4.1 Article

Is R(+)-Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side

期刊

ADDICTION BIOLOGY
卷 26, 期 2, 页码 -

出版社

WILEY
DOI: 10.1111/adb.12892

关键词

alcohol use disorder; GABAB receptor; operant oral alcohol self-administration; R(+)-Baclofen; RS(+/-)-Baclofen; S(-)-Baclofen

资金

  1. Ministry of Higher Education, Research and Innovation
  2. Conseil regional de Picardie
  3. INSERM

向作者/读者索取更多资源

Research suggests that R(+)-Baclofen is more effective than RS(+/-)-Baclofen in reducing ethanol intake and seeking, while S(-)-Baclofen and RS(+/-)-Baclofen may lead to an increase in alcohol intake in certain individuals.
For several decades, studies conducted to evaluate the efficacy of RS(+/-)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(+/-)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(+/-)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(+/-)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(+/-)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(+/-)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(+/-)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake.

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