Compulsive Alcohol Use Research Articles

Experimental Models of Alcohol Use Disorder and Their Application for Pathophysiological Investigations.

Alcohol use disorder (AUD) is a complex disorder characterized by compulsive alcohol use and a lack of control over alcohol intake. Several experimental methods using mouse models have been developed to improve research regarding this disorder. Mouse behavioral paradigms are advantageous in inducing alcohol dependence and evaluating alcohol intake, circumventing ethical issues, and increasing experimental control over human-based experiments. These behavioral methods typically fall under one of two categories: forced exposure and voluntary consumption. This paper highlights two common paradigms used to study AUD in rodent models: one forced exposure method (use of a vapor inhalation system for alcohol exposure) and one voluntary consumption method (the two-bottle choice procedure). The effectiveness and experimental validity of these behavioral paradigms for pathophysiological investigations of AUD and how they can be combined are also discussed, along with their individual strengths and weaknesses. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Vapor inhalation for exposure to alcohol Basic Protocol 2: Intermittent access two-bottle choice procedure (acquisition) Basic Protocol 3: Intermittent access two-bottle choice procedure (measurement) Alternate Protocol: Sucrose fading to encourage voluntary alcohol consumption.

Is DNA methylation in the brain a mechanism of alcohol use disorder?

Alcohol use disorder (AUD) is a worldwide problem. Unfortunately, the molecular mechanisms of alcohol misuse are still poorly understood, therefore successful therapeutic approaches are limited. Accumulating data indicate that the tendency for compulsive alcohol use is inherited, suggesting a genetic background as an important factor. However, the probability to develop AUD is also affected by life experience and environmental factors. Therefore, the epigenetic modifications that are altered over lifetime likely contribute to increased risk of alcohol misuse. Here, we review the literature looking for the link between DNA methylation in the brain, a common epigenetic modification, and AUD-related behaviors in humans, mice and rats. We sum up the main findings, identify the existing gaps in our knowledge and indicate future directions of the research.

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes, dopamine (DA), is suspected to play an important role in this pathology, but its exact role remains to be determined. Here, we found that rats expressing compulsive-like alcohol use, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that chemogenetic-induced selective hypodopaminergia of this pathway resulted in compulsive-like alcohol self-administration in otherwise resilient rats, accompanied by the emergence of alcohol withdrawal-like motivational impairments (i.e., impaired motivation for a natural reinforcer). Finally, the use of the monoamine stabilizer OSU6162, previously reported to correct hypodopaminergic states, transiently decreased compulsive-like alcohol self-administration in vulnerable rats. These results suggest a potential critical role of tonic nigrostriatal hypodopaminergic states in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

Brain mechanisms of compulsive alcohol use.

Brain mechanisms of compulsive alcohol use.

A neural substrate of compulsive alcohol use.

Alcohol intake remains controlled in a majority of users but becomes "compulsive," i.e., continues despite adverse consequences, in a minority who develop alcohol addiction. Here, using a footshock-punished alcohol self-administration procedure, we screened a large population of outbred rats to identify those showing compulsivity operationalized as punishment-resistant self-administration. Using unsupervised clustering, we found that this behavior emerged as a stable trait in a subpopulation of rats and was associated with activity of a brain network that included central nucleus of the amygdala (CeA). Activity of PKCδ+ inhibitory neurons in the lateral subdivision of CeA (CeL) accounted for ~75% of variance in punishment-resistant alcohol taking. Activity-dependent tagging, followed by chemogenetic inhibition of neurons activated during punishment-resistant self-administration, suppressed alcohol taking, as did a virally mediated shRNA knockdown of PKCδ in CeA. These findings identify a previously unknown mechanism for a core element of alcohol addiction and point to a novel candidate therapeutic target.

The Role of Social Stress in the Development of Inhibitory Control Deficit: A Systematic Review in Preclinical Models.

Inhibitory control deficit and impulsivity and compulsivity behaviours are present in different psychopathological disorders such as addiction, obsessive-compulsive disorders and schizophrenia, among others. Social relationships in humans and animals are governed by social organization rules, which modulate inhibitory control and coping strategies against stress. Social stress is associated with compulsive alcohol and drug use, pointing towards a determining factor in an increased vulnerability to inhibitory control deficit. The goal of the present review is to assess the implication of social stress and dominance on the vulnerability to develop impulsive and/or compulsive spectrum disorders, with the aid of the information provided by animal models. A systematic search strategy was carried out on the PubMed and Web of Science databases, and the most relevant information was structured in the text and tables. A total of 34 studies were recruited in the qualitative synthesis. The results show the role of social stress and dominance in increased drug and alcohol use, aggressive and impulsive behaviour. Moreover, the revised studies support the role of Dopaminergic (DA) activity and the alterations in the dopaminergic D1/D2 receptors as key factors in the development of inhibitory control deficit by social stress.

The contribution of medium spiny neuron subtypes in the nucleus accumbens core to compulsive-like ethanol drinking

Compulsive alcohol use, or drinking that persists despite negative or aversive consequences, is a defining characteristic of alcohol use disorder. Here, chemogenetic technology (i.e. Designer Receptors Exclusively Activated by Designer Drugs; DREADDs) was used to inhibit or excite the NAc core or selectively inhibit D1-or D2 receptor-expressing neurons in the NAc core to understand the role of the NAc core and how these subpopulations of neurons may influence compulsive-like ethanol (EtOH) drinking using C57BL/6J, Drd1-cre, and Drd2-cre male and female mice. Compulsive-like EtOH drinking was modeled with a two-bottle choice, drinking in the dark paradigm. The major finding of this study was that mice decreased compulsive-like EtOH intake when the NAc core was inhibited and there was no change of EtOH + quinine intake when the NAc core was excited. Interestingly, inhibition of D1-or D2 receptor-expressing neurons did not alter compulsive-like EtOH intake. Control experiments showed that NAc core excitation and selective inhibition of D1-or D2-receptor-expressing neurons had no effect on baseline EtOH drinking, intake of water, or intake of quinine-adulterated water. CNO reduced amphetamine-induced locomotion in the D1-CRE+ (but not the D2CRE+) group in a control experiment. Finally, pharmacological antagonism of D1 and D2 receptors together, but not separately, reduced quinine-resistant EtOH drinking. These results suggest that the NAc core is a critical region involved in compulsive-like EtOH consumption, and that both D1-and D2 receptor-expressing medium spiny neurons participate in controlling this behavior.

Differential effects of quinine adulteration of alcohol on seeking and drinking.

Alcohol dependence is characterized by compulsive alcohol use. Alcohol-paired stimuli can drive compulsive alcohol use, induce craving, and lead to relapse. Alcohol dependence is highly heritable, and individuals with a family history are at elevated risk to develop an alcohol use disorder. Understanding the association between genetic vulnerability to alcohol dependence and neural alterations that promote an addiction phenotype are critical to the prevention and treatment of alcohol dependence. Here we use selectively bred alcohol-preferring P rats and their progenitor strain, Wistar rats, to investigate the relationship between genetic liability and alcohol-seeking and drinking behaviors in a discriminative stimuli paradigm. To further investigate strain differences in motivated responding, alcohol was adulterated with quinine, and intake and responding were assessed. While both strains learned to discriminate between stimuli that predicted alcohol availability, P rats learned faster and consumed more alcohol. Quinine adulteration reduced ethanol intake in both strains with no effect on ethanol-seeking measures. These data suggest genetic vulnerability to alcohol dependence is associated with increased motivated behaviors and highlight the utility of P rats in teasing apart the neural mechanisms associated with this phenotype. Additionally, these data suggest a dissociation between the neural systems that engage ethanol drinking versus compulsive ethanol seeking.

New Challenges in Addiction Medicine: COVID-19 Infection in Patients With Alcohol and Substance Use Disorders-The Perfect Storm.

New Challenges in Addiction Medicine: COVID-19 Infection in Patients With Alcohol and Substance Use Disorders-The Perfect Storm.

Possible Role of CRF-Hcrt Interaction in the Infralimbic Cortex in the Emergence and Maintenance of Compulsive Alcohol-Seeking Behavior.

Alcohol use disorder (AUD) is a chronic, relapsing disorder that is characterized by the compulsive use of alcohol despite numerous health, social, and economic consequences. Initially, the use of alcohol is driven by positive reinforcement. Over time, however, alcohol use can take on a compulsive quality that is driven by the desire to avoid the negative consequences of abstinence, including negative affect and heightened stress/anxiety. This transition from positive reinforcement- to negative reinforcement-driven consumption involves the corticotropin-releasing factor (CRF) system, although mounting evidence now suggests that the CRF system interacts with other neural systems to ultimately produce behaviors that are symptomatic of compulsive alcohol use, such as the hypocretin (Hcrt) system. Hypocretins are produced exclusively in the hypothalamus, but Hcrt neurons project widely throughout the brain and reach regions that perform regulatory functions for numerous behavioral and physiological responses-including the infralimbic cortex (IL) of the medial prefrontal cortex (mPFC). Although the entire mPFC undergoes neuroadaptive changes following prolonged alcohol exposure, the IL appears to undergo more robust changes compared with other mPFC substructures. Evidence to date suggests that the IL is likely involved in EtOH-seeking behavior, but ambiguities with respect to the specific role of the IL in this regard make it difficult to draw definitive conclusions. Furthermore, the manner in which CRF interacts with Hcrt in this region as it pertains to alcohol-seeking behavior is largely unknown, although immunohistochemical and electrophysiological experiments have shown that CRF and Hcrt directly interact in the mPFC, suggesting that the interaction between CRF and Hcrt in the IL may be critically important for the development and subsequent maintenance of compulsive alcohol seeking. This review aims to consolidate recent literature regarding the role of the IL in alcohol-seeking behavior and to discuss evidence that supports a functional interaction between Hcrt and CRF in the IL.

Is Addiction Really a Chronic Relapsing Disorder?: Commentary on Kelly et al. "How Many Recovery Attempts Does It Take to Successfully Resolve an Alcohol or Drug Problem? Estimates and Correlates From a National Study of Recovering U.S. Adults".

The most widely used definitions of drug addiction are of the condition having a chronic course that is typically characterized by relapse. The National Institute on Drug Abuse (NIDA), for example, defines addiction as "a chronic, relapsing disorder characterized by compulsive drug seeking and use despite adverse consequences" (NIDA, 2019). With regard to alcohol addiction, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) similarly defines alcohol use disorder as "a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using" (NIAAA, 2019).

A Retrospective Study of Hospital Recidivism Among Patients with Alcohol Use Disorders Treated with Intramuscular Naltrexone.

IntroductionAlcohol use disorder is a chronic, relapsing condition that is associated with compulsive alcohol use and loss of control of alcohol intake. It is a common problem in the hospital setting. It has also become a public health dilemma. This study seeks to analyze the benefit of long-acting naltrexone. This well-studied agent is indicated for alcohol use disorder.MethodsThis was a retrospective cohort study between July 1, 2016, and October 31, 2017, using Meditech's Pharmacy Admission Report (MPAR), which is the community hospital's network's electronic medical record (EMR) system as the data source "alcohol use disorders" covers a broad spectrum of sub-diagnoses. The patients were selected after they were admitted with a primary diagnosis of alcohol abuse dependence (APDRG v34code).ResultsThe readmission rate in the study population (intramuscular naltrexone) was 2.86% and readmission in the control population (standard of care) was 25.70%. Patients diagnosed with alcohol abuse dependence are at a significantly decreased risk for readmission if treated with intramuscular naltrexone (odds ratio (OR) 8.5%; 95% confidence interval (CI) 0.0115, 0.6300; p=0.0159).ConclusionThis study showed that treating patients admitted under the diagnosis of alcohol abuse dependence with intramuscular naltrexone may be an effective intervention in reducing hospital readmission. Additional studies are warranted to clarify and establish optimal treatment strategies.

Minding the treatment gap: results of the Singapore Mental Health Study

PurposeTo establish the 12-month treatment gap and its associated factors among adults with mental disorders in the Singapore resident population using data from the second Singapore Mental Health Study and to examine the changes since the last mental health survey conducted in 2010.Methods6126 respondents were administered selected modules of the Composite International Diagnostic Interview, to assess major depressive disorder (MDD), dysthymia, bipolar disorder, generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD) and alcohol use disorder (AUD) (which included alcohol abuse and dependence). Past year treatment gap was defined as the absolute difference between the prevalence of a particular mental disorder in the past 12 months preceding the interview and those who had received treatment for that disorder.ResultsThe prevalence of overall 12-month treatment gap in this population was high (78.6%). A multiple logistic regression analysis revealed significantly higher odds of treatment gap among those diagnosed with OCD (compared to those with MDD) and in those with a comorbid chronic physical disorder; while those who had primary education and below and those who were unemployed were less likely to have a treatment gap as compared to those with post-secondary education and those employed, respectively.ConclusionsThe high treatment gap in the population is concerning and highlights the need to promote help-seeking and uptake of treatment. Given the unique demographic characteristics, i.e., those with higher education and employed were more likely not to seek treatment, targeted interventions in the educational and workplace settings should be implemented.

Female Rodents Yield New Insights into Compulsive Alcohol Use and the Impact of Dependence: Commentary on Xie etal., 2019, "Sex Differences in Ethanol Reward Seeking Under Conflict in Mice".

Female Rodents Yield New Insights into Compulsive Alcohol Use and the Impact of Dependence: Commentary on Xie etal., 2019, "Sex Differences in Ethanol Reward Seeking Under Conflict in Mice".

Neuroimaging in alcohol use disorder: From mouse to man.

This article provides an overview of recent advances in understanding the effects of alcohol use disorders (AUD) on the brain from the perspective of magnetic resonance imaging (MRI) research in preclinical models and clinical studies. As a noninvasive investigational tool permitting assessment of morphological, metabolic, and hemodynamic changes over time, MRI offers insight into the dynamic course of alcoholism beginning with initial exposure through periods of binge drinking and escalation, sobriety, and relapse and has been useful in differential diagnosis of neurological diseases associated with AUD. Structural MRI has revealed acute and chronic effects of alcohol on both white and gray matter volumes. MR Spectroscopy, able to quantify brain metabolites in vivo, has shed light on biochemical alterations associated with alcoholism. Diffusion tensor imaging permits microstructural characterization of white matter fiber tracts. Functional MRI has allowed for elucidation of hemodynamicresponses at rest and during task engagement. Positron emission tomography, a non-MRI imaging tool, has led to a deeper understanding of alcohol-induced receptor and neurotransmitter changes during various stages of drinking and abstinence. Together, such in vivo imaging tools have expanded our understanding of the dynamic course of alcoholism including evidence for regional specificity of the effects of AUD, hints at mechanisms underlying the shift from casual to compulsive use of alcohol, and profound recovery with sustained abstinence.

Compulsivity in Alcohol Use Disorder and Obsessive Compulsive Disorder: Implications for Neuromodulation.

Alcohol use Disorder (AUD) is one of the leading causes of morbidity and mortality worldwide. The progression of the disorder is associated with the development of compulsive alcohol use, which in turn contributes to the high relapse rate and poor longer term functioning reported in most patients, even with treatment. While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines AUD by a cluster of symptoms, parsing its heterogeneous phenotype by domains of behavior such as compulsivity may be a critical step to improve outcomes of this condition. Still, neurobiological underpinnings of compulsivity need to be fully elucidated in AUD in order to better design targeted treatment strategies. In this manuscript, we review and discuss findings supporting common mechanisms between AUD and OCD, dissecting the construct of compulsivity and focusing specifically on characteristic disruptions in habit learning and cognitive control in the two disorders. Finally, neuromodulatory interventions are proposed as a probe to test compulsivity as key pathophysiologic feature of AUD, and as a potential therapy for the subgroup of individuals with compulsive alcohol use, i.e., the more resistant stage of the disorder. This transdiagnostic approach may help to destigmatize the disorder, and suggest potential treatment targets across different conditions.

What Can Neuroimaging of Human Alcohol Drinkers Tell Us About Compulsive Alcohol Use?

What Can Neuroimaging of Human Alcohol Drinkers Tell Us About Compulsive Alcohol Use?

Neural Correlates of Compulsive Alcohol Seeking in Heavy Drinkers

BackgroundCompulsive alcohol use, the tendency to continue alcohol seeking and taking despite negative consequences, is a hallmark of alcohol use disorder. Preclinical rodent studies have suggested a role for the medial prefrontal cortex, anterior insula, and nucleus accumbens in compulsive alcohol seeking. It is presently unknown whether these findings translate to humans. We used a novel functional magnetic resonance imaging paradigm and tested the hypothesis that heavy drinkers would compulsively seek alcohol despite the risk of an aversive consequence, and that this behavior would be associated with the activity of frontostriatal circuitry. MethodsNon–treatment-seeking heavy and light drinkers (n = 21 per group) completed a functional magnetic resonance imaging paradigm in which they could earn alcohol or food points at various threat levels (i.e., various probabilities of incurring an aversive consequence). Brain function was evaluated when individuals had the opportunity to earn reward points at the risk of an aversive consequence, an electric shock on the wrist. ResultsCompared with light drinkers, heavy drinkers attempted to earn more aversion-paired alcohol points. Frontostriatal circuitry, including the medial prefrontal cortex, anterior insula, and striatum, was more active in this group when viewing threat-predictive alcohol cues. Heavy drinkers had increased connectivity between the anterior insula and the nucleus accumbens. Greater connectivity was associated with more attempts to earn aversion-paired alcohol points and self-reported compulsive alcohol use scores. ConclusionsHigher activation of frontostriatal circuitry in heavy drinkers may contribute to compulsive alcohol seeking. Treatments that disrupt this circuitry may result in a decrease in compulsive alcohol use.

Novel human genome variants associated with alcohol use disorders identified in a Lithuanian cohort.

Background.Alcohol use disorder (AUD) is a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using (1). Abusive alcohol consumption directly affects a person’s physical and psychological health and social life. The World Health Organization has shown that Lithuania is a leading country in pure alcohol consumption in the world (2). The aim of this study is to find novel genome variants that are associated with the AUD in the Lithuanian cohort.Materials and methods.A case-control study included 294 individuals of Lithuanian ethnicity, who were divided into two groups based on their habits of alcohol use. Single nucleotide polymorphism array analysis was performed using Illumina HiScanSQ™ genome analyzer.Results.Our study showed that rs686141T>C variant in NALCN gene is more prevalent in the non-drinker group compared to the alcohol drinker group (relative allele frequency, respectively: 0.38 and 0.27, OR = 0.60 (CI 95% 0.37–0.98), p = 0.0408). Meanwhile, rs6354C>A, in SLC6A4 gene, variant’s genotype distribution showed statistically significant difference between the non-drinker and alcohol drinker group (distribution of genotypes in the case group: 9/72/172 (CC/CA/AA) and in the control group: 5/7/29, p = 0.0264).Conclusion.We analyzed 23 genes associated with AUD and identified two novel genome variants (rs686141T>C and rs6354C>A). The study shows that genome analysis is an important tool for AUD research. The results supplement the known information about genes associated with AUD.

The interplay between ventro striatal BDNF levels and the effects of valproic acid on the acquisition of ethanol-induced conditioned place preference in mice.

Alcohol addiction is a chronic, relapsing and progressive brain disease with serious consequences for health. Compulsive use of alcohol is associated with the capacity to change brain structures involved with the reward pathway, such as ventral striatum. Recent evidence suggests a role of chromatin remodeling in the pathophysiology of alcohol dependence and addictive-like behaviors. In addition, neuroadaptive changes mediated by the brain-derived neurotrophic factor (BDNF) seems to be an interesting pharmacological target for alcoholism treatment. In the present study, we evaluated the effects of the deacetylase inhibitor valproic acid (VPA) (300mg/kg) on the conditioned rewarding effects of ethanol using conditioned place preference (CPP) (15% v/v; 2g/kg). Ethanol rewarding effect was investigated using a biased protocol of CPP. BDNF levels were measured in the ventral striatum. Ethanol administration induced CPP. VPA pretreatment did not reduce ethanol-CPP acquisition. VPA pretreatment increased BDNF levels when compared to ethanol induced-CPP. VPA pretreatment increased BDNF levels even in saline conditioned mice. Taken together, our results indicate a modulatory effect of VPA on the BDNF levels in the ventral striatum. Overall, this study brings initial insights into the involvement of neurotrophic mechanisms in the ventral striatum in ethanol-induced addictive-like behavior.