Feature Of Alcohol Use Disorder Research Articles

In natura heart rate variability predicts subsequent alcohol use in individuals in early recovery from alcohol use disorder.

Impairment in autonomic self-regulatory functioning reflected by reduced heart rate variability (HRV) is a common feature of alcohol use disorder (AUD) and is believed to heighten AUD relapse risk. However, to date, no study has explored associations between in natura HRV and subsequent alcohol use among individuals seeking AUD recovery. In this study, 42 adults in the first year of a current AUD recovery attempt were monitored for 4 days using ambulatory electrocardiogram, followed by 90 days of alcohol use monitoring using timeline follow-back. HRV indices (independent variables) reflecting autonomic neurocardiac engagement were calculated from electrocardiogram recordings. Alcohol use (dependent variable) was calculated from timeline follow-back and expressed as per cent days abstinent (PDA). The sample was 73.81% White/European American, 19.05% Black/African American, 4.76% Asian, and 2.38% Other race/Mixed race. As predicted, higher parasympathetically mediated HRV and lower heart rate were associated with greater PDA over 90-day follow-up. Additionally, interactions between these measures and baseline PDA indicated higher parasympathetically mediated HRV and lower heart rate mitigated the deleterious positive association between baseline and follow-up alcohol use. Including factors known to influence alcohol use and/or HRV in the models did not meaningfully alter their results. Findings are consistent with psychophysiological theories implicating autonomic self-regulatory functioning in AUD treatment outcomes and suggest that select HRV indices may have utility as indicants of risk for alcohol use lapse in individuals in early AUD recovery. Findings provide theoretical support for HRV Biofeedback for this population, which exercises the psychophysiological systems that support self-regulation.

Polygenic influences on the behavioral effects of alcohol withdrawal in a mixed-ancestry population from the collaborative study on the genetics of alcoholism (COGA)

Alcohol withdrawal (AW) is a feature of alcohol use disorder that may occur in up to half of individuals with chronic, heavy alcohol consumption whenever alcohol use is abruptly stopped or significantly reduced. To date, few genes have been robustly associated with AW; this may be partly due to most studies defining AW as a binary construct despite the multiple symptoms and their range in severity from mild to severe. The current study examined the effects of genome-wide loci on a factor score for AW in high risk and community family samples in the Collaborative Study for the Genetics of Alcoholism (COGA). In addition, we tested whether differentially expressed genes associated with alcohol withdrawal in model organisms are enriched in human genome-wide association study (GWAS) effects. Analyses employed roughly equal numbers of males and females (mean age 35, standard deviation = 15; total N = 8009) and included individuals from multiple ancestral backgrounds. Genomic data were imputed to the HRC reference panel and underwent strict quality control procedures using Plink2. Analyses controlled for age, sex, and population stratification effects using ancestral principal components. We found support that AW is a polygenic disease (SNP-heritability = 0.08 [95 % CI = 0.01, 0.15; pedigree-based heritability = 0.12 [0.08,0.16]. We identified five single nucleotide variants that met genomewide significance, some of which have previously been associated with alcohol phenotypes. Gene-level analyses suggest a role for COL19A1 in AW; H-MAGMA analyses implicated 12 genes associated with AW. Cross-species enrichment analyses indicated that variation within genes identified in model organism studies explained <1 % of the phenotypic variability in human AW. Notably, the surrounding regulatory regions of model organism genes explained more variance than expected by chance, indicating that these regulatory regions and gene sets may be important for human AW. Lastly, when comparing the overlap in genes identified from the human GWAS and H-MAGMA analyses with the genes identified from the animal studies, there was modest overlap, indicating some convergence between the methods and organisms.

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.

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.

Repeated, moderate footshock reduces the propensity to relapse to alcohol seeking in female, but not male, iP rats.

Persistent alcohol use despite negative consequences is a key feature of alcohol use disorder (AUD) and is typically assessed using punishment in animal models. This study examined relapse-like behavior in male and female alcohol-preferring iP rats following punishment-imposed voluntary abstinence to alcohol seeking. We focused on alcohol seeking in the punishment-associated environment after prolonged abstinence. Finally, we sought to understand the predictability of relapse-like behavior by examining AUD comorbidities, namely, anxiety-like behavior and the response to repeated, moderate punishment. We found no sex differences in operant self-administration of alcohol. However, we did find a reduced propensity to relapse in the punishment-associated environment in female rats following prolonged abstinence. Relapse propensity was associated with the response to punishment during operant training, but not prior anxiety-like behavior. Together these results highlight the importance of studying sex differences in relapse to alcohol seeking. In addition, the behavioral response to a negative consequence may be a predictor of relapse, particularly in females. Improving our understanding of the sexually dimorphic responses in alcohol seeking may be a powerful tool for designing personalized, or at least sex-specific, approaches to treatment and rehabilitation programs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BNST-Anterior Insula Resting State Functional Connectivity Correlates With Drinking Outcomes in Treatment-Seeking Alcohol Use Disorder Participants

A feature of alcohol use disorder (AUD) is the heightened anxiety and negative affective state that occurs during abstinence, which often drives relapse. Elucidating the neural substrates underlying this phenomenon may guide more targeted and effective therapy for AUD. Recent preclinical evidence has implicated an anterior insula (AI)- bed nucleus of the striae terminalis (BNST) circuit in negative affective behaviors during abstinence, and recent human literature has revealed structural connectivity between the AI and BNST.

Neurobiological aspects of pain in the context of alcohol use disorder.

Alcohol is an effective and widely utilized analgesic. However, the chronic use of alcohol can actually facilitate nociceptive sensitivity over time, a condition known as hyperalgesia. Excessive and uncontrollable alcohol drinking is also a hallmark feature of alcohol use disorder (AUD). Both AUD and chronic pain are typically accompanied by negative affective states that may underlie reinforcement mechanisms contributing to AUD maintenance or progression. Frequent utilization of alcohol to relieve pain in individuals suffering from AUD or other chronic pain conditions may thus represent a powerful negative reinforcement construct. This chapter will describe ties between alcohol-mediated pain relief and potential exacerbation of AUD. We describe neurobiological systems engaged in alcohol analgesia as well as systems recruited in the development and maintenance of AUD and hyperalgesia. Although few effective therapies exist for either chronic pain or AUD, the common interaction of these conditions will likely lead the way for promising new discoveries of more effective and even simultaneous treatment of AUD and co-morbid hyperalgesia. An abundance of neurobiological findings from multiple laboratories has implicated a potentiation of central amygdala (CeA) signaling in both pain and AUD, and these data also suggest that attenuation of stress-related systems (including corticotropin-releasing factor, vasopressin, and glucocorticoid receptor activity) would be particularly effective and comprehensive therapeutic strategies targeting the critical intersection of somatic and motivational mechanisms driving AUD, including alcohol-induced hyperalgesia.

Compulsive alcohol consumption is regulated by dorsal striatum fast-spiking interneurons.

Compulsive alcohol consumption is a core, treatment-resistant feature of alcohol use disorder. The dorsomedial and dorsolateral striatum support goal-directed and habitual action strategies, respectively. How ethanol targets dorsolateral striatum to drive compulsive consumption is poorly understood. Parvalbumin-expressing striatal fast-spiking interneurons comprise ~1% of the total neuronal striatal population, are enriched dorsolaterally and are functionally modulated by ethanol. To test whether fast-spiking interneurons are necessary for the development of compulsive ethanol consumption, we selectively ablated these neurons in adult male and female C57BL/6 J mice undergoing a voluntary chronic intermittent ethanol consumption paradigm followed by a compulsive ethanol drinking assay. Fast-spiking interneuron ablation curtailed the development of organized ethanol lick sequence behavior, reduced ethanol consumption, and abrogated compulsive consumption of ethanol with the added bitterant quinine. In contrast, fast-spiking interneuron ablation did not affect any index of water or sucrose consumption. These data causally implicate the minority striatal fast-spiking interneuron population as a key component of compulsive ethanol consumption.

Withdrawal from chronic ethanol exposure increases postsynaptic glutamate function of insular cortex projections to the rat basolateral amygdala

A key feature of alcohol use disorder (AUD) is negative affect during withdrawal, which often contributes to relapse and is thought to be caused by altered brain function, especially in circuits that are important mediators of emotional behaviors. Both the agranular insular cortex (AIC) and the basolateral amygdala (BLA) regulate emotions and are sensitive to ethanol-induced changes in synaptic plasticity. The AIC and BLA are reciprocally connected; and the effects of chronic ethanol exposure on this circuit have yet to be explored. Here, we use a combination of optogenetics and electrophysiology to examine the pre- and postsynaptic changes that occur to AIC-BLA synapses following withdrawal from 7- or 10-days of chronic intermittent ethanol (CIE) exposure. While CIE/withdrawal did not alter presynaptic glutamate release probability from AIC inputs, withdrawal from 10, but not 7, days of CIE increased AMPA receptor-mediated postsynaptic function at these synapses. Additionally, NMDA receptor-mediated currents evoked by electrical stimulation of the external capsule, which contains AIC afferents, were also increased during withdrawal. Notably, a single subanesthetic dose of ketamine administered at the onset of withdrawal prevented the withdrawal-induced increases in both AMPAR and NMDAR postsynaptic function. Ketamine also prevented the withdrawal-induced increases in anxiety-like behavior measured using the elevated zero maze. Together, these findings suggest that chronic ethanol exposure increases postsynaptic function within the AIC-BLA circuit and that ketamine can prevent ethanol withdrawal-induced alterations in synaptic plasticity and negative affect.

Anterior Insular Cortex is Critical for the Propensity to Relapse Following Punishment-Imposed Abstinence of Alcohol Seeking.

Humans with alcohol use disorder typically abstain because of the negative consequences associated with excessive drinking, and exposure to contexts previously associated with alcohol use can trigger relapse. We used a rat model that captures a characteristic of this human condition: namely voluntary abstinence from alcohol use because of contingent punishment. There is substantial variability in the propensity to relapse following extended periods of abstinence, and this is a critical feature preventing the successful treatment of alcohol use disorder. Here we examined relapse following acute or prolonged abstinence. In male alcohol preferring P rats, we found an increased propensity to relapse in Context B, the punishment context after prolonged abstinence. Next, we found that neither alcohol intake history nor the motivational strength of alcohol predicted the propensity to relapse. We next examined the putative circuitry of context-induced relapse to alcohol seeking following prolonged abstinence using Fos as a marker of neuronal activation. The anterior insular cortex (AI) was the only brain region examined where Fos expression correlated with alcohol seeking behavior in Context B after prolonged abstinence. Finally, we used local infusion of GABAA and GABAB receptor agonists (muscimol + baclofen) to show a causal role of the AI in context-induced relapse in Context B, the punishment context after prolonged abstinence. Our results show that there is substantial individual variability in the propensity to relapse in the punishment-associated context after prolonged abstinence, and this is mediated by activity in the AI.SIGNIFICANCE STATEMENT A key feature of alcohol use disorder is that sufferers show an enduring propensity to relapse throughout their lifetime. Relapse typically occurs despite the knowledge of adverse consequences including health complications or relationship breakdowns. Here we use a recently developed rodent model that recapitulates this behavior. After an extended period of abstinence, relapse propensity is markedly increased in the "adverse consequence" environment, akin to humans with alcohol use disorder relapsing in the face of adversity. From a circuitry perspective, we demonstrate a causal role of the anterior insular cortex in relapse to alcohol seeking after extended abstinence following punishment imposed voluntary cessation of alcohol use.

The clinical features of alcohol use disorders in biological and step‐fathers that predict risk for alcohol use disorders in offspring

Given that Alcohol Use Disorder (AUD) is clinically heterogeneous, can we, in a large epidemiological sample using public registries, identify clinical features of AUD cases in biological and step-fathers that index, respectively, genetic and familial-environmental risk for AUD in their offspring? From all father-offspring pairs where the father had AUD and the offspring was born 1960-1990, we identified not-lived-with (NLW) biological fathers (n = 38,376) and step-father pairs (n = 9,711). The relationship between clinical and historical features of the father's AUD and risk for AUD in offspring was assessed by linear hazard regression. Age at first registration for AUD and recurrence of AUD registration were significantly stronger predictors of risk for AUD in the offspring of NLW fathers than in step-fathers. By contrast, number of AUD registrations in NLW fathers and step-fathers were equally predictive of risk for AUD in offspring. However, while the number of step-father AUD registrations that occurred when he was living them with significantly predicted risk for AUD in his step-children, the number of registrations that occurred when not residing with his step-children was unassociated with their AUD risk. In an epidemiological sample, we could meaningfully differentiate between features of AUD in fathers that indexed genetic risk which was transmitted to biological offspring (early age at onset and recurrence) versus indexed environmental risk (registrations while rearing) which increased risk in step-children.

Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption.

Long lasting abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to brain adaptations leading to ethanol toxicity and AUD. We employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has been shown to induce progressive ethanol consumption in rodents. Brain CIE-responsive expression networks were identified by microarray analysis across five regions of the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-hours to 7-days following CIE. Weighted Gene Correlated Network Analysis (WGCNA) was used to identify gene networks over-represented for CIE-induced temporal expression changes across brain regions. Differential gene expression analysis showed that long-lasting gene regulation occurred 7-days after the final cycle of ethanol exposure only in prefrontal cortex (PFC) and hippocampus. Across all brain regions, however, ethanol-responsive expression changes occurred mainly within the first 8-hours after removal from ethanol. Bioinformatics analysis showed that neuroinflammatory responses were seen across multiple brain regions at early time-points, whereas co-expression modules related to neuroplasticity, chromatin remodeling, and neurodevelopment were seen at later time-points and in specific brain regions (PFC or HPC). In PFC a module containing Bdnf was identified as highly CIE responsive in a biphasic manner, with peak changes at 0 hours and 5 days following CIE, suggesting a possible role in mechanisms underlying long-term molecular and behavioral response to CIE. Bioinformatics analysis of this network and several other modules identified Let-7 family microRNAs as potential regulators of gene expression changes induced by CIE. Our results suggest a complex temporal and regional pattern of widespread gene network responses involving neuroinflammatory and neuroplasticity related genes as contributing to physiological and behavioral responses to chronic ethanol.

REVIEW: Non‐human primate models of inheritance vulnerability to alcohol use disorders

Many animal species have been used to model certain aspects of alcohol use and addiction. However, there are complex behavioral and social features of alcohol use disorders that are not easily modeled in animal species. This review considers both the limitations and advantages of using a non-human primate to model alcohol use disorders and discusses how non-human primates can be particularly useful for studying how genetic variants interact with social factors, temperament and alcohol response as motivating factors for alcohol consumption and abstinence. Genetic variants in rhesus macaques (Macaca mulatta) that are functionally equivalent to those increasing addiction vulnerability in humans influence temperament, stress reactivity and alcohol response in addition to voluntary alcohol consumption. Non-human primate models may also have translational value for understanding of how variants within addiction and abuse vulnerability genes influence alcohol-induced neuroadaptation, neuropathology and treatment response.