Rodent models for compulsive alcohol intake

Hopf, F. Woodward; Lesscher, Heidi M. B.

doi:10.1016/j.alcohol.2014.03.001

Cited by 163 publications

(182 citation statements)

References 117 publications

(249 reference statements)

Supporting

Mentioning

176

Contrasting

Order By: Relevance

“…Following repeated cycles of CIE exposure and withdrawal, striatal-based habit-like learning is enhanced (DePoy et al , 2013) as is aversion-resistant drinking (e.g. footshock, quinine) suggesting that alterations in corticostriatal circuits such as those including the LOFC may develop during alcohol dependence and contribute to escalations in ethanol intake and loss of control over drinking (Hopf and Lesscher, 2014). The reduced quinine sensitivity of OFC-lesioned CIE exposed mice observed in the present study may reflect these types of alterations.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice

et al. 2016

View full text Add to dashboard Cite

Long-term consumption of ethanol affects cortical areas that are important for learning and memory, cognition, and decision-making. Deficits in cortical function may contribute to alcohol-abuse disorders by impeding an individual’s ability to control drinking. Previous studies from this laboratory show that acute ethanol reduces activity of lateral orbitofrontal cortex (LOFC) neurons while chronic exposure impairs LOFC-dependent reversal learning and induces changes in LOFC excitability. Despite these findings, the role of LOFC neurons in ethanol consumption is unknown. To address this issue, we examined ethanol drinking in adult C57Bl/6J mice that received an excitotoxic lesion or viral injection of the inhibitory DREADD (designer receptor exclusively activated by designer drug) into the LOFC. No differences in ethanol consumption were observed between sham and lesioned mice during access to increasing concentrations of ethanol (3–40%) every other day for 7 weeks. Adulterating the ethanol solution with saccharin (0.2%) or quinine (0.06 mM) enhanced or inhibited, respectively, consumption of the 40% ethanol solution similarly in both groups. Using a chronic intermittent ethanol (CIE) vapor exposure model that produces dependence, we found no difference in baseline drinking between sham and lesioned mice prior to vapor treatments. CIE enhanced drinking in both groups as compared to air-treated animals and CIE treated lesioned mice showed an additional increase in ethanol drinking as compared to CIE sham controls. This effect persisted during the first week when quinine was added to the ethanol solution but consumption decreased to control levels in CIE lesioned mice in the following 2 weeks. In viral injected mice, baseline drinking was not altered by expression of the inhibitory DREADD receptor and repeated cycles of CIE exposure enhanced drinking in DREADD and virus control groups. Consistent with the lesion study, treatment with clozapine-N-oxide (CNO) further enhanced consumption only in CIE exposed DREADD mice with no change in air-treated mice. These results suggest that the LOFC is not critical for the initiation and maintenance of ethanol drinking in non-dependent mice, but may regulate the escalated drinking observed during dependence.

show abstract

Section: Discussionmentioning

confidence: 99%

Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Compulsive alcohol intake, where drinking persists despite the knowledge of associated negative consequences, is considered a major obstacle when treating AUDs (Anton, 2000; Anton et al, 1996; Hopf and Lesscher, 2014; Koob and Volkow, 2010; Larimer et al, 1999; Modell et al, 1992; Naqvi et al, 2014; Sinha, 2009; Tiffany and Conklin, 2000). Therefore, to effectively reduce the impact of AUDs, it is critical to understand the mechanisms that drive this consequence-resistant, compulsive-like alcohol consumption.…”

Section: Introductionmentioning

confidence: 99%

“…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

Self Cite

View full text Add to dashboard Cite

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

“…Parallels to the tendency among humans with alcohol use disorders to disregard negative, or aversive, outcomes to obtain and consume alcohol have received recent focus in basic research. Indeed, the need for an improved model of aversion-resistant alcohol intake to facilitate identification of molecular mechanisms and assist in the development of therapies is elegantly described in a recent review by Hopf and Lesscher (2014).…”

Section: Introductionmentioning

confidence: 99%

Long-Term Alcohol Drinking Reduces the Efficacy of Forced Abstinence and Conditioned Taste Aversion in Crossed High-Alcohol-Preferring Mice

O’Tousa

Grahame

2016

Alcohol Clin Exp Res

View full text Add to dashboard Cite

Background Negative outcomes of alcoholism are progressively more severe as the duration of problem alcohol use increases. Additionally, alcoholics demonstrate tendencies to neglect negative consequences associated with drinking and/or to choose to drink in the immediate presence of warning factors against drinking. The recently derived crossed High-Alcohol Preferring (cHAP) mice, which volitionally drink to heavier intoxication (as assessed by BEC) than other alcohol-preferring populations, as well as spontaneously escalating their intake, may be a candidate to explore mechanisms underlying long-term excessive drinking. Here we hypothesized that an extended drinking history would reduce the ability of two manipulations (forced abstinence and conditioned taste aversion) to attenuate drinking. Methods Experiment 1 examined differences between groups drinking for either 14 or 35 days, half of each subjected to 7 days of forced abstinence and half not, to characterize potential changes in post-abstinence drinking resulting from an extended drinking history. Experiment 2 used a conditioned taste aversion procedure to assess stimulus specificity of the ability of an aversive flavorant to decrease alcohol consumption. Experiment 3 used this taste aversion procedure to assess differences among groups drinking for 1, 14, or 35 days in their propensity to overcome this aversion when the flavorant was mixed with either ethanol or water. Results Experiment 1 demonstrated that although forced abstinence decreased alcohol consumption in mice with a 14-day drinking history, it failed to do so in mice drinking alcohol for 35 days. Experiment 2 showed that the addition of a flavorant only suppressed alcohol drinking if an aversion to the flavorant was previously established. Experiment 3 demonstrated that an extended drinking history expedited extinction of suppressed alcohol intake caused by a conditioned aversive flavor. Conclusions These data show that a history of long-term drinking in cHAP mice attenuates the efficacy of interventions that normally reduce drinking. Analogous to alcoholics who may encounter difficulties in limiting their intake, cHAP mice with long drinking histories are relatively insensitive both to abstinence and signals of harmful consequences. We propose that the cHAP line may be a valid model for adaptations that occur following extended heavy alcohol drinking.

show abstract

Rodent models for compulsive alcohol intake

Cited by 163 publications

References 117 publications

Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice

Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice

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

Long-Term Alcohol Drinking Reduces the Efficacy of Forced Abstinence and Conditioned Taste Aversion in Crossed High-Alcohol-Preferring Mice

Contact Info

Product

Resources

About