Mechanism of Action of Acamprosate
Acamprosate restores the balance between excitatory glutamatergic and inhibitory GABAergic neurotransmission that becomes disrupted during chronic alcohol exposure and withdrawal, primarily through modulation of NMDA receptors and antagonism of metabotropic glutamate receptor subtype 5 (mGluR5). 1
Primary Mechanism: Glutamatergic System Modulation
Chronic alcohol exposure upregulates the glutamatergic system, and when alcohol is abruptly withdrawn, the brain experiences excessive glutamatergic activity that acamprosate attenuates. 2
Acamprosate acts as an antagonist at the mGluR5 metabotropic glutamate receptor, which provides a unifying explanation for its diverse neurochemical effects in alcohol dependence. 3, 2
The drug reduces the surge in glutamic acid release that occurs following alcohol withdrawal, protecting neurons from excitotoxicity that may contribute to neuronal loss in chronic alcohol dependence. 2
Secondary Mechanism: NMDA Receptor Interaction
Acamprosate exhibits a biphasic effect on NMDA receptors, acting as a partial co-agonist—at low concentrations (30 μM) it enhances low NMDA-induced excitation, while at higher concentrations (100-400 μM) it inhibits NMDA-mediated excitation by 50-70%. 4
The drug inhibits neuronal hyperexcitability by antagonizing excitatory amino acid activity and reducing calcium ion fluxes through NMDA receptor channels. 5
GABAergic System Involvement
While acamprosate has a chemical structure similar to GABA and the neuromodulator taurine, its effects on GABAA receptors are secondary to its glutamatergic actions. 1, 3
At higher concentrations (200 μM), acamprosate increases GABAA-mediated inhibition, though blockade of GABAA receptors only partially abolishes its inhibitory effects, confirming that NMDA modulation is the predominant mechanism. 4
Clinical Implications of the Mechanism
The glutamatergic hypothesis explains acamprosate's ability to reduce cue-elicited drinking behaviors, as glutamatergic neurotransmission plays a critical role in the acquisition of these conditioned responses. 2
Acamprosate does not cause alcohol aversion, does not produce a disulfiram-like reaction with ethanol ingestion, and has no anticonvulsant, antidepressant, or anxiolytic activity outside its effects on alcohol dependence. 1
The drug exhibits no abuse potential, does not produce withdrawal symptoms at therapeutic doses, and is not associated with the development of tolerance or dependence. 1
Pharmacological Specificity
Acamprosate's effects appear specific to alcohol and the mechanisms of alcohol dependence—it dose-dependently reduces voluntary ethanol consumption in alcohol-dependent animals without affecting total fluid intake or food consumption. 5
The drug does not undergo metabolism and is excreted unchanged via the kidneys, which explains its safety in patients with hepatic impairment where other alcohol dependence medications are contraindicated. 1