Acamprosate is an FDA-approved medication for the treatment of
alcoholism that is unfortunately only effective in certain patients. Although
acamprosate is known to stabilize the hyper-glutamatergic state in
alcoholism,
pharmacological mechanisms of action in brain tissue remains unknown. To investigate the mechanism of
acamprosate efficacy, the authors employ a pharmacoproteomics approach using an animal model of
alcoholism, type 1 equilibrative
nucleoside transporter (ENT1) null mice. The results demonstrate that
acamprosate treatment significantly decreased both
ethanol drinking and preference in ENT1 null mice compared to that of wild-type mice. Then, to elucidate
acamprosate efficacy mechanism in ENT1 null mice, the authors utilize label-free quantification proteomics comparing both genotype and
acamprosate treatment effects in the nucleus accumbens (NAc). A total of 1040
protein expression changes are identified in the NAc among 3634 total
proteins detected. The proteomics and Western blot result demonstrate that
acamprosate treatment decreased EAAT expression implicating stabilization of the hyper-glutamatergic condition in ENT1 null mice. Pathway analysis suggests that
acamprosate treatment in ENT1 null mice seems to rescue
glutamate toxicity through restoring of RTN4 and NF-κB medicated neuroimmune signaling compared to wild-type mice. Overall, pharmacoproteomics approaches suggest that neuroimmune restoration is a potential efficacy mechanism in the
acamprosate treatment of certain sub-populations of alcohol dependent subjects.