MECHANISM OF ACTION OF ACAMPROSATE - PART II - ETHANOL DEPENDENCE MODIFIES EFFECTS OF ACAMPROSATE ON NMDA RECEPTOR-BINDING IN MEMBRANES FROM RAT CEREBRAL-CORTEX

Acamprosate is a putative anticraving drug used to maintain abstinence in alcohol-dependent patients. Its mechanism of action is uncertain, but the drug is thought to interact with neuronal NMDA receptors and c alcium channels, and these proteins are implicated in the induction of alcohol dependence. In these experiments, the effects of acamprosate were studied on the binding of the NMDA receptor ligand [H-3]dizocilpi ne to rat brain membranes under nonequilibrium conditions; 10 mu M glu tamate and 1 mu M glycine were present in the binding assays to partia lly activate the receptor. At clinically relevant concentrations (in t he micromolar range), acamprosate significantly enhanced [H-3]dizocilp ine binding to cortical membranes from control animals (suggesting tha t acamprosate may increase the rate of association of the radioligand) , whereas at higher concentrations binding was inhibited. This effect is consistent with a partial agonist effect of acamprosate on the NMDA receptor protein. However, when rats were made dependent on ethanol ( exposure to the drug for 10 days by inhalation) and cortical membranes were prepared from these animals, acamprosate in vitro no longer prod uced any enhancement of [H-3]dizocilpine binding. Similar results were obtained when membranes were used from rats that had received 400 mg/ kg/day of acamprosate in their drinking water with or without concurre nt ethanol inhalation for 10 days, Thus, in brain membranes from all t hese treatment groups, acamprosate in vitro caused inhibition of [H-3] dizocilpine binding only. The results suggest that acamprosate may hav e excitatory or inhibitory effects on NMDA receptors, depending on the experimental conditions. The effects of the drug on this system appea r to be shifted toward inhibition in alcohol dependence, and this find ing may be important to its clinical mechanism.