Individual Variation in Alcohol Intake Predicts Reinforcement, Motivation, and Compulsive Alcohol Use in Rats

Spoelder, Marcia; Hesseling, Peter; Baars, Annemarie M.; Klooster, José G. Lozeman-van ‘t; Rotte, Marthe D.; Vanderschuren, Louk J. M. J.; Lesscher, Heidi M. B.

doi:10.1111/acer.12891

Cited by 52 publications

(77 citation statements)

References 49 publications

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“…The rapid development of aversion-resistant alcohol drinking in C57BL/6 mice is in strong contrast to rats, where several months of intermittent alcohol intake are required for Wistar rats to develop quinine-resistant drinking patterns (Hopf and Lesscher, 2014, Hopf et al, 2010, Loi et al, 2010, Seif et al, 2013, Seif et al, 2015 and Spoelder et al, 2015). Although there are many species differences that might explain these dissimilarities, one clear finding is that C57BL/6 mice drink high levels of alcohol from the onset, with binge-like levels of alcohol intake even during a first, 4-h drinking session (Mulligan et al, 2011).…”

Section: Discussionmentioning

confidence: 95%

A single alcohol drinking session is sufficient to enable subsequent aversion-resistant consumption in mice

Lei

Wegner

et al. 2016

Alcohol

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Addiction is mediated in large part by pathological motivation for rewarding, addictive substances, and alcohol-use disorders (AUDs) continue to extract a very high physical and economic toll on society. Compulsive alcohol drinking, where intake continues despite negative consequences, is considered a particular obstacle during treatment of AUDs. Aversion-resistant drives for alcohol have been modeled in rodents, where animals continue to consume even when alcohol is adulterated with the bitter tastant quinine, or is paired with another aversive consequence. Here, we describe a two-bottle choice paradigm where C57BL/6 mice first had 24-h access to 15% alcohol or water. Afterward, they drank quinine-free alcohol (alcohol-only) or alcohol with quinine (100 μM), in a limited daily access (LDA) two-bottle-choice paradigm (2 h/day, 5 days/week, starting 3 h into the dark cycle), and achieved nearly binge-level blood alcohol concentrations. Interestingly, a single, initial 24-h experience with alcohol-only enhanced subsequent quinine-resistant drinking. In contrast, mice that drank alcohol–quinine in the 24-h session showed significantly reduced alcohol–quinine intake and preference during the subsequent LDA sessions, relative to mice that drank alcohol-only in the initial 24-h session and alcohol–quinine in LDA sessions. Thus, mice could find the concentration of quinine we used aversive, but were able to disregard the quinine after a single alcohol-only drinking session. Finally, mice had low intake and preference for quinine in water, both before and after weeks of alcohol-drinking sessions, suggesting that quinine resistance was not a consequence of increased quinine preference after weeks of drinking of alcohol–quinine. Together, we demonstrate that a single alcohol-only session was sufficient to enable subsequent aversion-resistant consumption in C57BL/6 mice, which did not reflect changes in quinine taste palatability. Given the rapid development of quinine-resistant alcohol drinking patterns, this model provides a simple, quick, and robust method for uncovering the mechanisms that promote aversion-resistant consumption.

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Section: Discussionmentioning

confidence: 95%

A single alcohol drinking session is sufficient to enable subsequent aversion-resistant consumption in mice

Lei

Wegner

et al. 2016

Alcohol

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“…Understanding these different types of motivation for alcohol may reveal subpopulations of alcohol use disorders, each with different neural substrates and different potential treatments. It is also important to note that some studies have demonstrated that, after approximately 2 months of homecage ethanol access, high-drinking animals show stronger operant ethanol seeking than do low-drinking animals (Spoelder et al, 2015). Therefore, it is possible that we may have observed a stronger relationship between homecage alcohol intake and self-administration in HR and LR rats had the homecage access period extended beyond two weeks.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have reported individual differences in alcohol preference in outbred rats (e.g., Momeni and Roman, 2014; Momeni et al, 2014; Pelloux et al, 2015; Sharko et al, 2013; Spoelder et al, 2015), though it is more common for studies to consider effects averaged across entire cohorts. The current results, combined with previous work from our lab (Lopez et al, 2016; Moorman and Aston-Jones, 2009), strongly indicate that these individual differences in ethanol motivation result, at least in part, from differential activation of the ORX system.…”

Section: Discussionmentioning

confidence: 99%

Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats

et al. 2017

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The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low-alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self-administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the ORX1R may be an important target for treating alcohol abuse.

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“…Since shock-resistant intake is considered to have face and predictive validity for compulsive intake in humans, e.g. for cocaine (Everitt and Robbins, 2005; Hopf and Lesscher, 2014; Lesscher and Vanderschuren, 2012), the observation of a similar circuit for shock- and quinine-resistant alcohol drinking (Seif et al, 2013) validates the use of alcohol-quinine drinking to model compulsive-like drives for alcohol (Hopf et al, 2010; Hopf and Lesscher, 2014; Lesscher et al, 2010; Loi et al, 2010; Marchant et al, 2013; Spanagel and Holter, 1999; Spoelder et al, 2015; Vengeliene et al, 2009). For the present studies, we utilized a recently developed compulsive-like drinking model in mice, modified from Lesscher et al (2010) where aversion-resistant alcohol drinking is apparent after only a single protracted session of alcohol-only consumption, and with binge-like blood alcohol levels (Lei et al, in press).…”

Section: Introductionmentioning

confidence: 92%

“…Therefore, to effectively reduce the impact of AUDs, it is critical to understand the mechanisms that drive this consequence-resistant, compulsive-like alcohol consumption. In this regard, voluntary drinking paradigms, where animals will drink despite pairing the alcohol with an aversive consequence (such as bitter-tasting quinine or foot-shock), have been utilized to model some compulsive-like aspects of AUDS in humans (Hopf et al, 2010; Hopf and Lesscher, 2014; Lesscher et al, 2010; Loi et al, 2010; Marchant et al, 2013; Spanagel and Holter, 1999; Spoelder et al, 2015; Vengeliene et al, 2009). In addition, we previously demonstrated that a similar corticoaccumbens circuit promotes both shock-resistant and quinine-resistant alcohol drinking (Seif et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice

Lei

Wegner

et al. 2016

Neuropharmacology

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Addiction is promoted by pathological motivation for addictive substances, and, despite extensive efforts, alcohol use disorders (AUDs) continue to extract a very high social, physical, and economic toll. Compulsive drinking of alcohol, where consumption persists even when alcohol is paired with negative consequences, is considered a particular obstacle for treating AUDs. Aversion-resistant alcohol intake in rodents, e.g. where rodents drink even when alcohol is paired with the bitter tastant quinine, has been considered to model some compulsive aspects of human alcohol consumption. However, the critical mechanisms that drive compulsive-like drinking are only beginning to be identified. The neuropeptide orexin has been linked to high motivation for cocaine, preferred foods, and alcohol. Thus, we investigated the role of orexin receptors in compulsive-like alcohol drinking, where C57BL/6 mice had 2-hr daily access to 15% alcohol with or without quinine (100 µM). We found that systemic administration of the widely used selective orexin-1 receptor (OX1R) blocker, SB-334867 (SB), significantly reduced compulsive-like consumption at doses lower than those reported to reduce quinine-free alcohol intake. The dose of 3-mg/kg SB, in particular, suppressed only compulsive-like drinking. Furthermore, SB did not reduce concurrent water intake during the alcohol drinking sessions, and did not alter saccharin+quinine consumption. In addition, the OX2R antagonist TCS-OX2-29 (3 or 10 mg/kg) did not alter intake of alcohol with or without quinine. Together, our results suggest that OX1R signaling is particularly important for promoting compulsive-like alcohol drinking, and that OX1Rs might represent a novel therapy to counteract compulsive aspects of human AUDs.

show abstract

Individual Variation in Alcohol Intake Predicts Reinforcement, Motivation, and Compulsive Alcohol Use in Rats

Abstract: These profound individual differences in alcohol intake, reinforcement, motivation, and AUD-like behavior provide a promising tool to unravel the neurobehavioral underpinnings of individual vulnerability for AUD.

Cited by 52 publications

References 49 publications

A single alcohol drinking session is sufficient to enable subsequent aversion-resistant consumption in mice

A single alcohol drinking session is sufficient to enable subsequent aversion-resistant consumption in mice

Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats

Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice

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