Acamprosate Produces Its Anti-Relapse Effects Via Calcium

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 acamprosatelike 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.

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

“…Another tentative explanation of our findings could be that enhanced calcium levels after sCT activation of renal calcitonin receptors reflect an increase in brain calcium levels consequently changing calcium influx/efflux in neuronal ion channels. On a similar note, a recent clinical study investigating the effects of acamprosate on alcohol-dependent individuals attributed the drug's effects to calcium levels and not to a specific CNS target (Spanagel et al 2014). Nevertheless, a number of studies investigating the effects of locally administered sCT on food intake accompanied by immunohistochemistry data have identified central sites of action, especially in areas of the mesolimbic dopamine system (Mietlicki-Baase et al 2013;Mietlicki-Baase & Hayes 2014;Reiner et al 2017).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…However, a recent study suggests that it is the calcium salt, rather than the purported NMDAR ligand N-acetylhomotaurinate, that ameliorates alcoholic behavior in both preclinical and clinical applications (Spanagel et al, 2014). Acamprosate is the subject of more clinical research than any other compound in this section, and meta-analyses suggest that it is effective in the treatment of alcoholism (Dranitsaris et al, 2009;Mason and Lehert, 2012;Jonas et al, 2014).…”

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

“…It should be noted that calcium has been suggested to be the active moiety of acamprosate (69). Recently it has been reported that plasma calcium concentrations in association with severity of alcohol dependence and its interaction with regulating pathways and alcohol craving in alcohol-dependent patients (70).…”