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.

Fig. 1

Ethanol intake (gram per kilogram) in mice on the fourth day of the repeated drinking-in-the-dark (DID) procedure. Animals were pretreated with either ADX71441 (3, 10, 30 mg/kg, p.o.) or its vehicle (1 % CMC, a) or naltrexone (NTX; 0.1, 1, 10 mg/kg, i.p.) and its vehicle (saline, SAL, b). Drinking from one bottle of 20 % ethanol was assessed every hour over the course of 4 h. Each point represents the observed mean (+SEM). *p <0.05, **p <0.01 vs. vehicle (n =12/group)

Fig. 2

Ethanol intake in mice on the test day of the intermittent access to ethanol (IA) procedure. Animals were pretreated with either ADX71441 (3, 10, 17 mg/kg, p.o.) or its vehicle (1 % CMC) before being given two-bottle choice and their alcohol and water consumption was monitored at 2, 4, and 24 h time points (n =12/group). Ethanol intake per unit of body weight (gram per kilogram; a), volume of ethanol (b), and water intake (ml; c) are portrayed over the time course of a test day. Each point represents the observed mean (+SEM). *p <0.05, **p <0.01 vs. vehicle

Fig. 3

Ethanol intake in mice on the test day of the IA procedure. Animals were pretreated with naltrexone (NTX; 0.1, 1, 10 mg/kg, i.p.) or saline (SAL) before being exposed to two-bottle choice and their ethanol and water consumption was monitored at 2, 4, and 24 h time points (n =12/group). Ethanol intake per unit of body weight (gram per kilogram; a), volume of ethanol (b), and water intake (milliliter; c) are portrayed over the time course of a test day. Each point represents the observed mean (+SEM). *p <0.05 vs. SAL

Fig. 4

Mean plasma concentration of ADX71441 (nanogram per milliliter) after p.o. administration of 10 mg/kg to male C57BL/6 mice (n =24). ADX71441-induced reduction in 20 % ethanol intake (ml) across 24 h in C57BL/6 J mice (n =12) in the intermittent access protocol. Portrayed is the percent change in ethanol intake from the vehicle baseline across 2, 4, and 24 h