Innate and Acquired Quinine‐Resistant Alcohol, but not Saccharin, Drinking in Crossed High–Alcohol‐Preferring Mice

Abstract

Background: Alcohol consumption despite aversive consequences is often a key component of an alcoholism diagnosis. Free-choice alcohol consumption despite bitter quinine adulteration in rodents has been seen following several months of free-choice drinking, but there has been little study of whether prolonged access to other palatable substances such as saccharin yields quinine resistance. Selectively bred crossed high-alcohol-preferring (cHAP) mice average blood alcohol levels of over 250 mg/dl during free-choice access, considerably higher than other models. We hypothesized that higher intakes would yield more rapid development of quinine-resistant alcohol (QRA) drinking and quinine-resistant saccharin (QRS) drinking.Methods: All experiments used male and female cHAP mice. Experiment 1 compared mice with either 0 or 5 weeks of alcohol drinking history, testing varying (0.032, 0.10, 0.32 g/l) quinine concentrations in ethanol. Experiment 2 examined whether innate QR may exist, comparing animals with a 1 or zero day of drinking history. Experiment 3 examined the effect of varying histories (0, 2, or 5 weeks) of free-choice 10% alcohol drinking on QR alcohol consumption at high quinine concentrations. Finally, Experiment 4 investigated the development of QRS drinking.Results: We found that we could not detect a history effect in commonly used quinine concentrations, indicating that cHAP mice are innately quinine resistant to 0.10 g/l quinine. However, we were able to determine that a 2-week drinking history was sufficient to induce QRA drinking in cHAP mice at extremely high quinine concentrations (0.74 and 0.32 g/l). However, the history effect was specific to QRA, a saccharin drinking history, did not yield QRS drinking.Conclusions: These data suggest that an alcohol drinking history induces maladaptive behaviors, such as drinking in spite of negative consequences, a pattern not seen with saccharin. Furthermore, a strong genetic predisposition to drink may promote an innate aversion resistance compared with commonly used inbred strains.

Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking

“…An absence of sex differences in quinine’s ability to reduce breakpoints for alcohol under a progressive ratio (PR) schedule in rats has also been reported [ 89 ]. We also note that while both alcohol exposure history and a history of early life stress can increase compulsion-like alcohol drinking, we have not found female vulnerability to compulsion to interact with either of those variables [ 80 , 92 ]. It is noteworthy that DID, a paradigm that reveals robust binge drinking, appears to mask sex differences in compulsion-like drinking [ 43 ].…”

Three Weeks of Binge Alcohol Drinking Generates Increased Alcohol Front‐Loading and Robust Compulsive‐Like Alcohol Drinking in Male and Female C57BL/6J Mice

“…The general procedure involves mice drinking in one of these models for a set amount of time, and then having their alcohol solution adulterated with quinine with concentrations varying from 100 to 1,000 μM, though most commonly 100 to 250 μM has been used. This has primarily been done in male mice with no investigation into sex differences, though more recently female mice have been included in QuA experiments (Bocarsly et al, 2019; Houck et al, 2019; Sneddon et al, 2020) with some directly testing sex difference hypotheses (Sneddon et al, 2019; Top of Form Fulenwider, et al, 2019; Shaw et al, 2020). Compulsive‐like QuA drinking is then determined by the definition wherein compulsive mice will consume the same amount of QuA as nonadulterated alcohol, whereas noncompulsive mice would consume significantly less QuA than nonadulterated alcohol.…”

Advances in understanding meso‐cortico‐limbic‐striatal systems mediating risky reward seeking

“…Susceptibility to the effect of positive punishment on reward seeking also appears to exist on a continuum, with some individuals being relatively more resistant to punishment-induced inhibition than others (Giuliano et al, 2018;Marchant et al, 2018;Spoelder et al, 2015Spoelder et al, , 2017. This spectrum of punishment sensitivity may be partially explained by genetic factors: for example, laboratory rats bred to prefer alcohol are often relatively resistant to positive punishment of alcohol drinking (in comparison to their non-preferring counterparts) (Giuliano et al, 2018;Houck et al, 2019;Timme et al, 2020), while various strains of commonly used laboratory mice exhibit marked differences in susceptibility to footshock or quinineinduced suppression of alcohol seeking (Halladay et al, 2017).…”

“…Punishment insensitivity following extended access or exposure to addictive drugs has been demonstrated for cocaine (Chen et al, 2013;Deroche-Gamonet, 2004;Kasanetz et al, 2010;Mitchell et al, 2014;Pelloux et al, 2007;Vanderschuren & Everitt, 2004) and alcohol (Barbier et al, 2017;Hopf et al, 2010;Houck et al, 2019;Kimbrough et al, 2017;Radke et al, 2017;Vendruscolo et al, 2012), as well as other addictive substances such as methamphetamine (Cadet et al, 2016;Torres et al, 2017) and fentanyl (Monroe & Radke, 2020). Extended cocaine access also causes cues associated with footshock to lose their ability to inhibit drug seeking, which is not true of extended exposure to natural rewards like sucrose (Vanderschuren & Everitt, 2004).…”