Role In Alcohol Use Disorders Research Articles

Current trends in the role of neuroinflammation & α-synuclein in alcohol use disorder: A systematic quantitative literature review.

The neurodegenerative effects alcohol use disorder (AUD) have been well characterized and are likely due to the long-term effects of alcohol on the brain. The molecular events that underlie regional neuronal loss are a focus of current research. Chronic inflammation in the central nervous system, termed neuroinflammation, contributes to the progressive loss of neurons in the brain. Using data from genome-wide association studies and genetic and gene expression data, α-synuclein was identified as a gene of interest for AUD almost 10 years ago. Despite this and the well-recognized role of α-synuclein in mediating neuroinflammation in other neurodegenerative diseases, its role in alcohol-induced brain damage and AUD is yet to be elucidated. This systematic literature review quantifies and analyzes relationships between AUD, α-synuclein, and neuroinflammation. The review identified fewer studies focused on the role in AUD of α-synuclein (30) than on neuroinflammation (177), with published studies heavily centered on the myeloid differentiation primary response 88 (MyD88)-dependent toll-like receptor 4 (TLR4) pathway. The systematic review revealed that no original literature investigates the roles of α-synuclein and neuroinflammation in AUD and that there are significantly fewer published articles on the role of α-synuclein in AUD than in other neuroinflammatory conditions. Studies of the role of neuroinflammation in AUD are largely centered on the TLR4 signaling cascade, followed by TLR2 and TLR3, and soluble cytokines such as IL-10, IL-1β, and TNF-α. Key research themes identified in other neurodegenerative disorders provide new insights for further investigation in AUD.

Epigenetic Dysregulation in Alcohol-Associated Behaviors: Preclinical and Clinical Evidence.

Alcohol use disorder (AUD) is characterized by loss of control over intake and drinking despite harmful consequences. At a molecular level, AUD is associated with long-term neuroadaptations in key brain regions that are involved in reward processing and decision-making. Over the last decades, a great effort has been made to understand the neurobiological basis underlying AUD. Epigenetic mechanisms have emerged as an important mechanism in the regulation of long-term alcohol-induced gene expression changes. Here, we review the literature supporting a role for epigenetic processes in AUD. We particularly focused on the three most studied epigenetic mechanisms: DNA methylation, Histone modification and non-coding RNAs. Clinical studies indicate an association between AUD and DNA methylation both at the gene and global levels. Using behavioral paradigms that mimic some of the characteristics of AUD, preclinical studies demonstrate that changes in epigenetic mechanisms can functionally impact alcohol-associated behaviors. While many studies support a therapeutic potential for targeting epigenetic enzymes, more research is needed to fully understand their role in AUD. Identification of brain circuits underlying alcohol-associated behaviors has made major advances in recent years. However, there are very few studies that investigate how epigenetic mechanisms can affect these circuits or impact the neuronal ensembles that promote alcohol-associated behaviors. Studies that focus on the role of circuit-specific and cell-specific epigenetic changes for clinically relevant alcohol behaviors may provide new insights on the functional role of epigenetic processes in AUD.

Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: A narrative review.

Unhealthy alcohol consumption is a global health problem. Adverse individual, public health, and socioeconomic consequences are attributable to harmful alcohol use. Epidemiological studies have shown that alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) are the top two pathologies among alcohol-related diseases. Consistent with the major role that the liver plays in alcohol metabolism, uncontrolled drinking may cause significant damage to the liver. This damage is initiated by excessive fat accumulation in the liver, which can further progress to advanced liver disease. The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation. Any molecule with dual-pronged effects at the central and peripheral organs controlling addictive behaviors and associated metabolic pathways are a potentially important therapeutic target for treating AUD and ALD. Ghrelin, a hormone primarily derived from the stomach, has such properties, and regulates both behavioral and metabolic functions. In this review, we highlight recent advances in understanding the peripheral and central functions of the ghrelin system and its role in AUD and ALD pathogenesis. We first discuss the correlation between blood ghrelin concentrations and alcohol use or abstinence. Next, we discuss the role of ghrelin in alcohol-seeking behaviors and finally its role in the development of fatty liver by metabolic regulations and organ crosstalk. We propose that a better understanding of the ghrelin system could open an innovative avenue for improved treatments for AUD and associated medical consequences, including ALD.

Subjective and Behavioral Impulsivity Differentially Moderate Within- and Between-Person Associations Between Physical Activity and Alcohol Consumption.

Evidence indicates a counterintuitive positive relationship between physical activity and alcohol consumption, suggesting that people who engage in more physical activity consume more alcohol. Impulsivity, which has a well-documented role in alcohol use disorders, has been shown to moderate the between-person physical activity-drinking association among emerging adults. However, only a handful of studies have explored within-person associations of physical activity and drinking and potential moderators of this relationship. The current study evaluated the effects of both subjective and behavioral impulsivity on the within- and between-person association between physical activity and alcohol consumption among college students. Undergraduate students (N = 250) between ages 18 and 25 years were asked to report their daily physical activity and drinking over 21 days. Physical activity was also recorded objectively through Pacer, a smartphone app. Subjective impulsivity was assessed using the UPPS-P Impulsive Behavior Scale, and behavioral impulsivity was evaluated using the Balloon Analogue Risk Task. Within- and between-subject physical activity-drinking associations were differentially moderated by behavioral impulsivity and self-reported impulsivity. For instance, behavioral impulsivity moderated the within-person association between drinking and self-reported vigorous physical activity, whereas negative urgency moderated the between-person association between drinking and objective physical activity. Impulsivity, whether measured subjectively or behaviorally, significantly moderates the physical activity-alcohol consumption association. Importantly, this effect operates differently when predicting variation in behavior within individuals as compared with predicting differences in behavior between individuals.

Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism

ObjectiveAlcohol consumption can increase circulating levels of fibroblast growth factor 21 (FGF21). The effects of FGF21 in the central nervous system are associated with the regulation of catecholamines, neurotransmitters that play a crucial role in reward pathways. This study aims to identify genetic variants associated with FGF21 levels and evaluate their functional role in alcohol use disorder (AUD). MethodsWe performed a genome-wide association study (GWAS) using DNA samples from 442 AUD subjects recruited from the Mayo Clinic Center for the Individualized Treatment of Alcoholism Study. Plasma FGF21 levels were measured using Olink proximity extension immunoassays. Alcohol consumption at time of entry into the study was measured using the self-reported timeline followback method. Functional genomic studies were performed using HepG2 cells and induced pluripotent stem cell (iPSC)-derived brain organoids. ResultsPlasma FGF21 levels were positively correlated with recent alcohol consumption and gamma-glutamyl transferase levels, a commonly used marker for heavy alcohol use. One variant, rs9914222, located 5’ of SNHG16 on chromosome 17 was associated with plasma FGF21 levels (p = 4.60E-09). This variant was also associated with AUD risk (β: −3.23; p:0.0004). The rs9914222 SNP is an eQTL for SNHG16 in several brain regions, i.e., the variant genotype was associated with decreased expression of SNHG16. The variant genotype for the rs9914222 SNP was also associated with higher plasma FGF21 levels. Knockdown of SNHG16 in HepG2 cells resulted in increased FGF21 concentrations and decreased expression and enzyme activity for COMT, an enzyme that plays a key role in catecholamine metabolism. Finally, we demonstrated that ethanol significantly induced FGF21, dopamine, norepinephrine, and epinephrine concentrations in iPSC-derived brain organoids. ConclusionsGWAS for FGF21 revealed a SNHG16 genetic variant associated with FGF21 levels which are associated with recent alcohol consumption. Our data suggest that SNHG16 can regulate FGF21 concentrations and decrease COMT expression and enzyme activity which, in turn, have implications for the regulation of catecholamines.(The ClinicalTrials.gov Identifier: NCT00662571)

Externalizing personality characteristics define clinically relevant subgroups of alcohol use disorder.

AimsHigher levels of externalizing characteristics, i.e. impulsivity, novelty seeking and aggression, could contribute to the development, progression and severity of alcohol use disorder (AUD). The present study aims to explore whether these externalizing characteristics together have a potential group-forming role in AUD using latent profile analysis (LPA).MethodsExternalizing characteristics of 102 AUD patients were analyzed using LPA to explore the group-forming role of externalizing symptoms; groups were compared in terms of demographic and alcohol-related variables, indices of psychopathological, depressive and anxiety symptom severity.ResultsLPA revealed and supported a two-group model based on externalizing symptoms. The group with higher levels of externalizing symptoms showed significantly elevated levels of alcohol-related and anxio-depressive symptoms.ConclusionsExternalizing characteristics converge and have a group-forming role in chronic AUD, and are associated with a more severe form of AUD. By making the diagnostic category less heterogeneous, these different subtypes within AUD may provide aid in tailoring treatments to patients’ specific needs.

Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats

Aberrant glucocorticoid signaling via glucocorticoid receptors (GR) plays a critical role in alcohol use disorder (AUD). Acute alcohol withdrawal and protracted abstinence in dependent rats are associated with increased GR signaling and changes in GR-mediated transcriptional activity in the rat central nucleus of the amygdala (CeA). The GR antagonist mifepristone decreases alcohol consumption in dependent rats during acute withdrawal and protracted abstinence. Regulation of CeA synaptic activity by GR is currently unknown. Here, we utilized mifepristone and the selective GR antagonist CORT118335 (both at 10 μM) as pharmacological tools to dissect the role of GR on GABA transmission in male, adult Sprague-Dawley rats using slice electrophysiology. We subjected rats to chronic intermittent alcohol vapor exposure for 5–7 weeks to induce alcohol dependence. A subset of dependent rats subsequently underwent protracted alcohol withdrawal for 2 weeks, and air-exposed rats served as controls. Mifepristone reduced the frequency of pharmacologically-isolated spontaneous inhibitory postsynaptic currents (sIPSC) in the CeA (medial subdivision) without affecting postsynaptic measures in all groups, suggesting decreased GABA release with the largest effect in dependent rats. CORT118335 did not significantly alter GABA transmission in naïve, but decreased sIPSC frequency in dependent rats. Similarly, mifepristone decreased amplitudes of evoked inhibitory postsynaptic potentials only in dependent rats and during protracted withdrawal. Collectively, our study provides insight into regulation of CeA GABAergic synapses by GR. Chronic ethanol enhances the efficiency of mifepristone and CORT118335, thus highlighting the potential of drugs targeting GR as a promising pharmacological avenue for the treatment of AUD.

RNA Solutions: Synthesizing Information to Support Transcriptomics (RNASSIST).

MotivationTranscriptomics is a common approach to identify changes in gene expression induced by a disease state. Standard transcriptomic analyses consider differentially expressed genes (DEGs) as indicative of disease states so only a few genes would be treated as signals when the effect size is small, such as in brain tissue. For tissue with small effect sizes, if the DEGs do not belong to a pathway known to be involved in the disease, there would be little left in the transcriptome for researchers to follow up with.ResultsWe developed RNA Solutions: Synthesizing Information to Support Transcriptomics (RNASSIST), a new approach to identify hidden signals in transcriptomic data by linking differential expression and co-expression networks using machine learning. We applied our approach to RNA-seq data of post-mortem brains that compared the Alcohol Use Disorder (AUD) group with the control group. Many of the candidate genes are not differentially expressed so would likely be ignored by standard transcriptomic analysis pipelines. Through multiple validation strategies, we concluded that these RNASSIST-identified genes likely play a significant role in AUD.Availability and implementationThe RNASSIST algorithm is available at https://github.com/netrias/rnassist and both the software and the data used in RNASSIST are available at https://figshare.com/articles/software/RNAssist_Software_and_Data/16617250.Supplementary information Supplementary data are available at Bioinformatics online.

Genetic association of FKBP5 with trait resilience in Korean male patients with alcohol use disorder

The FKBP5 gene is known to have an important role in alcohol use disorder (AUD) in response to stress and has been reported to affect stress responses by interacting with childhood trauma. This study investigated the effects of the FKBP5 polymorphism rs1360780 and childhood trauma on trait resilience in male patients with AUD. In addition, allele-specific associations between FKBP5 DNA methylation and resilience were examined. In total, 297 men with AUD were assessed for alcohol use severity, childhood trauma, resilience, and impulsivity. Genotyping for FKBP5 rs1360780 and DNA methylation were analyzed. The effects of the rs1360780 single nucleotide polymorphism (SNP) and clinical variables on resilience were tested using linear regression analysis. Possible associations between FKBP5 DNA methylation and resilience were tested with partial correlation analysis. The rs1360780 risk allele, a low education level, and high impulsivity were associated with diminished resilience, whereas no significant main or interaction effect of childhood trauma with the SNP rs1360780 genotype on resilience was shown. No significant association between FKBP5 DNA methylation and resilience was found. The present study demonstrated the involvement of the rs1360780 risk allele in trait resilience in men with AUD, suggesting that the genetic vulnerability of FKBP5 may influence resilience related to AUD.

Effect of acute alcohol intoxication on scale-free neural activity in the lateral septum in rats

Electrophysiological recordings of brain activity show both oscillatory dynamics that typically are analyzed in the time-frequency domain to describe brain oscillatory phenomena and scale-free arrhythmic activity defined as neural noise. Recent studies consider this arrhythmic fractal dynamics of neural noise as a sensitive biomarker of a number of cognitive processes, activity of neurotransmitter systems, changes that accompany neurodegenerative and psychiatric disorders including alcohol use disorder. We tested the changes in neural noise induced by acute alcohol intoxication in the lateral septum for the entire spectrum (1–200 Hz) of local field potential signal and for frequency specific ranges (delta, theta, beta, gamma and epsilon bands). Five male Wistar rats were implanted with intracranial electrodes and local field potential signal was measured for baseline activity and activity induced by acute ethanol intoxication (2 g/kg). Change in neural noise dynamics was assessed as a change in the slope of linear regression fit of power spectral density curves in double logarithmic scale. In our study alcohol resulted in lower incline of scale-free activity in the lateral septum for high frequency range and for the whole spectrum, which is interpreted generally as increase in neural noise and change in neuronal processing in a more stochastic way initiated by the acute alcohol intoxication. At the same time, we observed decrease in neural noise for low frequency range. The observed changes may be related to the shift of the excitatory-inhibitory balance towards inhibition and changes in neurotransmission mostly in the GABAergic system. Scale-free activity was sensitive in the conditions of acute alcohol intoxication, therefore to understand its role in alcohol use disorder we need more data and studies on the underlying processes. Future studies should include simultaneous recordings and analysis of arrhythmic dynamics with the oscillatory and multiunit spiking activity in the lateral septum. It can reveal the contribution of different-scale processes in changes driven by acute alcohol intoxication and clarify the specific electrophysiological mechanisms.

Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder.

Alcohol use disorder is a pervasive and detrimental condition that involves changes in neuroplasticity and neurogenesis. Alcohol activates the neuroimmune system and alters the inflammatory status of the brain. Tumour necrosis factor (TNF) is a well characterised neuroimmune signal but its involvement in alcohol use disorder is unknown. In this review, we discuss the variable findings of TNF’s effect on neuroplasticity and neurogenesis. Acute ethanol exposure reduces TNF release while chronic alcohol intake generally increases TNF levels. Evidence suggests TNF potentiates excitatory transmission, promotes anxiety during alcohol withdrawal and is involved in drug use in rodents. An association between craving for alcohol and TNF is apparent during withdrawal in humans. While anti-inflammatory therapies show efficacy in reversing neurogenic deficit after alcohol exposure, there is no evidence for TNF’s essential involvement in alcohol’s effect on neurogenesis. Overall, defining TNF’s role in alcohol use disorder is complicated by poor understanding of its variable effects on synaptic transmission and neurogenesis. While TNF may be of relevance during withdrawal, the neuroimmune system likely acts through a larger group of inflammatory cytokines to alter neuroplasticity and neurogenesis. Understanding the individual relevance of TNF in alcohol use disorder awaits a more comprehensive understanding of TNF’s effects within the brain.

A Critical Review of Alcohol Administration Guidelines in Laboratory Medication Screening Research: Is It Time to Include Treatment Seekers?

Human laboratory studies play an important role in alcohol use disorder (AUD) medication development. Medications that are found to be safe and effective during human laboratory screening will then move to more expensive clinical trials in patient populations. Given the gatekeeping role of human laboratory studies in the medication development pipeline, it is critical that these studies accurately forecast how pharmacotherapies will perform under true-to-life clinical conditions. On the other hand, the design of these studies also must adhere to ethical guidelines: certain aspects of clinical reality cannot be incorporated into screening studies because doing so might place the participant at risk for harm or breach other ethical guidelines. Conventions exist that guide the resolution of these conflicting ideals. This article considers the practice of recruiting non-treatment-seeking heavy drinkers to participate in laboratory screening studies. By convention, volunteers are excluded from laboratory screening studies that involve alcohol administration if they are deemed "treatment seeking," meaning that they recently stopped drinking or are motivated to do so. Although this common practice may reduce risk to participants, findings may not accurately predict medication effects on treatment seekers. Indeed, there is empirical evidence that treatment seekers differ from nontreatment seekers in their responses to medications (Neuropsychopharmacology 2017a; 42: 1776; Am J Drug Alcohol Abuse 2017b; 43: 703; J Psychiatr Res 2006; 40: 383). Here, we argue for the importance of recruiting treatment seekers for this research due to their qualitative difference from nontreatment seekers. We argue that these individuals should be the default population in human laboratory medication screening studies. We conclude by discussing 2 case examples of medication experiments led by our research groups that involved administering medications to treatment seekers.

Attentional and approach biases to alcohol cues among young adult drinkers: An ecological momentary assessment study.

Alcohol-specific attentional biases (AttB) and approach biases (AppB) are postulated to play a role in alcohol use disorders but their association with drinking in young adults remains unknown. A subsample of young adults with risky alcohol use (N = 296) enrolled in a randomized trial, testing different text message interventions completed weekly tasks via a mobile app for up to 14 weeks: Alcohol Stroop was used to measure AttB and Approach-Avoidance Task was used to measure AppB. Participants also provided reports of their alcohol consumption up to twice per week. We analyzed feasibility of measuring alcohol biases on mobile phones, whether repeated testing and conditions of testing affected mean reaction times (RTs), and whether mean AttB and AppB scores were associated with baseline alcohol use severity and same-day binge drinking (4+/5+ drinks per occasion for women/men). Task completion decreased from 93% on Week 1% to 39% by Week 14 with a mean of 8.2 weeks completed. Mean RTs for Alcohol Stroop decreased over weeks assessed. RTs to Stroop and Approach-Avoid tasks were longer when participants reported distractions or after alcohol and/or drug use. Mean AttB and AppB scores were not associated with baseline drinking, and within-day fluctuations of AttB and AppB scores did not predict same day binge drinking. Barriers to measuring alcohol biases in the natural environment include learning effects, contextual influences of distractions and prior alcohol/drug use, and absence of robust associations of RTs to alcohol cues with either baseline or same-day alcohol consumption. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Gut Microbiota-Induced Changes in β-Hydroxybutyrate Metabolism Are Linked to Altered Sociability and Depression in Alcohol Use Disorder

Patients with alcohol use disorder (AUD) present with important emotional, cognitive, and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show that gut dysbiosis is associated with metabolic alterations that affect behavioral (depression, sociability) and neurobiological (myelination, neurotransmission, inflammation) processes involved in alcohol addiction. By transplanting the gut microbiota from AUD patients to mice, we point out that the production of ethanol by specific bacterial genera and the reduction of lipolysis are associated with a lower hepatic synthesis of β-hydroxybutyrate (BHB), which thereby prevents the neuroprotective effect of BHB. We confirm these results in detoxified AUD patients, in which we observe a persisting ethanol production in the feces as well as correlations among low plasma BHB levels and social impairments, depression, or brain white matter alterations.

Voluntary alcohol consumption is increased in female, but not male, oxytocin receptor knockout mice.

IntroductionThe oxytocin (Oxt) system, while typically associated with the neural regulation of social behaviors, also plays a role in an individual's vulnerability to develop alcohol use disorders (AUD). In humans, changes to the Oxt system, due to early life experience and/or genetic mutations, are associated with increased vulnerability to AUD. While a considerable amount is known about Oxt's role in AUD in males, less is known or understood, about how Oxt may affect AUD in females, likely due to many clinical and preclinical studies of AUD not directly considering sex as a biological variable. This is unfortunate given that females are more vulnerable to the effects of alcohol and have increased alcohol consumption, as compared to males. Therefore, in the current study we wanted to determine whether genetic disruption of the Oxt receptor (Oxtr), that is, Oxtr knockout (−/−) mice, affected stress‐induced alcohol consumption in males and females. We hypothesized that genetic disruption of the Oxtr would result in increased stress‐induced alcohol consumption in both males and females compared to wild‐type (+/+) controls. Though, we predicted that these disruptions might be greater in female Oxtr −/− mice.MethodsTo test this hypothesis, a two‐bottle preference test was utilized along with the forced swim test (FST), and pre‐ and poststress alcohol consumption and preference measured within each sex (males and females were run separately). As a follow‐up experiment, a taste preference test, to control for possible genotypic differences in taste, was also performed.ResultsIn males, we found no significant genotypic differences in alcohol consumption or preference. However, in females, we found that genetic disruption of the Oxtr resulted in a greater consumption of alcohol both pre‐ and poststress compared to controls.ConclusionThese data suggest that in females, disruptions in Oxt signaling may contribute to increased vulnerability to alcohol‐associated addiction.

Orbitofrontal Cortex Encodes Preference for Alcohol.

Orbitofrontal cortex (OFC) plays a key role in representation and regulation of reward value, preference, and seeking. OFC function is disrupted in drug use and dependence, but its specific role in alcohol use disorders has not been thoroughly studied. In alcohol-dependent humans OFC activity is increased by alcohol cue presentation. Ethanol (EtOH) also alters OFC neuron excitability in vitro, and OFC manipulation influences EtOH seeking and drinking in rodents. To understand the relationship between OFC function and individual alcohol use, we recorded OFC neuron activity in rats during EtOH self-administration, characterizing the neural correlates of individual preference for alcohol. After one month of intermittent access to 20% EtOH, male Long-Evans rats were trained to self-administer 20% EtOH, 10% EtOH, and 15% sucrose. OFC neuronal activity was recorded and associated with task performance and EtOH preference. Rats segregated into high and low EtOH drinkers based on homecage consumption and operant seeking of 20% EtOH. Motivation for 10% EtOH and sucrose was equally high in both groups. OFC neuronal activity was robustly increased or decreased during sucrose and EtOH seeking and consumption, and strength of changes in OFC activity was directly associated with individual preference for 20% EtOH. EtOH-associated OFC activity was more similar to sucrose-associated activity in high versus low EtOH drinkers. The results show that OFC neurons are activated during alcohol seeking based on individual preference, supporting this brain region as a potential substrate for alcohol motivation that may be dysregulated in alcohol misuse.

Forced Abstinence From Alcohol Induces Sex-Specific Depression-Like Behavioral and Neural Adaptations in Somatostatin Neurons in Cortical and Amygdalar Regions.

Forced abstinence (FA) from alcohol has been shown to produce a variety of anxiety- and depression-like symptoms in animal models. Somatostatin (SST) neurons, a subtype of GABAergic neurons found throughout the brain, are a novel neural target with potential treatment implications in affective disorders, yet their role in alcohol use disorders (AUD) remains to be explored. Here, we examined the neuroadaptations of SST neurons during forced abstinence from voluntary alcohol consumption. Following 6 weeks of two-bottle choice alcohol consumption and protracted forced abstinence, male and female C57BL/6J mice exhibited a heightened, but sex-specific, depressive-like behavioral profile in the sucrose preference test (SPT) and forced swim test (FST), without changes in anxiety-like behaviors in the elevated plus maze (EPM) and open field test (OFT). FST-induced cFos expressions in the prefrontal cortex (PFC) and ventral bed nucleus of the stria terminalis (vBNST) were altered in FA-exposed female mice only, suggesting a sex-specific effect of forced abstinence on the neural response to acute stress. SST immunoreactivity in these regions was unaffected by forced abstinence, while differences were seen in SST/cFos co-expression in the vBNST. No differences in cFos or SST immunoreactivity were seen in the lateral central nucleus of the amygdala (CEA) and the basolateral amygdala (BLA). Additionally, SST neurons in female mice displayed opposing alterations in the PFC and vBNST, with heightened intrinsic excitability in the PFC and diminished intrinsic excitability in the vBNST. These findings provide an overall framework of forced abstinence-induced neuroadaptations in these key brain regions involved in emotional regulation and processing.

Differential brain responses for perception of pain during empathic response in binge drinkers compared to non-binge drinkers

Individuals who engage in binge drinking behaviors may show evidence of impaired cognitive function and emotional dysregulation. Impaired empathy, characterized by a reduced ability to understand and respond appropriately to feelings of others, is increasingly recognized for its role in Alcohol Use Disorders (AUD). The present study examined a population of young adult social drinkers to compare individuals who show binge drinking behavior to those who do not on measures of empathic processing and associated neural responses. A secondary aim explored similarities and differences between binge drinkers living in the UK and France. Alcohol drinking history and impulsivity ratings were recorded from seventy-one participants [(37 UK (Binge drinkers N = 19); 34 France (Binge drinkers N = 17)], who then underwent a neuroimaging study. During functional magnetic resonance imaging, participants viewed images of bodily pain (vs. no-pain), while adopting the perspective of self (pain recipient) or other (observer of someone else experiencing pain). Anterior midcingulate cortex (aMCC) and insula activation distinguished pain from no-pain conditions. Binge drinkers showed stronger regional neural activation than non-binge drinkers within a cluster spanning fusiform gyrus and inferior temporal gyrus, encompassing the Fusiform Body Area. Binge drinkers compared to non-binge drinkers also took longer to respond when viewing pictures depicting pain, in particular when adopting the perspective of self. Relationships between changes in brain activation and behavioural responses in pain versus no pain conditions (self or other perspective) indicated that whereas non-binge drinkers engage areas supporting self to other distinction, binge drinkers do not. Our findings suggest that alcohol binge drinking is associated with different empathy-related behavioral and brain responses, consistent with the proposed importance of empathy in the development of AUD.

The Gut Microbiota Drives Metabolic Disorders Which Compromise Sociability in Alcoholic Patients

Patients with alcohol use disorder (AUD) present with important emotional, cognitive and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show for the first time that the gut microbiota drives behavioral features of alcohol addiction including reduced sociability. By transplanting the gut microbiota from AUD patients to mice, we pointed out that the production of ethanol by specific bacterial genera, is associated with a lower hepatic synthesis of beta-hydroxybutyrate (BHB), and thereby prevent the protective effect of BHB on social behavior, neuroinflammation and neurotransmission. We confirmed this hypothesis detoxified AUD patients, in which we observed a persisting ethanol production in the feces as well as correlations between low plasma BHB levels and social impairments. Our data support new pathways involved in behavioral disorders associated with alcohol addiction, that could be considered for future treatments.

Brain responses to anticipating and receiving beer: Comparing light, at-risk, and dependent alcohol users.

Impaired brain processing of alcohol‐related rewards has been suggested to play a central role in alcohol use disorder. Yet, evidence remains inconsistent and mainly originates from studies in which participants passively observe alcohol cues or taste alcohol. Here, we designed a protocol in which beer consumption was predicted by incentive cues and contingent on instrumental action closer to real life situations. We predicted that anticipating and receiving beer (compared with water) would elicit activity in the brain reward network and that this activity would correlate with drinking level across participants.The sample consisted of 150 beer‐drinking males, aged 18 to 25 years. Three groups were defined based on alcohol use disorders identification test (AUDIT) scores: light drinkers (n = 39), at‐risk drinkers (n = 64), and dependent drinkers (n = 47). fMRI measures were obtained while participants engaged in the beer incentive delay task involving beer‐ and water‐predicting cues followed by real sips of beer or water.During anticipation, outcome notification and delivery of beer compared with water, higher activity was found in a reward‐related brain network including the dorsal medial prefrontal cortex, orbitofrontal cortex, and amygdala. Yet, no activity was observed in the striatum, and no differences were found between the groups.Our results reveal that anticipating, obtaining, and tasting beer activates parts of the brain reward network, but that these brain responses do not differentiate between different drinking levels.