Abstract
Alcoholism is one of the most prevalent neuropsychiatric diseases, having an enormous health and socioeconomic impact. Along with a few other medications, acamprosate (Campral—calcium-bis (N-acetylhomotaurinate)) is clinically used in many countries for relapse prevention. Although there is accumulated evidence suggesting that acamprosate interferes with the glutamate system, the molecular mode of action still remains undefined. Here we show that acamprosate does not interact with proposed glutamate receptor mechanisms. In particular, acamprosate does not interact with NMDA receptors or metabotropic glutamate receptor group I. In three different preclinical animal models of either excessive alcohol drinking, alcohol-seeking, or relapse-like drinking behavior, we demonstrate that N-acetylhomotaurinate by itself is not an active psychotropic molecule. Hence, the sodium salt of N-acetylhomotaurinate (i) is ineffective in alcohol-preferring rats to reduce operant responding for ethanol, (ii) is ineffective in alcohol-seeking rats in a cue-induced reinstatement paradigm, (iii) and is ineffective in rats with an alcohol deprivation effect. Surprisingly, calcium salts produce acamprosate-like effects in all three animal models. We conclude that calcium is the active moiety of acamprosate. Indeed, when translating these findings to the human situation, we found that patients with high plasma calcium levels due to acamprosate treatment showed better primary efficacy parameters such as time to relapse and cumulative abstinence. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.
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Acknowledgements
We would like to thank Sabrina Koch for the excellent technical assistance. We are also grateful to Thamil Annamalai, Wondwessen Mengesha for conducting the rat PK studies; Wendy Luo and Deborah Behrman for analytical PK sample analyses, Dr Juthamas Sukbuntherng and Shubhra Upadhyay for calculating PK parameters; Emily Tate and Heather Kerr for managing cell culture support; Sheila Irao, Dong Zhang, George Chiang, and Mirna Rodriguez for mGluR transfection and expression experiments, and clone selection; Tracy Dias and Tania Chernov-Rogan for the in vitro receptor binding studies and running the functional assays; Dr David J. Wustrow for general support and valuable stimulating discussions, Toño Estrada and Yanping Pu for technical assistance. This work was supported by the Bundesministerium für Bildung und Forschung (NGFN Plus; FKZ: 01GS08152, see under Spanagel et al, 2010 (Spanagel et al, 2010) and www.ngfn-alkohol.de). AJL is a Principal Fellow of the NHMRC, Australia and also supported by the Victorian Government’s Operational Infrastructure Support Program.
AUTHOR CONTRIBUTIONS
RS designed experiments, analyzed data, and wrote the manuscript; VV conducted the ADE experiments and analyzed data; BJ, WNF, and MAG led the overall project at XenoPort, Inc., provided Na-AOTA and coordinated all in vitro and in vivo studies and PK analyses; KG and XZ conducted electrophysiological studies; EVK and AJL did the behavioral work in iP rats; AJL assisted in manuscript writing; FK conducted the clinical study.
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Spanagel, R., Vengeliene, V., Jandeleit, B. et al. Acamprosate Produces Its Anti-Relapse Effects Via Calcium. Neuropsychopharmacol 39, 783–791 (2014). https://doi.org/10.1038/npp.2013.264
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DOI: https://doi.org/10.1038/npp.2013.264
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