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

Abstract

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.

The Novel Positive Allosteric Modulator of the GABAB Receptor, KK-92A, Suppresses Alcohol Self-Administration and Cue-Induced Reinstatement of Alcohol Seeking in Rats

“…The suppressing effect of KK-92A on alcohol self-administration may therefore be the sum of two converging actions at the GABA B receptor: (i) agonistic activity, resembling the suppressing effect of the prototypic GABA B receptor agonist, baclofen, on alcohol-related behaviors (see Colombo and Gessa, 2018); (ii) positive allosteric modulation. The agonistic component of KK-92A might also be responsible for the reducing effect of KK-92A on sucrose self-administration, replicating the ability of baclofen to affect sucrose self-administration in rats at the same doses that reduced alcohol self-administration (e.g., Anstrom et al, 2003;Janak and Gill, 2003;Maccioni et al, 2005Maccioni et al, , 2008bEcheverry-Alzate et al, 2021).…”

Dissecting operant alcohol self‐administration using saccharin‐fading procedure

“…As mentioned above, there are studies in which animals are trained to consume alcohol in a two-bottle-choice drinking procedure or are exposed to chronic alcohol vapor inhalation in order to induce dependence. 46 These types of procedures, as well as the use of alcohol-preference animals, make OSA a paradigm with multiple alternatives. For future complementary studies, it would be interesting to carry out studies using groups of animals exposed to other ratio schedules, as well as modifying the alcohol introduction and concentration increase process, to find the ideal protocol to reach stable levels of alcohol consumption.…”

“…In this way, although OSA is often used to study voluntary alcohol consumption in preclinical models and leads to stable and moderate consumption levels, this paradigm can be combined with others to achieve high levels of consumption. As mentioned above, there are studies in which animals are trained to consume alcohol in a two‐bottle‐choice drinking procedure or are exposed to chronic alcohol vapor inhalation in order to induce dependence 46 . These types of procedures, as well as the use of alcohol‐preference animals, make OSA a paradigm with multiple alternatives.…”

Baclofen decreases compulsive alcohol drinking in rats characterized by reduced levels of GAT‐3 in the central amygdala

“…Baclofen was administered IP in a volume of 1 ml/kg. These doses of baclofen have been shown in rats to yield no unspecific effects 9 , to result in plasma concentrations ~2,000 and 500 ng/mL after 30 and 180 min, respectively and to be linearly related to the ability of baclofen to decrease instrumental responding for alcohol 45 …”

“…Hab: habituation; Mol: molecular analysis; s: session; Sacch choice: saccharin choice respectively and to be linearly related to the ability of baclofen to decrease instrumental responding for alcohol. 45…”