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Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine‐Sensitive Acamprosate Binding Site in Rat Brain
Author(s) -
Naassila Mickaël,
Hammoumi Saloua,
Legrand Elisabeth,
Durbin Philippe,
Daoust Martine
Publication year - 1998
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1998.tb03871.x
Subject(s) - acamprosate , spermidine , dizocilpine , pharmacology , nmda receptor , chemistry , binding site , spermine , biochemistry , receptor , biology , antagonist , enzyme , naltrexone
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 [ 3 H]acam‐prosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [ 3 H]acamprosate to rat brain membranes with a KD of 120 μM and a B max of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC 50 : 13.32 ± 1.1 μM; 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 Sr 2+ ). Conversely, acamprosate displaced [ 14 C]spermidine binding from rat brain membranes with an IC 50 , of 645 μM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in B max 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 [ 3 H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [ 3 H]dizocilpine binding at concentrations in the 5 to 200 μ range. However, under conditions of maximal receptor activation (100 μM glutamate, 30 μM glycine), acamprosate only inhibited [ 3 H]dizocilpine binding (at concentrations concentrations > 100 μM). When these binding studies were performed in the presence of 1 μM spermidine, the enhancing effects of acamprosate on [ 3 H]dirocilpine 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.