Abstracts from New Researchers 2007

2nd International Congress of Biological Psychiatry, Santiago, Chile, April 17-20, 2007.

Alcohol dependence and acamprosate. How does it work?
Blednov Y.A. and Harris R.A.
University of Texas, Waggoner Center for Alcohol and Addiction Research, Austin, TX 78712.
Introduction. Acamprosate is an abstinence-promoting drug widely used in the treatment of alcohol dependence but which has a mechanism of action that has remained obscure for many years. Recently, this drug has been suggested to interact with excitatory glutamatergic neurotransmission as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) (see De Witte et al., 2005 for rev.). We showed that mice lacking mGluR5 demonstrate a variety of changes in ethanol-induced behavior, including reduced severity to acute ethanol-induced withdrawal (ACWITH) and increased sensitivity to sedative (hypnotic) effect of ethanol (Blednov et al., 2004).
Methods. To evaluate possible connections between mGluR5, ethanol-induced behavior and pharmacological effects of acamprosate, we studied acamprosate on ACWITH and ethanol-induced LORR in mGluR5 knockout mice. The effects of acamprosate were compared with a mGluR5 antagonist, MPEP.
Results. Only high (45 mg/kg) but not low (10 mg/kg) doses of MPEP significantly potentiated the LORR induced by injection of low dose of ethanol (3.2 g/kg) in wild type mice. However, both doses of MPEP significantly reduced the severity of ACWITH in wild type mice. Only high (300 mg/kg and 400 mg/kg) but not low (200 mg/kg) doses of acamprosate potentiated the LORR induced by injection of low dose of ethanol (3.2 g/kg) in wild type mice. Both low (200 mg/kg) and high (300 mg/kg) doses of acamprosate reduced the severity of ACWITH in wild type mice. Similar with MPEP the protective effect of acamprosate was found only when it was injected before but not after the injection of ethanol. No effects of acamprosate or MPEP on ethanol-induced LORR and ACWITH were found in mGluR5 knockout mice.
Conclusions.  We show that the pharmacological effects of acamprosate on ethanol-induced behavior (LORR and ACWITH) are similar to effects of the selective mGluR5 antagonist – MPEP. Moreover, no effects of acamprosate were found in mutant mice lacking the mGluR5 receptor. There results support the hypothesis that effects of acamprosate on ethanol-induced behavior can be mediated by mGluR5 and selective antagonists of mGluR5 can be useful for treatment of alcoholism.

Supported by the National Institute of Alcohol Abuse and Alcoholism, NIH (AA U01 13520 -INIA Project).

Conclusions and Future Directions:  An alcohol deprivation effect was not seen during this experiment.  The control group and the ADE group never significantly differed during the four weeks of deprivation and drinking.  In the future we could try the same experimental design using a lower drinking strain of mice, like FVB/NJ, that does not show an aversion to alcohol, although C57BL/6J female mice are capable of drinking to considerably higher levels than seen here.  It is also possible that a longer initial access period is needed.  We could increase the initial access period by offering 2-bottle choice unlimited access to 20% ethanol followed by the same weekly deprivation and DID cycle as this study. Although a 6-week acclimation period is traditional before looking for an ADE in 2-bottle designs, how long this period needs to be is not clear