Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/11891
Title: Acamprosate produces its anti-relapse effects via calcium.
Authors: Spanagel, Rainer;Vengeliene, Valentina;Jandeleit, Bernd;Fischer, Wolf-Nicolas;Grindstaff, Kent;Zhang, Xuexiang;Gallop, Mark A;Krstew, Elena V;Lawrence, Andrew J;Kiefer, Falk
Affiliation: XenoPort, Inc., Santa Clara, CA, USA
Florey Institute of Neuroscience & Mental Health, University of Melbourne, Melbourne, Australia
Institute of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
Department of Addictive Behavior and Addiction Medicine, Central Institute for Mental Health, Mannheim, Germany.
Issue Date: 30-Sep-2013
Citation: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology 2013; 39(4): 783-91
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.
Internal ID Number: 24081303
URI: http://ahro.austin.org.au/austinjspui/handle/1/11891
DOI: 10.1038/npp.2013.264
URL: http://www.ncbi.nlm.nih.gov/pubmed/24081303
Type: Journal Article
Subjects: Alcohol Deterrents.pharmacology.therapeutic use
Alcoholism.drug therapy.metabolism
Animals
Calcium.metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Excitatory Amino Acid Agents.pharmacology
Excitatory Postsynaptic Potentials.drug effects
GABA Agents.pharmacology
Humans
In Vitro Techniques
Male
Membrane Potentials.drug effects.genetics
Patch-Clamp Techniques
Rats
Rats, Sprague-Dawley
Rats, Wistar
Receptors, N-Methyl-D-Aspartate.genetics.metabolism
Secondary Prevention
Taurine.analogs & derivatives.chemistry.pharmacology.therapeutic use
Xenopus laevis
Appears in Collections:Journal articles

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