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 (IC(50) approx. 5.5mM) and Xenopus oocytes (NR1-1a/NR2A assemblies: IC(50) approx. 350 microM, NR1-1a/NR2B: IC(50) approx. 250 microM) consistently revealed only a weak antagonism of acamprosate on native or recombinant NMDA-receptors. In HEK-293 cells, acamprosate showed almost no effect on NR1-1a/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.
Rammes
G
G
Clinical Neuropharmacology, Max-Planck-Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany. rammes@mpipsykl.mpg.de
Mahal
B
B
Putzke
J
J
Parsons
C
C
Spielmanns
P
P
Pestel
E
E
Spanagel
R
R
Zieglgänsberger
W
W
Schadrack
J
J
D000077443:Acamprosate; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014981:Xenopus
D000427:Alcohol Deterrents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D013654:Taurine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D000077443:Acamprosate; D008559:Memantine