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system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn.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

This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were (1) Characterization of Synaptic Loss in Cerebella of Mature and Senescent Rats after Lengthy Chronic Ethanol Consumption, (2) Ethanol Withdrawal Both Causes Neurotoxicity and Inhibits Neuronal Recovery Processes in Rat Organotypic Hippocampal Cultures, (3) Binge Drinking-Induced Brain Damage: Genetic and Age Related Effects, (4) Binge Ethanol-Induced Brain Damage: Involvement of Edema, Arachidonic Acid and Tissue Necrosis Factor alpha (TNFalpha), and (5) Cyclic AMP Cascade, Stem Cells and Ethanol. Taken together these studies suggest that alcoholic neurodegeneration occurs through multiple mechanisms and in multiple brain regions both during intoxication and withdrawal.

This article explores the mechanisms of action and the potential responder profile of acamprosate, a compound efficacious in relapse prevention of alcoholism. New evidence at the molecular and cellular level suggests that acamprosate attenuates hyper-glutamatergic states that occur during early abstinence and involves iono (NMDA)- and metabotrotropic (mGluR5) glutamate receptors along with augmented intracellular calcium release and electrophysiological changes. Thus mutant mice with enhanced glutamate levels exhibit higher alcohol consumption than wild type mice and respond better to acamprosate, demonstrating that acamprosate acts mainly on a hyper-glutamatergic system. This mode of action further suggests that acamprosate exhibits neuroprotective properties. In rats, cue-induced reinstatement behavior is significantly reduced by acamprosate treatment whereas cue-induced craving responses in alcohol-dependent patients seem not to be affected by this treatment. An ongoing study ("Project Predict") defines specific responder profiles for an individualized use of acamprosate and naltrexone. Neurophysiological as well as psychometric data are used to define 2 groups of patients: "reward cravers" and "relief cravers". While naltrexone should work better in the first group, acamprosate is hypothesized to be efficacious in the latter where withdrawal associated and/or cue induced hyper-glutamatergic states are thought to trigger relapse. Further research should target the definition of subgroups applying endophenotypic approaches, e.g. by detecting a hyperglutamatergic syndrome using MR spectroscopy.

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Na-acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-acamprosate and SIB-1893 support an interaction of Na-acamprosate at mGluR5s. The neuroprotective properties of acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs.

The morbidity and mortality resulting from alcohol-related diseases impose a substantive cost to society globally. To minimize the financial burden on society and improve the quality of life for individuals suffering from the ill effects of alcohol abuse, researchers in the alcohol field are focused on understanding the mechanisms by which alcohol-related diseases develop and progress. Since ethical concerns and inherent difficulties limit the amount of alcohol abuse research that can be performed in humans, most is performed in laboratory animals. This article summarizes the various laboratory models of alcohol abuse that are currently available and are used to study the mechanisms by which alcohol abuse induces organ damage and immune defects. The strengths and weaknesses of each of the models are discussed. Integrated into the review are the presentations that were made in the symposium “Methods of Ethanol Application in Alcohol Model – How Long is Long Enough” at the joint 2008 Research Society on Alcoholism (RSA) and International Society for Biomedical Research on Alcoholism (ISBRA) meeting, Washington, DC, emphasizing the importance not only of selecting the most appropriate laboratory alcohol model to address the specific goals of a project but also of ensuring that the findings can be extrapolated to alcohol-induced diseases in humans.

From this model of long-term ethanol exposure and withdrawal, the functional interplay between mGluR5s and NMDARs might represent a novel target for the prevention of neurotoxicity associated with ethanol withdrawal.

Naltrexone and acamprosate may ultimately prove to be useful additions to pharmacotherapy for alcoholism by reducing relapse. Naltrexone is a relatively selective competitive antagonist at mu-opioid receptors, and this activity may explain its anti-relapse action either because endogenous opioids are involved in the positively reinforcing effects of alcohol and/or because these same transmitters are involved in the conditioned anticipation of these effects. In contrast, the pharmacology of acamprosate is still poorly understood. This is not surprising because it is a small flexible molecule with similarities to several neuro-active amino acids and is used in high doses. All these factors suggest that it may have multiple actions. Currently, the best explanation for the effects of acamprosate seems to be that it inhibits the glutamatergic transmitter system involved in both the negative reinforcing effects of alcohol and the conditioned ''pseudo-withdrawal'' that may be important in cue-induced relapse. (Am J Addict 2003;12[Suppl 1]:S3^S11) S3