Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine‐Sensitive Acamprosate Binding Site in Rat Brain

Abstract

It has been suggested that the anticraving drug, acamprosate, acts via the glutamatergic system, but the exact mechanism of action is still unknown. The aim of this study was to characterize [3H]acamprosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [3H]acamprosate to rat brain membranes with a KD of 120 microM and a Bmax of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC50: 13.32 +/- 1.1 microM; Hill coefficient = 1.04), and arcaine and glutamate both potentiated the inhibitory effect of spermidine. Acamprosate binding to the acamprosate binding site was also sensitive to inhibition by divalent cations (Ca2+, Mg2+, and Sr2+). Conversely, acamprosate displaced [14C]spermidine binding from rat brain membranes with an IC50 of 645 microM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in Bmax and binding affinity for spermidine, suggesting an allosteric interaction between acamprosate and a spermidine binding site. These data are consistent with an effect of acamprosate on the NMDA receptor protein complex, and acamprosate was also found to alter binding of [3H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [3H]dizocilpine binding at concentrations in the 5 to 200 microM range. However, under conditions of maximal receptor activation (100 microM glutamate, 30 microM glycine), acamprosate only inhibited [3H]dizocilpine binding (at concentrations concentrations >100 microM). When these binding studies were performed in the presence of 1 microM spermidine, the enhancing effects of acamprosate on [3H]dizocilpine binding were inhibited. The results show that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as "partial co-agonist" at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol-dependent patients during abstinence.

Efficacy of acamprosate in the treatment of alcohol-dependent outpatients

“…Acamprosate has been considered as a partial co-agonist of the NMDA receptor. 6,7 These actions of acamprosate are compatible with the hypothesis that this medication suppresses the hyperactivity associated to high levels of excitation of the glutamate receptor during alcohol withdrawal in dependent patients. Therefore, this medication reduces the toxicity induced by glutamate.…”

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

“…Acamprosate also has some effects in preventing aversive effects associated with ethanol withdrawal (Spanagel et al, 1996b;Cole et al, 2000). In vitro studies have suggested that acamprosate may be acting as a partial co-agonist at the N-methyl-D-aspartate receptor Zeise et al, 1993;Dahchour et al, 1998;Koob et al, 2002;al Qatari et al, 1998;Naassila et al, 1998), a neuropharmacological action that might explain its blockade of excessive drinking and attenuation of the motivational effects of abstinence from ethanol. The present study was initiated to test the hypothesis that the anti-alcohol-dependence effects of acamprosate might generalize to opiate dependence.…”

A Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Acamprosate and Naltrexone

“…NMDA receptors are involved with long-term potentiation, an electrophysiological phenomena involving longlasting, activity-dependent increases in the strength of synaptic transmission, which appears to be an intermediate step required for memory storage (Malenka 1991). Recent evidence suggests that acamprosate may act as a partial co-agonist at the NMDA receptor (Naassila et al 1998;al Qatari et al 1998). The acamprosate cognitive data are consistent with pre-clinical and human studies that show d-cycloserine, a partial agonist of the glycine site on the NMDA receptor, did not affect acquisition of new learning, but did improve performance during the retention phase of tasks Pussinen et al 1997;Tsai et al 1999;Wesnes et al 1991).…”