Alterations in the rate of binge ethanol consumption: implications for preclinical studies in mice

Abstract

The rate at which alcohol (ethanol) is consumed has direct impact on its behavioral and subjective effects. For this reason, alterations in the pattern of ethanol consumption as a function of drinking history might be critical to the development and maintenance of alcoholism. Furthermore, because pharmacological interventions aimed at disrupting the motivation to consume ethanol are dependent on the brain/plasma concentrations present when an individual is most likely to engage in consumption of this substance, characterizing temporal drinking patterns might be useful to determine the timing of such treatments. The primary goal of the present study was to evaluate alterations in the timecourse of daily binge (Drinking-in-the-dark; DID) ethanol consumption. We gave 14 daily 2 hour DID ethanol or water access sessions to male C57BL/6J (B6) mice using a state of the art volumetric drinking monitoring device. We then, primarily as a proof-of-principle, used the GABAB allosteric modulator GS39783 (GS) to determine how this compound influenced the timecourse of binge-like ethanol intake. The rate of ethanol consumption increased dramatically over sessions with the majority occurring in the first few minutes of the final session. Additionally, ethanol consumption occurring immediately following access was almost completely abolished in mice pretreated with GS; an effect which was ethanol-specific only at this early time interval. These data characterize progressive alterations in the rate of ethanol intake using the DID model and suggest that careful consideration of prior ethanol history and timing of drug administration are warranted when interpreting results of preclinical drug administration studies.

“Wired,” Yet Intoxicated: Modeling Binge Caffeine and Alcohol Co‐Consumption in the Mouse

“…This pattern is consistent with what we typically observe in DID (Linsenbardt and Boehm, 2012, Linsenbardt and Boehm, 2013). For the 0.05% analysis (W, E, C5, EC5), no factors or interactions reached statistical significance (all p ’s > 0.083; Figures 1A/C).…”

“…Although a different question, caffeine may alter alcohol intake probed at later time points (beyond 2 hours). Male B6 mice will drink alcohol to the point of sedation in the DID paradigm (Linsenbardt and Boehm, 2013; current study), but this is not observed in combination with caffeine. Therefore, extending the access period may allow more time for this activity difference to influence ethanol intake differences between groups.…”

Adenosinergic regulation of binge-like ethanol drinking and associated locomotor effects in male C57BL/6J mice

“…Indeed, one previous study showed that pre-treatment with DPCPX attenuated the development of rapid tolerance to alcohol’s ataxic effect in mice (Batista et al, 2005), suggesting that A 1 receptor activation is involved in the adaptive response to alcohol intoxication. Our lab and others have shown that longer DID access (~2-4 weeks opposed to 1 week) produces ataxic tolerance (Linsenbardt et al, 2011), alterations in associated locomotion (Linsenbardt and Boehm, 2014, Linsenbardt et al, 2011, Fritz et al, 2014a), and the rate of alcohol intake (Wilcox et al, 2014, Linsenbardt and Boehm, 2014), perhaps indicating that the duration of alcohol access in this model may also alter sensitivity to one or both of these compounds. In addition, animals in our study were freely consuming alcohol in their home cage versus operant chambers in other studies.…”

“…Although the dose × time interaction was not statistically significant ( p > 0.05), we also analyzed intake during the first 30 min portion of DID drinking separately on the basis of previous observations that male B6 mice consume alcohol most heavily within this early phase of DID (Wilcox et al, 2014, Linsenbardt and Boehm, 2014). The 6 mg/kg dose effectively reduced early alcohol drinking [ F 3,34 = 87.71, p < 0.01], an effect that appears to be largely responsible for its reduction in overall alcohol intake.…”

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

“…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.…”