The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801

NMDA-receptor-mediated mechanisms may be crucial in addictive states, e.g. alcoholism, and provide a target for the novel anti-craving compound acamprosate. Here. the pharmacological effects of acamprosate on NMDA-receptors were studied using electrophysiological techniques in different cell lines in vitro. Additionally, a possible modulation of brain NMDA-receptor subunit expression was examined in vivo in rats, and compared to two effective non-competitive NMDA-receptor antagonists, memantine and MK-801. Electrophysiology in cultured hippocampal neurons (IC50 approx. 5.5 mM) and Xenopus oocytes (NR1-la/NR2A assemblies: IC50 approx. 350 muM. NR1-1a/NR2B: IC50 approx. 250 muM) consistently revealed only a weak antagonism of acamprosate on native or recombinant NMDA-receptors. In HEK-293 cells, acamprosate showed almost no effect on NR1-la/NR2A or NR1-1a/NR2B recombinants (IC(50)s not calculated). Protein blotting demonstrated an up-regulation of NMDA-receptor subunits after acamprosate as well as after memantine or MK-801, in comparison to controls. After acamprosate, protein levels were increased in the cortex (NR1-3/1-4: 190+/-11% of controls) and hippocampus (NR1-1/1-2: 163+/-11%). The up-regulations observed after memantine (cortex, NR2B: 172+/-17%; hippocampus, NR1-1/1-2: 156+/-8%) or MK-801 (cortex. NR2B: 174+/-22%: hippocampus, NR1-1/1-2: 140+/-3%) were almost identical. No changes were detected in the brainstem. The present data indicate an extremely weak antagonism of NMDA-receptors by acamprosate. However, its ability to modulate the expression of NMDA-receptor subunits in specific brain regions - shared with the well established NMDA-antagonists memantine and MK-801 - may be of relevance for its therapeutic profile, especially considering the growing importance of NMDA-receptor plasticity in the research of ethanol addiction. (C) 2001 Elsevier Science Ltd. All rights reserved.