Compulsive Drinking Research Articles

Serum BDNF and pro-BDNF levels in alcohol use disorders according to depression status: An exploratory study of their evolution two months after withdrawal

BackgroundAlcohol use disorders (AUDs) are complex pathologies with a myriad of molecular actors involved in both disease progression and remission. Brain-derived neurotrophic factor (BDNF) is suspected to be one such actor due to its neurotrophic effects. The BDNF precursor, pro-BDNF, has different effects, as it mainly promotes neuronal apoptosis. Both forms also play a role in depression and depressive episodes (DE). The aim of this exploratory study was to compare serum BDNF and pro-BDNF levels in patients with AUDs after withdrawal and according to DE status with those of controls without AUDs or DE. Materials and methodsNinety-nine AUD patients and 40 controls were included. Questionnaires were used to assess both alcohol and psychiatric domains: the severity of hazardous alcohol consumption was assessed using Alcohol Use Disorders Identification Test (AUDIT), craving was assessed using Obsessive and Compulsive Drinking Scale (OCDS), anxiety was assessed with Hamilton Anxiety Rating Scale (HAM-A) and depression with Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected during two visits: at the time of alcohol withdrawal (M0) and two months later (M2). ELISAs to measure serum BDNF and pro-BDNF levels were performed. AUD patients were categorized according to depression status at M2. Forty-five patients remained abstinent whereas 54 relapsed. BDNF serum levels rose after alcohol withdrawal, but pro-BDNF levels did not vary between M0 and M2. ResultsAUD subjects without DE at M2 had higher BDNF levels at both M0 and M2 than AUD subjects with DE at M2. AUD subjects showed lower MADRS and OCD scores at M2 than at M0. AUD subjects without DE had lower BDNF levels at M0 than controls but not at M2, regardless of abstinence maintenance. ConclusionBDNF serum levels were reduced in AUD patients compared to controls and were further reduced in patients with both AUDs and DE. Alcohol withdrawal treatment was sufficient to induce an increase in serum BDNF levels after 2 months, regardless of whether abstinence was maintained during this time period.

Electroconvulsive Therapy for Psychogenic Polydipsia and Hyponatremia in Chronic Schizophrenia: A Case Report and Literature Review.

Compulsive drinking of excessive quantities of water, called psychogenic polydipsia (PP), is a challenging complication of chronic psychotic disorders, which can lead to hyponatremia and downstream morbidity or mortality. Treatments include behavioral modifications such as free water restriction, medications to modify free water excretion, and psychotropic medications to target psychotic symptoms. However, in many cases, these options remain ineffective and/or intolerable, necessitating chronic institutionalization with poor patient quality of life. Here we report the use of an acute course of 8 sessions of bilateral electroconvulsive therapy (ECT) in a 57-year-old man with chronic schizophrenia, PP, and moderate hyponatremia refractory to standard treatments in an inpatient psychiatric setting. Serum sodium normalized and remained stable during and immediately following his ECT course, despite chronic hyponatremia with high variability for months prior to ECT initiation. A literature review found remarkably few reported cases of ECT for PP in chronic schizophrenia, a surprising result given the use of this modality for patients with psychotic illness in many countries. Our findings support future investigation into the clinical utility and mechanism of ECT for PP in this patient population.

Characterization in the rat of the individual tendency to rely on alcohol to cope with distress and the ensuing vulnerability to drink compulsively.

Only some vulnerable individuals who recreationally drink alcohol eventually develop the compulsive drinking pattern that characterizes alcohol use disorder. A new frontier in biomedical research lies in understanding the neurobehavioural mechanisms of this individual vulnerability, a necessary step towards developing novel effective therapeutic strategies. Translational research has been hindered by the lack of valid, reliable and robust approaches that enable the study of the influence of the reliance on alcohol to cope with stress or self-medicate negative emotional states on the subsequent transition to alcohol use disorder. We have therefore developed a behavioural task in the rat that enables the investigation of the neural and cellular basis of the exacerbation of the vulnerability to develop compulsive alcohol drinking by the use of alcohol to develop an adjunctive, anxiolytic, polydipsic drinking behaviour in a schedule-induced polydipsia procedure. Hence, in our task, alcohol is introduced in the schedule-induced polydipsia context after several weeks of training with water so that rats are exposed to alcohol for the first time in a distressing context and learn to drink alcohol as a coping strategy. Capitalizing on this protocol, we have consistently been able to identify a subpopulation of rats that were unable to learn to cope with negative states by drinking water and relied on alcohol to do so. This maladaptive reliance on alcohol drinking to cope with distress has been shown to be associated with an exacerbation of the subsequent transition to compulsive drinking. Furthermore, these vulnerable rats reached blood alcohol levels comparable to that of intoxication in humans, thereby developing two key features of alcohol use disorder, namely excessive alcohol intake and compulsive drinking. Altogether, this behavioural task provides a novel and unique tool for the investigation of the neurobehavioural mechanisms underlying the exacerbation of the individual vulnerability to developing compulsive alcohol drinking by the use of alcohol as a strategy to cope with distress, and for the evaluation of the efficacy of potential therapeutic strategies in a personalized medicine approach. This procedure, which focuses on an understudied but key factor of the development of alcohol use disorder, may become widely used as it benefits the fields of alcohol, emotion regulation and stress, the interest in which has substantially increased since the evidence of a profound exacerbation of alcohol use and alcohol-related negative consequences by the distress and social isolation engendered by the various measures implemented worldwide in response to the COVID-19 pandemic.

Neural Activity in the Anterior Insula at Drinking Onset and Licking Relates to Compulsion-Like Alcohol Consumption.

Much remains unknown about the etiology of compulsion-like alcohol drinking, where consumption persists despite adverse consequences. The role of the anterior insula (AIC) in emotion, motivation, and interoception makes this brain region a likely candidate to drive challenge-resistant behavior, including compulsive drinking. Indeed, subcortical projections from the AIC promote compulsion-like intake in rats and are recruited in heavy-drinking humans during compulsion for alcohol, highlighting the importance of and need for more information about AIC activity patterns that support aversion-resistant responding. Single-unit activity was recorded in the AIC from 15 male rats during alcohol-only and compulsion-like consumption. We found three sustained firing phenotypes, sustained-increase, sustained-decrease, and drinking-onset cells, as well as several firing patterns synchronized with licking. While many AIC neurons had session-long activity changes, only neurons with firing increases at drinking onset had greater activity under compulsion-like conditions. Further, only cells with persistent firing increases maintained activity during pauses in licking, suggesting roles in maintaining drive for alcohol during breaks. AIC firing was not elevated during saccharin drinking, similar to lack of effect of AIC inhibition on sweet fluid intake in many studies. In addition, we observed subsecond changes in AIC neural activity tightly entrained to licking. One lick-synched firing pattern (determined for all licks in a session) predicted compulsion-like drinking, while a separate lick-associated pattern correlated with greater consumption across alcohol intake conditions. Collectively, these data provide a more integrated model for the role of AIC firing in compulsion-like drinking, with important relevance for how the AIC promotes sustained motivated responding more generally.

Effects of fisetin on ethanol-induced rewarding properties in mice

ABSTRACT Background: Alcohol use disorder (AUD) is a chronic relapsing disorder associated with compulsive drinking of alcohol. Natural flavonoid fisetin affects a variety of transmitter systems relevant to AUD, such as aminobutyric acid, N-methyl-D-aspartate, and dopamine, as well as peroxisome proliferator-activated receptors. Objectives: This study investigated fisetin’s impact on the motivational properties of ethanol using conditioned place preference (CPP) in mice (n = 50). Methods: Mice were conditioned with ethanol (2 g/kg, i.p.) or saline on alternating days for 8 consecutive days and were given intragastric (i.g.) fisetin (10, 20, or 30 mg/kg, i.g.), 45 min before ethanol conditioning. During extinction, physiological saline was injected to the control and ethanol groups, and fisetin was administered to the fisetin groups. To evaluate the effect of fisetin on the reinstatement of ethanol-induced CPP, fisetin was given 45 min before a priming dose of ethanol (0.4 g/kg, i.p.; reinstatement test day). Results: Fisetin decreased the acquisition of ethanol-induced CPP (30 mg/kg, p < .05) and accelerated extinction (20 and 30 mg/kg, p < .05). Furthermore, fisetin attenuated reinstatement of ethanol-induced CPP (30 mg/kg, p < .05). Conclusions: Fisetin appears to diminish the rewarding properties of ethanol, as indicated by its inhibitory effect and facilitation of extinction in ethanol-induced CPP. These findings imply a potential therapeutic application of fisetin in preventing ethanol-seeking behavior, promoting extinction, and reducing the risk of relapse.

Compulsive Drinking Behavior, Anger and Self-Esteem Among Patients with Alcohol Dependence Syndrome

Compulsive Drinking Behavior, Anger and Self-Esteem Among Patients with Alcohol Dependence Syndrome

Adaptor protein complex 2 in the orbitofrontal cortex predicts alcohol use disorder.

Alcohol use disorder (AUD) is a life-threatening disease characterized by compulsive drinking, cognitive deficits, and social impairment that continue despite negative consequences. The inability of individuals with AUD to regulate drinking may involve functional deficits in cortical areas that normally balance actions that have aspects of both reward and risk. Among these, the orbitofrontal cortex (OFC) is critically involved in goal-directed behavior and is thought to maintain a representation of reward value that guides decision making. In the present study, we analyzed post-mortem OFC brain samples collected from age- and sex-matched control subjects and those with AUD using proteomics, bioinformatics, machine learning, and reverse genetics approaches. Of the 4,500+ total unique proteins identified in the proteomics screen, there were 47 proteins that differed significantly by sex that were enriched in processes regulating extracellular matrix and axonal structure. Gene ontology enrichment analysis revealed that proteins differentially expressed in AUD cases were involved in synaptic and mitochondrial function, as well as transmembrane transporter activity. Alcohol-sensitive OFC proteins also mapped to abnormal social behaviors and social interactions. Machine learning analysis of the post-mortem OFC proteome revealed dysregulation of presynaptic (e.g., AP2A1) and mitochondrial proteins that predicted the occurrence and severity of AUD. Using a reverse genetics approach to validate a target protein, we found that prefrontal Ap2a1 expression significantly correlated with voluntary alcohol drinking in male and female genetically diverse mouse strains. Moreover, recombinant inbred strains that inherited the C57BL/6J allele at the Ap2a1 interval consumed higher amounts of alcohol than those that inherited the DBA/2J allele. Together, these findings highlight the impact of excessive alcohol consumption on the human OFC proteome and identify important cross-species cortical mechanisms and proteins that control drinking in individuals with AUD.

Anatomical, Functional, and Transcriptional Organization of Cortical Circuits Mediating Compulsive Drinking

Anatomical, Functional, and Transcriptional Organization of Cortical Circuits Mediating Compulsive Drinking

Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment.

Harmful alcohol use is responsible for a group of disorders collectively named alcohol use disorders (AUDs), according to the DSM-5 classification. The damage induced by alcohol depends on the amount, time, and consumption patterns (continuous and heavy episodic drinking). It affects individual global well-being and social and familial environments with variable impact. Alcohol addiction manifests with different degrees of organ and mental health detriment for the individual, exhibiting two main traits: compulsive drinking and negative emotional states occurring at withdrawal, frequently causing relapse episodes. Numerous individual and living conditions, including the concomitant use of other psychoactive substances, lie in the complexity of AUD. Ethanol and its metabolites directly impact the tissues and may cause local damage or alter the homeostasis of brain neurotransmission, immunity scaffolding, or cell repair biochemical pathways. Brain modulator and neurotransmitter-assembled neurocircuitries govern reward, reinforcement, social interaction, and consumption of alcohol behaviors in an intertwined manner. Experimental evidence supports the participation of neurotensin (NT) in preclinical models of alcohol addiction. For example, NT neurons in the central nucleus of the amygdala projecting to the parabrachial nucleus strengthen alcohol consumption and preference. In addition, the levels of NT in the frontal cortex were found to be lower in rats bred to prefer alcohol to water in a free alcohol-water choice compared to wild-type animals. NT receptors 1 and 2 seem to be involved in alcohol consumption and alcohol effects in several models of knockout mice. This review aims to present an updated picture of the role of NT systems in alcohol addiction and the possible use of nonpeptide ligands modulating the activity of the NT system, applied to experimental animal models of harmful drinking behavior mimicking alcohol addiction leading to health ruin in humans.

Ghrelin and impulsivity relationship in alcohol-dependent patients and healthy individuals.

Abundant research indicates that ghrelin hormone levels are associated with alcohol use and addiction. One of the mediators of this association may be impulsivity, which is one of the common traits observed in alcohol addiction and some eating disorders. This study evaluated participants with alcohol dependency and healthy volunteers to determine whether trait impulsivity and ghrelin levels are associated. This study analyzed trait impulsivity scores and fasting serum ghrelin levels of 44 males with alcohol dependency and 48 healthy male participants. The Barratt Impulsiveness Scale and the UPPS Impulsive Behaviour Scale (UPPS) were used to measure trait impulsivity levels. Penn Alcohol Craving Scale and Yale Brown Obsessive Compulsive Drinking Scale for heavy drinking were used to assess craving at the baseline and after the detoxification period. Alcohol-dependent patients' fasting ghrelin levels were significantly higher than that of healthy participants. Ghrelin plasma levels were positively correlated with UPPS total impulsivity scores and sensation-seeking among healthy individuals. In alcohol-dependent participants, there was a positive correlation between UPPS urgency scores obtained at the baseline and fasting ghrelin levels before and after the detoxification period. Ghrelin-impulsivity relationship could be observed in certain dimensions of impulsivity in both alcohol-dependent and healthy individuals and even independent of the effect of alcohol. Although the associated impulsivity dimensions differ in different groups, the results are parallel to other studies in terms of demonstrating the relationship between ghrelin and impulsivity.

Addiction, Waste(d) Labor, and the Debate of the Carpenter's Tools

Addiction, Waste(d) Labor, and the <i>Debate of the Carpenter's Tools</i>

Celastrus paniculatus and memantine prevent alcohol dependence and improve decision making in alcohol dependent C57BL6 mice

Background: Alcohol use disorder poses a huge burden with only a handful of approved drugs. AUD is associated with impaired decision-making that leads to compulsive drinking despite negative consequences. A drug that decreases alcohol consumption as well as improves decision-making may thus prove more useful. This study was planned to evaluate the effect of two drugs, Celastrus paniculatus and memantine on alcohol preference and decision impairment in alcohol-dependent mice. Methods: In part 1, the effect of both the study drugs on alcohol consumption was studied using intermittent access model in 70 male C57BL6 mice. In part 2, effect of drugs on decision making was studied using the rodent version of Iowa gambling task. Mice were divided in seven study groups: Group 1-3: Celastrus paniculatus (140, 280, and 560 mg/kg), Group 4: memantine (25 mg/kg), Group 5: vehicle control 1 (Milk), Group 6: vehicle control 2 (normal saline) and Group 7: naltrexone(1mg/kg). Results: Percentage alcohol preference was lower in test groups i.e., Celastrus paniculatus at medium (40.90±15.18%) and high doses (31.79±7.46%) vs. milk (82.74±8.53%; p&lt;0.05); and in memantine group (36.28±10.99%) vs. normal saline (83.27±5.51%; p&lt;0.05). The results were not significantly different to Naltrexone (19.70±6.90%). Percentage preference to disadvantageous arms was also lower in Celastrus paniculatus, at medium (50.52±1.92%) and high doses (48.11±2.43%) compared to milk (54.47±2.73%; p&lt;0.05) and memantine (47.45±1.67%) compared to normal saline (54.00±2.73%; p&lt;0.05), indicating better decision-making ability in the test groups. The findings were comparable to Naltrexone group (45.43±2.52%). Conclusions: These results indicate that Celastrus paniculatus and memantine reduce alcohol consumption and improve decision making in alcohol-dependent mice.

The Relationship Between Early Maladaptive Schemas and Coping Styles, Reasons for Drinking, Craving and Remission in Patients with Alcohol Use Disorder.

Alcohol Use Disorder (AUD) is a serious mental disorder that affects the individual, family, environment and society as a whole. In this study, we aimed to analyze the relationship between early maladaptive schemas and coping styles, with craving, reasons for consumption and finally remission history. This is a cross sectional study. We included 90 Erenköy Mental Health and Neurological Diseases Training and Research Hospital AMATEM patients with AUD according to DSM-5. AUD diagnosis is confirmed by SCID-5 CV. Subjects with additional psychiatric conditions are excluded. Subjects without withdrawal symptoms by CIWA-Ar are included. Sociodemographic data form, Young Schema Questionnaire Short form-3, Young Rygh Avoidance Inventory, Young Compensation Inventory, Drinking Motives Questionnaire-Revised, Obsessive Compulsive Drinking Scale was applied. Our findings show that male subjects who have early maladaptive schemas, especially in Impaired autonomy and performance; Failure, Disconnection and rejection; Social İsolation/alienation, Impaired Limits; Insufficient Self-Control/Self-Discipline domains, experience more cravings. Individuals coping with the Psychosomatism, Activity and Distraction, and Rebellion schemes experienced more craving. Those who coped with 'schema avoidance' tended towards alcohol consumption with Coping Motivation, and those who coped with 'schema compensation' with Impact Enhancement and Social motivations. There was no significant difference between the scores of the scales and the craving levels between the groups with and without a history of permanent remission. The data in our study showed that early maladaptive schemas and ways of coping with schemas are associated with craving. In the early stages of treatment, it is important to consider cognitive intervention focused on schemas and coping styles.

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

RationaleBrain iron accumulation has been observed in neuropsychiatric disorders and shown to be related to neurodegeneration.ObjectivesIn 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.MethodsBased 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.ResultsWhole-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.ConclusionsIncreased 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.

The relationship between the clinical characteristics of patients with alcohol use disorder and drinking motives

Changes in the motivational structure are considered one of the central characteristics of Alcohol Use Disorder (AUD). The latest motivational models of AUD were developed based on recent neurobiological research findings. According to these models, three main drinking motives can be identified — drinking as a reward, as a relief, and as a habit. The goal of the study was to explore the main differences in the psychological and clinical characteristics of patients with AUD depending on the predominant drinking motive. For this study, 76 individuals (50 men (65.79 %), average age 42.25 ± 9.36 y. o. (М ± SD)) undergoing in-patient treatment for the symptoms of AUD were recruited. The following methods were used: clinical interview, UCLA Reward, Relief, Habit Drinking Scale, Penn Alcohol Craving Scale, Obsessive Compulsive Drinking Scale, Hospital Anxiety and Depression Scale, Snaith-Hamilton Pleasure Scale, Behavioral Activation Scale/Behavioral Inhibition Scale, and Cognitive Emotion Regulation Questionnaire. The participants were divided into three groups depending on their predominant drinking motive. The participants with the predominant “drinking as a habit” motivation reported using strategies of “refocusing on planning” and “positive reappraisal” significantly less often. At the same time, the intensity of “drinking as a habit” motive positively correlated with the severity of anxiety and depressive symptoms, and negatively — with the strength of the behavioral inhibition system. The participants with the “drinking as a reward” motivation reported having greater reward responsiveness as compared to the combined group of participants with the relief and habit drinking motives. The intensity of “drinking as a relief” motivation positively correlated with the severity of depressive symptoms. It was also noted that the participants, who did not identify the predominant drinking motive, reported having decreased levels of emotional and physical functioning and less frequent use of the certain adaptive emotional regulation strategies. In contrast with the previous studies, the relationship between the prevailing drinking motives and characteristics of drinking or the severity of AUD was not identified.

Crossed high alcohol preferring mice exhibit aversion-resistant responding for alcohol with quinine but not footshock punishment.

A symptom of alcohol use disorder (AUD) is compulsive drinking, or drinking that persists despite negative consequences. In mice, aversion-resistant models are used to model compulsive-like drinking by pairing the response for alcohol with a footshock or by adding quinine, a bitter tastant, to the alcohol solution. crossed High Alcohol Preferring (cHAP) mice, a selectively bred line of mice that consumes pharmacologically relevant levels of alcohol, demonstrate a high level of aversion-resistance to quinine-adulterated alcohol. The current study investigated quinine-resistant and footshock-resistant responding for 10% ethanol in male and female cHAP mice with vs. without a history of alcohol exposure. cHAP mice were first trained to respond for 10% ethanol in an operant-response task. Next, mice were exposed to water or 10% ethanol for twelve 24-h sessions using a two-bottle choice procedure. Footshock-resistant ethanol responding was then tested in the operant chamber by pairing a footshock (0.35mA) with the nose-poke response during one session. Quinine-resistant responding for alcohol was tested over five sessions (500-2500μM quinine). Finally, footshock sensitivity was assessed using a flinch, jump, vocalize test. Alcohol exposure history did not influence responses for 10% ethanol or either measure of aversion-resistance. Further, cHAP mice were sensitive to footshock punishment but continued to respond for alcohol at all quinine concentrations. No sex differences were observed in any measure of alcohol responding, but female cHAP mice were less sensitive to footshock than males. These results replicate and extend the previous demonstration of a robust, innate resistance to quinine aversion in cHAP mice and further suggest that this tendency is not observed when footshock is used to punish drinking.

Changes in Alcohol Consumption among Users of an Internet Drug Forum during a COVID-19 Lockdown.

The aim of the present study was to assess the frequency and clinical correlates of users of an Internet drug forum who changed their alcohol use during the March-May 2020 COVID-19 lockdown in France. An anonymous Internet-based cross-sectional survey during the COVID-19 lockdown was used via messages on a French Internet drug forum. Participants reported any increase in their alcohol consumption during the lockdown. Alcohol craving and depressive/anxiety symptoms were assessed using the Obsessive and Compulsive Drinking scale (OCDS) and Hospital Anxiety and Depression scale (HADS). Of 1310 respondents, 974 (79% of 1270) participants reported alcohol use before lockdown. During the lockdown, 405 participants (41.6%; IC95 (38.5-44.7)) reported an increase. Odds of an increase in alcohol consumption was higher for those with HADS scores higher than 7 (aOR: 2.19; p = 0.00002), OCDS scores greater than 7 (aOR: 3.50; p < 0.001), and daily psychostimulant use (aOR: 1.85; p = 0.002). Users of an Internet drug forum who reported high levels of depressive symptoms, high levels of alcohol craving, and the use of psychostimulants were more likely to increase alcohol consumption during a COVID-19 lockdown.

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.

Theta oscillatory dynamics of inhibitory control, error processing, and post-error adjustments: Neural underpinnings and alcohol-induced dysregulation in social drinkers.

BackgroundAlcohol intoxication impairs inhibitory control, resulting in disinhibited, impulsive behavior. The anterior cingulate cortex (ACC) plays an essential role in a range of executive functions and is sensitive to the effects of alcohol, which contributes to the top‐down cognitive dysregulation. This study used a multimodal approach to examine the acute effects of alcohol on the neural underpinnings of inhibitory control, inhibition failures, and neurobehavioral optimization as reflected in trial‐to‐trial dynamics of post‐error adjustments.MethodsAdult social drinkers served as their own controls by participating in the Go/NoGo task during acute alcohol and placebo conditions in a multi‐session, counterbalanced design. Distributed source modeling of the magnetoencephalographic signal was combined with structural magnetic resonance imaging to characterize the spatio‐temporal dynamics of inhibitory control in the time‐frequency domain.ResultsSuccessful response inhibition (NoGo) elicited right‐lateralized event‐related theta power (4 to 7 Hz). Errors elicited a short‐latency increase in theta power in the dorsal (dACC), followed by activity in the rostral (rACC), which may underlie an affective “oh, no!” orienting response to errors. Error‐related theta in the dACC was associated with subsequent activity of the motor areas on the first post‐error trial, suggesting the occurrence of post‐error output adjustments. Importantly, a gradual increase of the dACC theta across post‐error trials closely tracked improvements in accuracy under placebo, which may reflect cognitive control engagement to optimize response accuracy. In contrast, alcohol increased NoGo commission errors, dysregulated theta during correct NoGo withholding, and abolished the post‐error theta enhancement of cognitive control.ConclusionsConfirming the sensitivity of frontal theta to inhibitory control and error monitoring, the results support functional and temporal dissociation along the dorso‐rostral axis of the ACC and the deleterious effects of alcohol on the frontal circuitry subserving top‐down regulation. Over time, alcohol‐induced disinhibition may give rise to compulsive drinking and contribute to alcohol misuse.

Fluorodeoxyglucose positron emission tomography scans in patients with alcohol use disorder.

Diminished uptake of fluorodeoxyglucose (FDG) has been observed in patients with alcohol use disorder (AUD) but little statistical contrast of the regional brain deficits has been undertaken. This study examined prefrontal cortex inter-regional Brodmann area differences to delineate patterns associated with behavioral, neurotransmitter, and general toxicity hypotheses of cerebral involvement in AUD. We obtained data from FDG positron emission tomography (PET) and anatomical magnetic resonance imaging (MRI) for 87 patients with AUD and 41 age- and sex-matched healthy volunteers. Patients were alcohol dependent and had negative breathalyzer tests at the time of imaging. They were assessed with the Beck Depression Inventory, Alcohol Urge Questionnaire, Obsessive Compulsive Drinking Scale, Spielberger State/Trait Anxiety Scale, Buss-Durkee Hostility Inventory, and the Drinker Inventory of Consequences (DrInC). PET images were co-registered to MRI and both voxel×voxel statistical mapping and stereotaxic regions of interest were obtained. Compared with healthy volunteers, patients with AUD had lower relative metabolic rates in the frontal, temporal, and parietal lobes, localizable most prominently to the dorsolateral and nearly all orbital prefrontal cortex, superior temporal gyrus, and inferior parietal lobule. In contrast, metabolic rates in the medial orbitofrontal and anterior cingulate cortex, and the subcortical structures (thalamus, cerebellum, ventral striatum, and the dorsal raphe nucleus) in patients were significantly greater. The severity of alcohol-related consequences as assessed by the DrInC scale was most highly associated with lower metabolism in the caudate, dorsolateral prefrontal, frontopolar, and anteroposterior cingulate cortex. Despite widespread metabolic abnormalities, decreases in AUD were most marked in frontal executive areas, consistent with diminished impulse control, and increases were most prominent in the striatum and cingulate areas, consistent with a suppressed reward system.