Alcohol solution strength preference predicts compulsive-like drinking behavior in rats.

BACKGROUND: Understanding compulsive drinking behavior is key to improving outcomes in the treatment of addiction. In the present study, we investigated compulsive-like drinking in alcohol-addicted rats using the alcohol deprivation effect (ADE) model of relapse behavior, which involves repeated deprivation and reintroduction phases; the latter approximate relapse. METHODS: High-resolution longitudinal drinking and locomotor data were measured while rats (n = 30) underwent a four-bottle (water, 5%, 10%, 20% alcohol v/v) free-choice ADE paradigm. Alcohol bottles were adulterated with the bitter compound quinine during a reintroduction phase to test for compulsive behavior. We characterized how drinking and locomotor behavior during ADE + quinine differed from a regular ADE and how, at the individual level, behavioral parameters extracted from the regular ADE related to compulsive-like drinking. Associations of drinking with locomotor activity were also examined. RESULTS: In the ADE with quinine, we observed reduced consumption of alcohol and a shift to preference for stronger alcohol. Quinine acted by decreasing both the access size and frequency of drinking of 5% alcohol while increasing the frequency of consumption of 20% alcohol. Preference for higher alcohol concentrations prior to the quinine challenge was associated with greater compulsive-like drinking behavior; higher baseline consumption of 20% alcohol correlated with more drinking of quinine-adulterated solutions while high frequency and amount of 5% alcohol consumption at baseline were correlated with being more strongly affected by quinine. Associations between locomotor activity and drinking behavior were observed at the hourly level. These associations reflected changing preferences across experimental phases. CONCLUSION: Drinking patterns, and specifically solution preference, may offer insights into the presentation of compulsive-like drinking. The findings provide a preclinical basis for observations from epidemiological studies that link higher risk and burden of alcohol-related disease to stronger alcohol concentrations and encourage further translational studies to better understand the underlying mechanisms.

Perineuronal nets in the insula regulate aversion-resistant alcohol drinking.

One of the most pernicious characteristics of alcohol use disorder is the compulsion to drink despite negative consequences. The insular cortex controls decision making under conditions of risk or conflict. Cortical activity is tightly controlled by inhibitory interneurons that are often enclosed by specialized extracellular matrix structures known as perineuronal nets (PNNs), which regulate neuronal excitability and plasticity. The density of PNNs in the insula increases after repeated bouts of binge drinking, suggesting that they may play a role in the transition from social to compulsive, or aversion-resistant, drinking. Here, we investigated whether insular PNNs play a role in aversion-resistant alcohol drinking using a mouse model in which ethanol was adulterated with the bitter tastant quinine. Disrupting PNNs in the insula rendered mice more sensitive to quinine-adulterated ethanol but not ethanol alone. Activation of the insula, as measured by c-fos expression, occurred during aversion-resistant drinking and was further enhanced by elimination of PNNs. These results demonstrate that PNNs control the activation of the insula during aversion-resistant drinking and suggest that proper excitatory/inhibitory balance is important for decision making under conditions of conflict. Disrupting PNNs in the insula or optimizing insula activation may be a novel strategy to reduce aversion-resistant drinking.

Additive influences of acute early life stress and sex on vulnerability for aversion-resistant alcohol drinking.

Acute early life stress (ELS) alters stress system functioning in adulthood and increases susceptibility to posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). The current study assessed the effects of acute, infant ELS on alcohol drinking, including aversion-resistant drinking, in male and female Long Evans rats. Acute ELS was induced using a stress-enhanced fear learning (SEFL) protocol that consisted of 15 footshocks delivered on postnatal day (PND) 17. Alcohol drinking during adolescence and adulthood was measured with a two-bottle choice intermittent alcohol access paradigm. Aversion-resistant drinking was assessed in adulthood by adding quinine (0.01, 0.1, and 1.0 g/L) to the alcohol bottle after 5 to 6 weeks and 11 to 12 weeks of drinking. ELS had minimal influences on adolescent and adult alcohol consumption and preference. However, ELS, sex, and alcohol exposure history all influenced aversion-resistant alcohol drinking in an additive fashion. Higher concentrations of quinine were tolerated in females, ELS-exposed rats, and after 11 to 12 weeks of drinking. Tests of quinine sensitivity in a separate cohort of animals found that rats can detect concentrations of quinine as low as 0.001 g/L in water and that quinine sensitivity is not influenced by sex or ELS exposure. These results agree with reports of sex differences in aversion-resistant drinking and are the first to demonstrate an influence of ELS on this behavior. Our results also suggest that a single traumatic stress exposure in infancy may be a promising model of comorbid PTSD and AUD and useful in studying the interactions between ELS, sex, and alcohol dependence.

Anticraving Effect of Baclofen in Alcohol-Dependent Patients.

BACKGROUND: Baclofen is a GABA-B receptor agonist currently used in the treatment of spasticity. In recent years, baclofen has been used to reduce craving, voluntary alcohol intake and withdrawal syndrome of alcoholic patients. To date, there are no data available to estimate the relationship between baclofen exposure and the variation of craving. The first objective of this study was to investigate the variation of craving as a function of exposure, and the second was to explore the possible existence of baclofen responders and nonresponders. METHODS: Sixty-seven outpatients, 43 men/24 women (weight: 73 kg [42 to 128]; age: 49 years old [29 to 68]) followed in the addictology unit, were studied during 3 months after treatment initiation. Baclofen was administered by oral route. Therapeutic drug monitoring enabled the measurement of plasma concentrations. Craving level was assessed by the Obsessive-Compulsive Drinking Scale (OCDS). A population pharmacokinetic (PK)-pharmacodynamic analysis of the OCDS variation following baclofen administration was performed. Demographic data, biological data, and tobacco consumption were tested for their influence on the parameters. RESULTS: Data were modeled with a 1-compartment model with first-order absorption and elimination. PK analysis confirms the results of our previous study. An Emax model best-described the exposure-OCDS relationship. None of the covariates tested was able to improve the fit or decrease intersubject variability. However, 2 subpopulations were defined for the exposure corresponding to half the maximal effect (BE50). The proportion of patients being classified as responders was 38% (95% confidence interval [CI] 7 to 76), the maximal decrease in OCDS (Emax ) was 72% (95% CI 25 to 85), and the BE50 was 12.6 (95% CI 0.02 to 74.3) or 4,390 (95% CI 20.4 to 31,800) h mg/l for responders and nonresponders, respectively. CONCLUSIONS: We defined the relationship between baclofen exposure and craving in patients with alcohol use disorder. Baclofen treatment decreased craving in all patients. However, we drew up the hypothesis of 2 subpopulations of patients differentiated by their speed of response. A wide interindividual variability in response was depicted, making it currently impossible to predict which group a patient will belong to.

Association between iron accumulation in the dorsal striatum and compulsive drinking in alcohol use disorder.

RATIONALE: Brain iron accumulation has been observed in neuropsychiatric disorders and shown to be related to neurodegeneration. OBJECTIVES: In this study, we used quantitative susceptibility mapping (QSM), an emerging MRI technique developed for quantifying tissue magnetic susceptibility, to examine brain iron accumulation in individuals with alcohol use disorder (AUD) and its relation to compulsive drinking. METHODS: Based on our previous projects, QSM was performed as a secondary analysis with gradient echo sequence images, in 186 individuals with AUD and 274 healthy participants. Whole-brain susceptibility values were calculated with morphology-enabled dipole inversion and referenced to the cerebrospinal fluid. Then, the susceptibility maps were compared between AUD individuals and healthy participants. The relationship between drinking patterns and susceptibility was explored. RESULTS: Whole-brain analyses showed that the susceptibility in the dorsal striatum (putamen and caudate) among AUD individuals was higher than healthy participants and was positively related to the Obsessive Compulsive Drinking Scale (OCDS) scores and the amount of drinking in the past three months. CONCLUSIONS: Increased susceptibility suggests higher iron accumulation in the dorsal striatum in AUD. This surrogate for the brain iron level was linearly associated with the compulsive drinking pattern and the recent amount of drinking, which provides us a new clinical perspective in relation to brain iron accumulation, and also might indicate an association of AUD with neuroinflammation as a consequence of brain iron accumulation. The iron accumulation in the striatum is further relevant for functional imaging studies in AUD by potentially producing signal dropout and artefacts in fMRI images.

Sex- and age-specific effects on the development of addiction and compulsive-like drinking in rats.

BACKGROUND: Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex is an important factor influencing disease dynamics in alcohol dependence. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest. METHODS: Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system, acquiring high-resolution data to study changes over the course of addictive behavior as well as compulsive-like drinking in cohorts of adolescent vs. adult as well as male vs. female rats. RESULTS: Female rats drank more alcohol than male rats during the whole experiment, drinking much more weak alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats during quinine taste adulteration. Increased consumption in females compared to males was driven by larger access sizes of alcohol. Differences in circadian patterns of movement were observed between groups. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). CONCLUSIONS: Our results suggest that there are sex-specific drinking patterns, not only in terms of total amount consumed, but specifically in terms of solution preference and access size. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior, and can inform the preclinical development of models of addiction, drug development and exploration of options for new treatments.

Various factors can influence the development of alcohol addiction, but studying these factors in humans over the long-term is challenging and costly. With modern sensing technologies, rodents can be monitored throughout the lifespan, providing detailed information obtained under controlled conditions. Previous research suggests sex- and age-dependent differences in addiction processes, with female rats consuming more alcohol and age at first drink resulting in heavier later consumption, but a better characterization of these is needed. Using a rodent model of addiction and relapse, collecting high-resolution longitudinal drinking data in a computerized system over ~ 11 months, we studied differences in the development of addiction and compulsive-like drinking in male vs female as well as adult vs adolescent rats. Female rats drank more alcohol than male rats during the whole experiment, drinking much more weaker alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats in an aversive taste challenge, displaying more compulsive-like drinking. Increased consumption in females compared to males was driven by larger amounts consumed per approach. Little effect of age of onset of drinking was observed. Our results suggest sex-specific differences in the development of drinking patterns and solution preference, not only in terms of total amount consumed. These findings highlight the importance of awareness of sex-specific factors when developing models of addiction, as well as eventual treatment strategies and interventions.

Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats.

With the substantial social and medical burden of addiction, there is considerable interest in understanding risk factors that increase the development of addiction. A key feature of alcohol use disorder (AUD) is compulsive alcohol (EtOH) drinking, where EtOH drinking becomes "inflexible" after chronic intake, and animals, such as humans with AUD, continue drinking despite aversive consequences. Further, since there is a heritable component to AUD risk, some work has focused on genetically-selected, EtOH-preferring rodents, which could help uncover critical mechanisms driving pathological intake. In this regard, aversion-resistant drinking (ARD) takes >1 month to develop in outbred Wistar rats (and perhaps Sardinian-P EtOH-preferring rats). However, ARD has received limited study in Indiana P-rats, which were selected for high EtOH preference and exhibit factors that could parallel human AUD (including front-loading and impulsivity). Here, we show that P-rats rapidly developed compulsion-like responses for EtOH; 0.4 g/L quinine in EtOH significantly reduced female and male intake on the first day of exposure but had no effect after one week of EtOH drinking (15% EtOH, 24 h free-choice paradigm). Further, after 4−5 weeks of EtOH drinking, males but not females showed resistance to even higher quinine (0.5 g/L). Thus, P-rats rapidly developed ARD for EtOH, but only males developed even stronger ARD with further intake. Finally, rats strongly reduced intake of quinine-adulterated water after 1 or 5 weeks of EtOH drinking, suggesting no changes in basic quinine sensitivity. Thus, modeling ARD in P-rats may provide insight into mechanisms underlying genetic predispositions for compulsive drinking and lead to new treatments for AUDs.

Validation and Factor Analysis of the Obsessive Compulsive Drinking Scale (OCDS) in the Chinese Population.

Obsessive Compulsive Drinking Scale (OCDS) was established and introduced to measure the craving for alcohol and the severity of alcohol dependence. However, the Chinese version of OCDS is still unavailable and has not been validated in the Chinese population. We tended to translate and validate the OCDS in Chinese. We translated original OCDS into Chinese through bi-direction translations and tested the reliability and validity. We found that Chinese OCDS had high internal consistency and good test-retest reliability. The Chinese OCDS also presented good internal structure to reflect the severity of alcohol dependence. The Chinese OCDS could be used in clinical studies and research among the Chinese population.

Associations of NLRP3 and CARD8 gene polymorphisms with alcohol dependence and commonly related psychiatric disorders: a preliminary study.

We investigated two functional polymorphisms in NLRP3 inflammasome genes (NLRP3 rs35829419 and CARD8 rs2043211) and their association with alcohol dependence and related anxiety, depression, obsession-compulsion, or aggression in 88 hospitalised alcohol-dependent patients, 99 abstinent alcohol-dependent participants, and 94 controls, all male Caucasian. Alcohol dependence-related psychiatric disorders were assessed with the Zung Depression and Anxiety scale, Buss-Durkee Hostility Inventory, Alcohol Use Disorders Identification Test, Brief Social Phobia Scale, Obsessive Compulsive Drinking Scale, and Yale-Brown Obsessive-Compulsive Scale. For genotyping we used the allele-specific quantitative polymerase chain reaction-based methods. The three groups differed significantly in CARD8 rs2043211 distribution (P=0.049; chi-squared=9.557; df=4). The NLPR3 rs35829419 polymorphism was not significantly associated with alcohol dependence. In hospitalised alcohol-dependent patients the investigated polymorphisms were not associated with scores indicating alcohol consumption or comorbid symptoms. In abstinent alcohol-dependent subjects homozygotes for the polymorphic CARD8 allele presented with the highest scores on the Zung Anxiety Scale (p=0.048; df=2; F=3.140). Among controls, CARD8 genotype was associated with high scores on the Obsessive Compulsive Drinking Scale (P=0.027; df=2; F=3.744). In conclusion, our results reveal that CARD8 rs2043211 may play some role in susceptibility to alcohol dependence, expression of anxiety symptoms in abstinent alcohol-dependent subjects, and in obsessive compulsive drinking in healthy controls. However, further studies with larger cohorts are required to confirm these preliminary findings.

Role of Naltrexone in Improving Compulsive Drinking in Psychogenic Polydipsia.

Psychogenic polydipsia or self-induced water intoxication is a potentially lethal condition seen in many chronic psychiatric patients. This is a literature review based on therapeutic significance of Naltrexone in improving compulsive water drinking behavior in chronic psychiatrically ill patients with psychogenic polydipsia. Naltrexone is an opioid antagonist approved by FDA for alcohol dependence. Extensive literature search provides a line of evidence that suggests correlation of opioid receptor with compulsive water ingestion in animals. However, there is limited data regarding clinical utility of naltrexone in improving psychogenic polydipsia in human species. This review highlights the necessity for further research and trials to elucidate the role of naltrexone in human psychogenic drinking behavior.

Body mass index and craving predict 24-month hospital readmissions of alcohol-dependent in-patients following withdrawal.

OBJECTIVE: Addictive alcohol drinking, craving, and overeating share common etiopathological mechanisms. We investigated whether body mass index (BMI) and craving predict outcome of alcohol-dependent in-patients. METHOD: The prospective study included 101 male and 72 female early-abstinent alcohol-dependent in-patients. Craving was quantified by Obsessive-Compulsive Drinking Scale (OCDS) scores. We documented alcohol-related readmissions over 24 months. RESULTS: In males, a higher BMI was associated with alcohol-related hospital readmission (median 26.1 vs. 23.1 kg/m2, P = .007) and correlated with more (ρ = 0.286, P = .004) and earlier readmissions (ρ = -0.256, P = .010). These associations were stronger in the subgroup of active smokers (n = 79; median 25.9 vs. 22.3 kg/m2, P = .005; ρ = 0.350, P = .002; ρ = -0.340, P = .002). BMI did not significantly predict outcome in females. Males with at least one readmission reported higher OCDS scores than those without (OCDS-total, OCDS-obsessive, OCDS-compulsive, P < .040), and the OCDS scores correlated with more readmissions (males: OCDS-total, OCDS-obsessive, OCDS-compulsive, ρ > 0.244, P < .014; females: OCDS-compulsive, ρ = 0.341, P = .003) and fewer days to first readmission (males: OCDS-total, OCDS-compulsive, ρ < -0.195, P < .050; females: OCDS-compulsive, ρ = -0.335, P = .004). The OCDS scores explained 9 to 19% of the relationship between BMI and outcome in males. CONCLUSION: BMI and craving are easily accessible outcome predictors of alcohol-related readmission following in-patient withdrawal treatment. They might be used to individualize relapse prevention in the future.

Converging Neurobiological Evidence In Primary Polydipsia Resembling Obsessive-Compulsive Disorder.

Compulsive water drinking can have phenomenological and pharmacotherapeutic similarities with obsessive-compulsive disorder (OCD). Substantiating neurobiological evidence is lacking for such an association. We report a patient who was referred with a diagnosis of primary polydipsia with no signs of organic pathology in structural neuroimaging. However, positron emission tomography revealed basal ganglia hypometabolism indicating that primary polydipsia with compulsive water drinking is neurobiologically related to OCD. The diagnostic complexities displayed by primary polydipsia and the use of systematic evaluation with supporting neuroimaging evidence in reaching a reliable diagnosis are discussed. The neurobiological evidence will foster the treatment decisions for starting anti-OCD measures when clinicians encounter patients with primary polydipsia exhibiting compulsive patterns of drinking. Nevertheless, such findings need to be replicated in future studies with a larger sample size.

The alcohol deprivation effect model for studying relapse behavior: a comparison between rats and mice.

Understanding the psychological mechanisms and underlying neurobiology of relapse behavior is essential for improving the treatment of addiction. Because the neurobiology of relapse behavior cannot be well studied in patients, we must rely on appropriate animal models. The alcohol deprivation effect (ADE) is a phenomenon in laboratory animals that models a relapse-like drinking situation, providing excellent face and predictive validity. In rodents, relapse-like behavior is largely influenced by the genetic make-up of an animal. It is not clear which other factors are responsible for variability of this behavior, but there seems to be no correlation between levels of baseline alcohol intake and the occurrence, duration, and robustness of the ADE. Rats that undergo long-term alcohol drinking for several months with repeated deprivation phases develop a compulsive drinking behavior during a relapse situation, characterized by insensitivity to taste adulteration with quinine, a loss of circadian drinking patterns during relapse-like drinking, and a shift toward drinking highly concentrated alcohol solutions to rapidly increase blood alcohol concentrations and achieve intoxication. Some mouse strains also exhibit an ADE, but this is usually of shorter duration than in rats. However, compulsive drinking in mice during a relapse situation has yet to be demonstrated. We extend our review section with original data showing that during long-term alcohol consumption, mice show a decline in alcohol intake, and the ADE fades with repeated deprivation phases. Furthermore, anti-relapse compounds that produce reliable effects on the ADE in rats produce paradoxical effects in mice. We conclude that the rat provides a better model system to study alcohol relapse and putative anti-relapse compounds.

Heart rate variability predicts alcohol craving in alcohol dependent outpatients: further evidence for HRV as a psychophysiological marker of self-regulation.

BACKGROUND: Past research has highlighted an important role of the autonomic nervous system in alcohol dependence and capacity for self-regulation. While previous studies have examined alcohol dependent inpatients, it remains unclear whether resting-state HRV, a potential psychophysiological marker of ones capacity for self-regulation, is related to craving in patients who currently consume alcohol. Thus, the aim of the present study was to determine whether HRV predicts alcohol craving in dependent individuals in the community. METHODS: Resting-state HRV and alcohol craving, as indexed by the obsessive compulsive drinking scale, were assessed in 26 alcohol dependent outpatients. RESULTS: Results supported hypotheses indicating that HRV accounts for an additional 12.1% of the variance in craving after controlling for age, anxiety and levels of alcohol consumption. Here we show for the first time that resting-state HRV predicts craving in alcohol dependent outpatients. CONCLUSION: Results provide important new evidence for a role of the autonomic nervous system in the maintenance of dependence disorders.