GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice

Abstract

GABA(B) agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA(B) agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA(B) positive modulation. These data question the safety of prescribing GABA(B) agonists to alcoholics since these drugs may potentiate ethanol's sedative/hypnotic effects during relapse.

Efficacy and Tolerability of Baclofen in Substance Use Disorders: A Systematic Review

“…This empirical calculation suggests the use of doses exceeding 30 mg/day. A preclinical study also demonstrated the existence of cross-tolerance between alcohol and baclofen, suggesting that subjects affected by AUDs may require even higher doses of baclofen [92]. …”

“…Finally, one study demonstrated the existence of cross-tolerance to the sedative effects of alcohol and baclofen; alcohol-tolerant mice were less sensitive to the sedative effects of baclofen than alcohol-naive mice [92]. …”

“…Specifically, treatment with baclofen has been reported to suppress the following: (1) alcohol drinking in rats exposed to the standard, home cage 2-bottle ‘alcohol versus water' choice regimen (a validated animal model of excessive alcohol consumption in humans) [29,85,86,87,88]; (2) relapse-like drinking in previously abstinent rats [89,90]; (3) alcohol reinforcing and motivational properties in rats, mice and nonhuman primates trained to perform a given amount of ‘work' (usually responding on a lever) to gain access to the alcohol solution [91,92,93,94,95,96,97,98,99]; (4) reinstatement of alcohol-seeking behavior triggered in rats by the noncontingent presentation of a complex of cues previously associated with alcohol availability [100]; (5) alcohol-induced conditioned place preference (CPP; index of alcohol rewarding properties) in mice [101], and (6) alcohol-induced stimulation of locomotor activity in rats and mice (index of alcohol euphorigenic properties) [102,103,104,105]. …”

Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABAB receptors

“…In this strain of mice, nonsweetened alcoholic solutions offered in operant procedures have marked reinforcing properties in long sessions (lasting 16 to 23 h) (Besheer et al, 2004Hodge et al, 2006;Risinger et al, 1998Risinger et al, , 2001Schroeder et al, 2003) and in foodrestricted mice (Elmer et al, 1986(Elmer et al, , 1988Middaugh et al, 1999;Hayward et al, 2004;Heidbreder et al, 2007). However, studies in ad libitum-fed C57BL/6J mice trained to respond to a plain ethanol solution in water in short sessions have given contrasting results in terms of the amount of ethanol self-administered (ranging from 0.14 to 1.00 g/kg) and in ethanol-maintained operant responding (Faccidomo et al, 2009;Middaugh et al, 2000;Salling et al, 2008).…”

Influence of reinforcement schedule on ethanol consumption patterns in non-food restricted male C57BL/6J mice

“…Although the reinforcing effects of ethanol have been successfully demonstrated when the drug is continuously available (Besheer et al, 2004;Hodge et al, 2006;Olive et al, 2000;Risinger et al, 1998Risinger et al, ,1999, data evaluating ethanol reinforcement in mice under a limited access condition is less well studied. Studies with mice responding on a fixed ratio 1 (FR1) (Middaugh et al 2000;Roberts et al 2000) or FR3 (Tsiang and Janak, 2006) reinforcement schedule reported ethanol intake approximating 0.5 g/kg, which correspond to values in rats responding on a FR schedule (e.g., Samson, 2000).…”