Jérome Jeanblanc

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Background and Purpose. Clinical studies on the effectiveness of Baclofen in alcohol use disorder (AUD) yielded mixed results possibly because of differential effects of the enantiomers and sex-related differences. Here we examined the effect of the different Baclofen enantiomers on ethanol intake and on evoked dopamine release in the core of the nucleus accumbens (NAcc) in male and female Long Evans rats. Experimental Approach. Fifteen rats from each sex were trained to chronically self-administer 20% ethanol solution in daily 15min sessions and were treated with the different enantiomers (RS(±), R(+) and R(-)). The effects on the evoked dopamine release within the core of the NAcc were measured in brain slices from the same animals using the fast scan cyclic voltammetry technique. Key Results. RS(±)-Baclofen reduced ethanol intake only in males. R-Baclofen completely abolished ethanol intake in males and only moderately decreased it in females. S(-)-Baclofen did not have any effect. In some individuals, especially in the females, both the RS(±) and the S(-)-Baclofen increased ethanol intake by at least 100%.There were no sex-differences in Baclofen pharmacokinetic but a strong negative correlation was found in females with a paradoxical effect of increased ethanol intake with higher blood Baclofen concentration. RS(±)- and S(-)-Baclofen produced a differential effect on evoked dopamine release in males. Conclusion and implications. Our results demonstrate a sex-dependent effect of the different enantiomers of Baclofen with negative effects in subgroup of females and should warrant future clinical studies on AUD pharmacotherapy that will deeply analyze gender difference.