Abstract
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 (NR1-1a/NR2A assemblies: IC50 approx. 350 μM, NR1-1a/NR2B: IC50 approx. 250 μM) 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 (IC50s 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.
Original language | English |
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Pages (from-to) | 749-760 |
Number of pages | 12 |
Journal | Neuropharmacology |
Volume | 40 |
Issue number | 6 |
DOIs | |
State | Published - May 2001 |
Externally published | Yes |
Keywords
- Acamprosate
- Alcohol
- Anti-craving compounds
- Ethanol
- MK-801
- Memantine
- NMDA-receptor
- Protein expression
- Splice variants
- Subunits