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Neuroprotective and Abstinence-Promoting Effects of Acamprosate

Elucidating the Mechanism of Action

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Abstract

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system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn.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

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Acknowledgements

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.

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  1. Biologie Du Comportement, Université Catholique de Louvain, Place Croix du Sud, 1-bte 10, B 1348, Louvain-la-Neuve, Belgium

    Philippe De Witte

  2. Department of Pharmacology, University of Kentucky, Lexington, Kentucky, USA

    John Littleton

  3. Conseil en Pharmacologie Clinique, Massy, France

    Philippe Parot

  4. Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California, USA

    George Koob

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  1. Philippe De Witte
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  2. John Littleton
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  3. Philippe Parot
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  4. George Koob
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Correspondence to Philippe De Witte.

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De Witte, P., Littleton, J., Parot, P. et al. Neuroprotective and Abstinence-Promoting Effects of Acamprosate. CNS Drugs 19, 517–537 (2005). https://doi.org/10.2165/00023210-200519060-00004

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  • DOI: https://doi.org/10.2165/00023210-200519060-00004

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