Sex-related differences in the efficacy of Baclofen enantiomers on
alcohol drinking and dopamine release in the core of the nucleus
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.