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Is R(+)‐Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side
Author(s) -
EcheverryAlzate Victor,
Jeanblanc Jérôme,
Sauton Pierre,
Bloch Vanessa,
Labat Laurence,
Soichot Marion,
Vorspan Florence,
Naassila Mickael
Publication year - 2021
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1111/adb.12892
Subject(s) - baclofen , alcohol dependence , abstinence , medicine , pharmacology , population , alcohol use disorder , anesthesia , ethanol , alcohol , agonist , chemistry , psychiatry , biochemistry , receptor , environmental health
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.