Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice

Abstract

Rationale A promising pharmacotherapy for alcohol use disorders has been positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB R) since GABAB R PAMs reduce ethanol drinking and self-administration in rodents. Objective The current studies investigated a novel, selective GABAB R PAM, ADX71441, in comparison to naltrexone in a protocol of ethanol binge-like drinking, drinking-in-the-dark (DID), and in a model of long-term, excessive drinking, intermittent access to ethanol (IA). Methods Male C57BL/6 J mice were given doses of ADX71441 (3, 10, 30 mg/kg, p.o.) before the fourth test day of repeated DID access to 20 % ethanol. Another group of mice had a history of 4 weeks of IA before ADX71441 (3, 10, 17 mg/ kg, p.o.) treatment. The opioid antagonist, naltrexone (0.1, 1, 10 mg/kg, i.p.), was administered to different groups of mice in both protocols as a positive control. Results In both DID and IA protocols, ADX71441 showed a selective and potent reduction of ethanol drinking, but not water drinking, while naltrexone had a more modest and transient effect on reducing ethanol drinking. The long-lasting effect of ADX71441 agrees with its plasma pharmacokinetics in showing peak concentrations at 2 h followed by a slow decay lasting well beyond 8 h. Conclusions These findings support previous studies demonstrating that GABAB R PAMs decrease voluntary ethanol intake without altering water intake. ADX71441 may be a worthwhile candidate for developing a treatment of alcoholism, yet its site of action in the brain and long-term pharmacological effects require further exploration.

Effects of Withania somnifera on oral ethanol self-administration in rats

“…Consistently, phaclofen also reduced the effect of baclofen on ethanol selfadministration. et al, 2010) as well as of GABA B receptor-positive allosteric modulators (Maccioni et al, 2008b;Hwa et al, 2014) in ethanol self-administration, which provides further support for the suggestion, previously anticipated by Ruiu et al (2013), that WSE might affect not only morphine-elicited but also ethanol-elicited reinforcement. Finally, in support of the pharmacological profile of WSE as a GABA B -like ligand, WSE affects saccharin reinforcement, an observation in agreement with that of Quintanilla et al (2008).…”

Alcohol dependence and free-choice drinking in mice

“…One possibility might be combining vapor inhalation procedures with the popular drinking-in-the-dark procedure that models binge drinking (Rhodes, Best, Belknap, Finn, & Crabbe, 2005; Rhodes et al, 2007), in which one session out of every 4 access sessions is 4 h in duration, leading to a large increase in ethanol intake. Additionally, given the recent demonstration that CIE exposure procedures could increase drinking in a continuous access model (Depoy et al, 2013), the CIE exposure procedures might be used in combination with the 24-h intermittent access model that has been shown to produce an escalation of intake in mice (Hwa et al, 2011; Hwa, Kalinichev, Haddouk, Poli, & Miczek, 2013; Melendez, 2011). Another intriguing alternative might be the use of several ethanol solutions in the same session, providing multiple choices for the mice.…”

Inhibition of alcohol self-administration by positive allosteric modulators of the GABAB receptor in rats: lack of tolerance and potentiation of baclofen

“…As mentioned above, the GABA B PAM, ADX71441, is presently approaching clinical evaluation (Addex Therapeutics 2013); ADX71441 has been reported to suppress alcohol intake in mice exposed to two experimental models of excessive alcohol drinking and binge-like drinking that possess remarkable predictive validity for AUD (Hwa et al 2014). Data collected with ADX71441 are closely consonant with those collected to date with all other GABA B PAMs and add further support to the hypothesis that the capacity of suppressing multiple alcohol-motivated behaviors in rodents is a common feature of the entire class of GABA B PAMs.…”

“…Specifically, treatment with most of the currently available, in vivo effective GABA B PAMs (namely, CGP7930, GS39783, BHF177, rac-BHFF, and ADX71441) has been reported to reduce several alcoholmotivated behaviors, including excessive alcohol drinking Loi et al 2013;Hwa et al 2014), binge-like drinking (Hwa et al 2014;Linsenbardt and Boehm 2014), operant, oral alcohol self-administration (Liang et al 2006;Maccioni et al 2007Maccioni et al , 2008Maccioni et al , 2009Maccioni et al , 2010aMaccioni et al , b, 2012, and alcohol-seeking behavior (LeiteMorris et al 2009;Maccioni et al 2010a) in rats and mice. Notably, these effects were produced at doses largely lower than those producing sedation or unselective reduction of other seeking and intake behaviors, suggesting that GABA B PAMs may possess a high therapeutic index and favorable "safety" profile.…”