Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors.
BACKGROUND
Several reported effects of acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether acamprosate could compete with trnas-ACPD (+/--1-aminocyclopentane-trans-1,3-dicarboxylic acid, an equimolecular mixture of 1S, 3R and 1R, 3S-ACPD and an agonist at both group I and group II mGluRs) sensitive binding sites and protect against trans-ACPD-induced neurotoxicity in organotypic hippocampal slice cultures.


METHODS
A P2 membrane preparation of cortices, cerebellums, and hippocampi of adult, male Sprague Dawley rats was used to determine the abilities of N-methyl-D-aspartic acid (NMDA) and trans-ACPD to displace [3H]glutamate in both the absence and the presence of the sodium salt of acamprosate (sodium mono N-acetyl homotaurine or Na-acamprosate). A comparison of the effects of 100 microM guanosine 5'-triphosphate on unlabeled glutamate, trans-ACPD, and Na-acamprosate was performed in the same paradigm. For the neurotoxicity studies, organotypic hippocampal slice cultures from male and female 8-day-old neonatal rats were exposed to either 500 microM -ACPD or 50 microM NMDA for 24 hr in normal culture medium containing serum on day 20 in vitro. The effects of Na-acamprosate and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at metabotropic type 5 receptors (mGluR5s), were assessed by determining differences in propidium iodide uptake as compared with neurotoxic challenges alone.


RESULTS
Na-acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na-acamprosate displayed total competition with trans-ACPD. The presence of 100 microM guanosine 5'-triphosphate differentially altered the displacing capabilities of the two mGluR agonists, unlabeled glutamate and trans-ACPD, as compared with Na-acamprosate. Na-acamprosate (200-1000 microM) and SIB-1893 (20-500 microM) both were neuroprotective against trans-ACPD induced neurotoxicity that likely results from mGluR potentiation of NMDARs. In turn, Na-acamprosate and SIB-1893 had no direct effects on NMDA-induced neurotoxicity.


CONCLUSIONS
Na-acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-acamprosate and SIB-1893 support an interaction of Na-acamprosate at mGluR5s. The neuroprotective properties of acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs.
Harris
Barton R
BR
Department of Molecular and Biomedical Pharmacology, University of Kentucky Chandler Medical Center, Lexington 40546-0236, USA.
Prendergast
Mark A
MA
Gibson
D Alex
DA
Rogers
D Trent
DT
Blanchard
John A
JA
Holley
Robert C
RC
Fu
May C
MC
Hart
Stewart R
SR
Pedigo
Norman W
NW
Littleton
John M
JM
D000077443:Acamprosate; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013654:Taurine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D013654:Taurine; D000077443:Acamprosate