats. Ann NY Acad Sci 1003:415–418PubMedCrossRefGoogle Scholar
  31. Kenny PJ, Boutrel B, Gasparini F, Koob GF, Markou A (2005) Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacology 179:247–254PubMedCrossRefGoogle Scholar
  32. Keys AS, Mark GP, Emre N, Meschul CK (1998) Reduced glutamate immunolabeling in the nucleus accumbens following extended withdrawal from self-administered cocaine. Synapse 30:393–401PubMedCrossRefGoogle Scholar
  33. Lee B, Platt DM, Rowlett JK, Adewale AS, Spealman RD (2005) Attenuation of behavioral effects of cocaine by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: comparison with dizocilpine. J Pharmacol Exp Ther 312:1232–1240PubMedCrossRefGoogle Scholar
  34. Le Magnen J, Tran G, Durlach J, Martin C (1987) Dose-dependent suppression of the high alcohol intake of chronically intoxicated rats by Ca-acetyl homotaurinate. Alcohol 4:97–102PubMedCrossRefGoogle Scholar
  35. Madamba SG, Schweitzer P, Zieglgänsberger W, Siggins GR (1996) Acamprosate (calcium acetylhomotaurinate) enhances the N-methyl-D-aspartate component of excitatory neurotransmission in rat hippocampal CA1 neurons in vitro. Alcohol Clin Exp Res 20:651–658PubMedCrossRefGoogle Scholar
  36. Maldonado C, Rodriguez-Arias M, Castillo A, Aguilar MA, Minarro J (2007) Effect of memantine and CNQX in the acquisition, expression and reinstatement of cocaine-induced conditioned place preference. Prog Neuropsychopharmacol Biol Psychiatry 31:932–939PubMedCrossRefGoogle Scholar
  37. McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23:3531–3537PubMedGoogle Scholar
  38. Mcgeehan AJ, Olive MF (2003) The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine. Br J Pharmacol 138:9–12PubMedCrossRefGoogle Scholar
  39. Mcgeehan AJ, Olive MF (2006) Attenuation of cocaine-induced reinstatement of cocaine conditioned place preference by acamprosate. Behav Pharmacol 17:363–367PubMedCrossRefGoogle Scholar
  40. Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK (2005) Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci 25:6389–6393PubMedCrossRefGoogle Scholar
  41. Naassila M, Legrand E, d'Alche-Birée F, Daoust M (1998) Cyamemazine decreases ethanol intake in rats and convulsions during ethanol withdrawal syndrome in mice. Psychopharmacology 140:421–428PubMedCrossRefGoogle Scholar
  42. Nalpas B, Dabadie H, Parot P, Paccalin J (1990) Acamprosate: from pharmacology to therapeutics. Encephale 16:175–179PubMedGoogle Scholar
  43. Park W-K, Bari AA, Jey AR, Anderson SM, Spealman RD, Rowlett JK, Pierce RC (2002) Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J Neurosci 22:2916–2925PubMedGoogle Scholar
  44. Popp RL, Lovinger DM (2000) Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons. Eur J Pharmacol 394:221–231PubMedCrossRefGoogle Scholar
  45. Rammes G, Mahal B, Putzke J, Parsons C, Spielmanns P, Pestel E, Spanagel R, Zieglgansberger W, Schadrack J (2001) 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 40:749–760PubMedCrossRefGoogle Scholar
  46. Rosenthal RN (2006) Current and future drug therapies for alcohol dependence. J Clin Psychopharmacol 26(Suppl 1):S20–S29CrossRefGoogle Scholar
  47. Schmidt HD, Anderson SM, Famous KR, Kumaresan V, Pierce RC (2005) Anatomy and pharmacology of cocaine priming-induced reinstatement of drug seeking. Eur J Pharmacol 526:65–76PubMedCrossRefGoogle Scholar
  48. Schneider U, Wohlfahrt K, Schulze-Bonhage A, Haacker T, Caspary A, Zedler M, Emrich HM (1998) Lack of psychotomimetic or impairing effects on psychomotor performance of acamprosate. Pharmacopsychiatry 31:110–113Google Scholar
  49. See RE, Kruzich PJ, Grimm JW (2001) Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior. Psychopharmacology 154:301–310PubMedCrossRefGoogle Scholar
  50. Soyka M, Roesner S (2006) New pharmacological approaches for the treatment of alcoholism. Expert Opin Pharmacother 7:2341–2353PubMedCrossRefGoogle Scholar
  51. Spanagel R, Hölter SM, (2000) Pharmacological validation of a new animal model of alcoholism. J Neural Transm 107:669–680PubMedCrossRefGoogle Scholar
  52. Spanagel R, Zieglgansberger W, Hundt W (1996) Acamprosate and alcohol. III. Effects of alcohol discrimination in the rat. Eur J Pharmacol 305:51–56PubMedCrossRefGoogle Scholar
  53. Spanagel R, Sillaber I, Zieglgansberger W, Corrigall WA, Stewart J, Shaham Y (1998) Acamprosate suppresses the expression of morphine-induced sensitization in rats but does not affect heroin self-administration or relapse induced by heroin or stress. Psychopharmacology 139:391–401PubMedCrossRefGoogle Scholar
  54. 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 11:35–42PubMedCrossRefGoogle Scholar
  55. Tessari M, Pilla M, Andreoli M, Hutcheson DM, Heidbreder CA (2004) Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. Eur J Pharmacol 499:121–133PubMedCrossRefGoogle Scholar
  56. Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613–672PubMedCrossRefGoogle Scholar
  57. Wilde MI, Wagstaff AJ (1997) Acamprosate: a review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification. Drugs 53:1038–1053PubMedCrossRefGoogle Scholar
  58. Zeise ML, Kasparow S, Capogna M, Zieglgänsberger W (1990) Calciumdiacetylhomotaurinate (CA-AOTA) decreases the action of excitatory amino acids in the rat neocortex in vitro. Prog Clin Biol Res 351:237–242PubMedGoogle Scholar
  59. Zeise ML, Kasparov S, Capogna M, Zieglgänsberger W (1993) Acamprosate (calciumacetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors. Eur J Pharmacol 231:47–52PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • M. Scott Bowers
    • 1
  • Billy T. Chen
    • 1
  • Jonathan K. Chou
    • 1
  • Megan P. H. Osborne
    • 2
  • Justin T. Gass
    • 2
  • Ronald E. See
    • 2
    • 3
  • Antonello Bonci
    • 1
    • 4
  • Patricia H. Janak
    • 1
    • 4
  • M. Foster Olive
    • 2
  1. 1.Ernest Gallo Clinic and Research Center, Department of NeurologyUniversity of California at San FranciscoEmeryvilleUSA
  2. 2.Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral SciencesMedical University of South CarolinaCharlestonUSA
  3. 3.Department of NeurosciencesMedical University of South CarolinaCharlestonUSA
  4. 4.Wheeler Center for the Neurobiology of AddictionUniversity of California at San FranciscoSan FranciscoUSA

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