Model Of Alcohol Use Disorder Research Articles

A Pilot Study: Treatment of High Alcohol Consumption in a Novel Minipig Model of Alcohol Use Disorder

ABSTRACT Three medications are FDA approved in the US for treatment of Alcohol Use Disorder (AUD), and a few others are used off-label. Patient compliance and efficacy in the broader population are major hurdles for current AUD medications. As a consequence, there is an urgent need for improved pharmacotherapeutics to complement behavioral approaches. Here, we report pilot testing of a minocycline analog, 10-butylether minocycline (BEM, 10 mg/kg p.o.), in two female minipigs with free-choice drinking to intoxication for nearly two and a half years. Each pig met DSM-5 criteria for diagnosis of severe AUD, and BEM reduced both alcohol intake and preference. BEM is currently undergoing testing for approval as an Investigational New Drug by the FDA for AUD treatment.

15. Transcriptomics reveals activation of the interferon pathway across multiple brain regions in the chronic ethanol model of alcohol use disorder

15. Transcriptomics reveals activation of the interferon pathway across multiple brain regions in the chronic ethanol model of alcohol use disorder

Prefrontal cortex glutamatergic adaptations in a mouse model of alcohol use disorder

Alcohol use disorder (AUD) produces cognitive deficits, indicating a shift in prefrontal cortex (PFC) function. PFC glutamate neurotransmission is mostly mediated by α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic receptors (AMPARs); however preclinical studies have mostly focused on other receptor subtypes. Here we examined the impact of early withdrawal from chronic ethanol on AMPAR function in the mouse medial PFC (mPFC). Dependent male C57BL/6J mice were generated using the chronic intermittent ethanol vapor-two bottle choice (CIE-2BC) paradigm. Non-dependent mice had access to water and ethanol bottles but did not receive ethanol vapor. Naïve mice had no ethanol exposure. We used patch-clamp electrophysiology to measure glutamate neurotransmission in layer 2/3 prelimbic mPFC pyramidal neurons. Since AMPAR function can be impacted by subunit composition or plasticity-related proteins, we probed their mPFC expression levels. Dependent mice had higher spontaneous excitatory postsynaptic current (sEPSC) amplitude and kinetics compared to the Naïve/Non-dependent mice. These effects were seen during intoxication and after 3–8 days withdrawal, and were action potential-independent, suggesting direct enhancement of AMPAR function. Surprisingly, 3 days withdrawal decreased expression of genes encoding AMPAR subunits (Gria1/2) and synaptic plasticity proteins (Dlg4 and Grip1) in Dependent mice. Further analysis within the Dependent group revealed a negative correlation between Gria1 mRNA levels and ethanol intake. Collectively, these data establish a role for mPFC AMPAR adaptations in the glutamatergic dysfunction associated with ethanol dependence. Future studies on the underlying AMPAR plasticity mechanisms that promote alcohol reinforcement, seeking, drinking and relapse behavior may help identify new targets for AUD treatment.

Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence

IntroductionAlcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology.SummaryFimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

Why stigma matters in addressing alcohol harm.

Alcohol problems are amongst the most stigmatised of conditions, resulting in multiple additional harms for people with alcohol use disorder. Alcohol stigma encompasses widely endorsed negative stereotypes leading to prejudice and discrimination towards people with alcohol use disorder. Self-stigma further harms individuals through preventing and undermining recovery. The persistence of alcohol stigma highlights the limitations of an illness model of alcohol use disorder for stigma reduction; in fact, many groups inadvertently reinforce stigma by emphasising the artificial line between 'normal' drinkers and the pathologised 'alcoholic other'. A public health case for alcohol stigma reduction highlights the need to address this societal false dichotomisation of problem drinkers. Promoting a continuum-aligned model of alcohol use disorder, a dynamic model of responsibility, and other evidence-led approaches such as person-first language by key stakeholders are recommended.

90. Radioligand Binding to Phosphodiesterase-4B as an Indirect Measure of Camp Cascade in a Rat Model of Alcohol Use Disorder

90. Radioligand Binding to Phosphodiesterase-4B as an Indirect Measure of Camp Cascade in a Rat Model of Alcohol Use Disorder

Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist.

The low affinity metabotropic glutamate receptor mGluR7 has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR7 agonists. Of particular interest is the chromane CVN636, a potent (EC50 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR7 compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR7 and glutamatergic dysfunction.

Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder

Alcohol use disorders can be driven by negative reinforcement. Alterations of the microtubule cytoskeleton have been associated with mood regulation in the context of depression. Notably, MAP4343, a pregnenolone derivative known to promote tubulin assembly, has antidepressant properties. In the present study, we tested the hypothesis that MAP4343 may reduce excessive alcohol drinking in a mouse model of alcohol dependence by normalizing affect during withdrawal. Adult male C57BL/6J mice were given limited access to voluntary alcohol drinking and ethanol intake escalation was induced by chronic intermittent ethanol (CIE) vapor inhalation. Chronic, but not acute, administration of MAP4343 reduced ethanol intake and this effect was more pronounced in CIE-exposed mice. There was a complex interaction between the effects of MAP4343 and alcohol on affective behaviors. In the elevated plus maze, chronic MAP4343 tended to increase open-arm exploration in alcohol-naive mice but reduced it in alcohol-withdrawn mice. In the tail suspension test, chronic MAP4343 reduced immobility selectively in Air-exposed alcohol-drinking mice. Finally, chronic MAP4343 countered the plasma corticosterone reduction induced by CIE. Parallel analysis of tubulin post-translational modifications revealed lower α-tubulin acetylation in the medial prefrontal cortex of CIE-withdrawn mice. Altogether, these data support the relevance of microtubules as a therapeutic target for the treatment of AUD.

Alterations and correlations of gut microbiota, fecal, and serum metabolome characteristics in a rat model of alcohol use disorder.

Growing evidence suggests the gut microbiota and metabolites in serum or fecal may play a key role in the process of alcohol use disorder (AUD). However, the correlations of gut microbiota and metabolites in both feces and serum in AUD subjects are not well understood. We established a rat model of AUD by a chronic intermittent ethanol voluntary drinking procedure, then the AUD syndromes, the gut microbiota, metabolomic profiling in feces and serum of the rats were examined, and correlations between gut microbiota and metabolites were analyzed. Ethanol intake preference increased and maintained at a high level in experimental rats. Anxiety-like behaviors was observed by open field test and elevated plus maze test after ethanol withdraw, indicating that the AUD rat model was successfully developed. The full length 16S rRNA gene sequencing showed AUD significantly changed the β-diversity of gut microbial communities, and significantly decreased the microbial diversity but did not distinctly impact the microbial richness. Microbiota composition significantly changed in AUD rats, such as the abundance of Romboutsia and Turicibacter were significantly increased, whereas uncultured_bacterium_o_Mollicutes_RF39 was decreased. In addition, the untargeted metabolome analysis revealed that many metabolites in both feces and serum were altered in the AUD rats, especially involved in sphingolipid metabolism and glycerophospholipid metabolism pathways. Finally, multiple correlations among AUD behavior, gut microbiota and co-changed metabolites were identified, and the metabolites were directly correlated with the gut microbiota and alcohol preference. The altered metabolites in feces and serum are important links between the gut microbiota dysbiosis and alcohol preference in AUD rats, and the altered gut microbiota and metabolites can be potentially new targets for treating AUD.

The effects of acamprosate on maternal and neonatal outcomes in a mouse model of alcohol use disorders

BackgroundDespite the teratogenic effects of alcohol, little is known about the safety of pharmacotherapies such as acamprosate for the treatment of alcohol use disorders in pregnancy. The aims of this study were to investigate, in a mouse model, the effects of maternally administered acamprosate on maternal and neonatal health, offspring neurodevelopment and behaviour, as well as examine whether acamprosate reduces the neurological harm associated with alcohol consumption in pregnancy. MethodsDams were randomly allocated to one of four treatment groups: (i) control (water), (ii) acamprosate (1.6 g/L), (iii) alcohol (5% v/v) or (iv) acamprosate and alcohol (1.6 g/L; 5% v/v ethanol) and exposed from 2-weeks pre-pregnancy until postpartum day 7. Gestational outcomes including litter size and sex ratio were assessed, in addition to early-life markers of neurodevelopment. At 8 weeks of age, motor coordination, anxiety, locomotion, and memory of the adult offspring were also examined. ResultsExposure to acamprosate did not affect maternal and birth outcomes (mating success, gestational weight gain, litter size, sex ratio), neonatal outcomes (head and body length, postnatal weight) or neurodevelopmental markers (righting reflex and negative geotaxis). Acamprosate exposure did not affect offspring motor control, locomotion or anxiety, however the effects on short-term memory remain uncertain. Prenatal alcohol exposed offspring exhibited various alterations, such as lower postnatal weight, smaller head (p = 0.04) and body lengths (p = 0.046) at postnatal day 70 (males only), increased negative geotaxis speed (p = 0.03), an increased time spent in the inner zone of the open field (p = 0.02). Acamprosate mitigated the effects of alcohol for negative geotaxis at postnatal day 7 (p = 0.01) and female offspring weight at postnatal day 70 (p = 0.03). ConclusionsOverall, we show that prenatal acamprosate exposure was not associated with poor maternal or neonatal health outcomes or impaired neurodevelopment and behaviour. However, acamprosate's effects on short-term memory remain uncertain. We present preliminary evidence to suggest acamprosate displayed some neuroprotective effects against damage caused by in utero alcohol exposure.

Impaired synaptic transmission in dorsal dentate gyrus increases impulsive alcohol seeking

Both human and animal studies indicate that the dentate gyrus (DG) of the hippocampus is highly exploited by drug and alcohol abuse. Yet, it is poorly understood how DG dysfunction affects addiction-related behaviors. Here, we used an animal model of alcohol use disorder (AUD) in automated IntelliCages and performed local genetic manipulation to investigate how synaptic transmission in the dorsal DG (dDG) affects alcohol-related behaviors. We show that a cue light induces potentiation-like plasticity of dDG synapses in alcohol-naive mice. This process is impaired in mice trained to drink alcohol. Acamprosate (ACA), a drug that reduces alcohol relapse, rescues the impairment of dDG synaptic transmission in alcohol mice. A molecular manipulation that reduces dDG synaptic AMPAR and NMDAR levels increases impulsive alcohol seeking during cue relapse (CR) in alcohol mice but does not affect alcohol reward, motivation or craving. These findings suggest that hindered dDG synaptic transmission specifically underlies impulsive alcohol seeking induced by alcohol cues, a core symptom of AUD.

Role of inflammation in alcohol-related brain abnormalities: a translational study.

Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver–brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an in vivo neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out ex vivo neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage.

An integrated multimodal model of alcohol use disorder generated by data-driven causal discovery analysis

Alcohol use disorder (AUD) has high prevalence and adverse societal impacts, but our understanding of the factors driving AUD is hampered by a lack of studies that describe the complex neurobehavioral mechanisms driving AUD. We analyzed causal pathways to AUD severity using Causal Discovery Analysis (CDA) with data from the Human Connectome Project (HCP; n = 926 [54% female], 22% AUD [37% female]). We applied exploratory factor analysis to parse the wide HCP phenotypic space (100 measures) into 18 underlying domains, and we assessed functional connectivity within 12 resting-state brain networks. We then employed data-driven CDA to generate a causal model relating phenotypic factors, fMRI network connectivity, and AUD symptom severity, which highlighted a limited set of causes of AUD. The model proposed a hierarchy with causal influence propagating from brain connectivity to cognition (fluid/crystalized cognition, language/math ability, & working memory) to social (agreeableness/social support) to affective/psychiatric function (negative affect, low conscientiousness/attention, externalizing symptoms) and ultimately AUD severity. Our data-driven model confirmed hypothesized influences of cognitive and affective factors on AUD, while underscoring that addiction models need to be expanded to highlight the importance of social factors, amongst others.

Profiling neuronal epigenomes in a mouse model of alcohol use disorder

Profiling neuronal epigenomes in a mouse model of alcohol use disorder

Targeting the subthalamic nucleus in a preclinical model of alcohol use disorder.

The subthalamic nucleus (STN) has only recently been considered to have a role in reward processing. In rats, inactivation of the STN by lesion or high-frequency stimulation (HFS) decreases motivation for cocaine but increases motivation for sucrose. For ethanol, the effect of STN lesion depends on the individual's baseline intake; decreasing motivation for ethanol in rats with lower ethanol intake, while increasing motivation for ethanol in rats with higher-but still limited-ethanol intake. However, the involvement of the STN in behaviour more closely resembling some aspects of alcohol use disorder has not been assessed. This study aimed to determine the effect of STN lesions on the escalation of ethanol intake, subsequent increases in the motivation to "work" for ethanol and the choice of ethanol over a non-drug alternative. We found that STN lesion prevented increases in ethanol intake observed during intermittent ethanol access and after a long period of ethanol privation. STN lesion also decreased the motivation to work for ethanol after escalated intake. Surprisingly, STN lesion increased the choice of alcohol over saccharin. This was associated with a blunting of the hedonic responses to the taste of the reinforcement alternatives. These results evidence the involvement of the STN in different ethanol-motivated behaviours and therefore position the STN as an interesting target for the treatment of alcohol use disorders.

The harmful dysfunction model of alcohol use disorder: revised criteria to improve the validity of diagnosis and prevalence estimates.

To formulate harmful dysfunction (HD) diagnostic criteria for alcohol use disorder (AUD) and test whether they increase validity relative to standard DSM criteria, as evidenced by lowered prevalence, increased validator levels including service use, severity and family history and enhanced specificity. DSM-IV AUD, DSM-IV dependence, DSM-5 AUD and HD AUD definitions were compared on eight validity related tests using nationally representative community data. United States. National Epidemiologic Survey of Alcoholism and Related Conditions (NESARC) respondents, aged 18-54 years (wave 1, n = 29 673; wave 2, n = 24 244). NESARC DSM-IV and DSM-5 criteria were taken from published studies. Whereas DSM-5 diagnosis requires any two AUD symptoms, HD criteria were constructed from NESARC items to require symptoms of both impaired-control dysfunction [withdrawal, drink to prevent/stop withdrawal, cannot stop/reduce drinking, or craving (wave 2 only)] and harm (sacrificed important activities, problems caring for home/family, job/school problems, health problems, psychological problems or problems with family/friends). Validators included service use, severity and family history, among others. Specificity was tested using a teen transient drinker criterion group. Compared with DSM-5 AUD (DSM-IV results were similar), HD criteria yielded lower prevalence (95% confidence intervals): HD life-time 6.7% (6.2, 7.2%), 1-year 2.3% (2.0, 2.5%); and DSM-5 life-time 38.2% (36.5, 39.9%), 1-year 12.4% (11.7, 13.1%). HD AUD was higher than DSM-5 on pathology validators, including: life-time alcohol-related service use: HD 41.0% (38.1, 43.9%), DSM-5 11.5% (10.7, 12.3%); severity (number of life-time alcohol symptoms): HD 20.8 (20.4, 21.2), DSM-5 10.6 (10.4, 10.8); and family history of alcohol problems: HD 50.1% (47.3, 52.9), DSM-5 32.8% (31.6, 34.0). HD criteria eliminated 83% of a DSM-5 teen transient drinker false-positives criterion group. Prevalence estimates of alcohol use disorder are lowered and diagnostic validity improved when using 'harmful dysfunction' diagnostic criteria compared with standard DSM criteria, partly by reducing misdiagnosis of teenage transient drinkers.

Alcohol inhibition of neurogenesis: A mechanism of hippocampal neurodegeneration in an adolescent alcohol abuse model

Adolescents diagnosed with an alcohol use disorder show neurodegeneration in the hippocampus, a region important for learning, memory, and mood regulation. This study examines a potential mechanism by which excessive alcohol intake, characteristic of an alcohol use disorder, produces neurodegeneration. As hippocampal neural stem cells underlie ongoing neurogenesis, a phenomenon that contributes to hippocampal structure and function, we investigated aspects of cell death and cell birth in an adolescent rat model of an alcohol use disorder. Immunohistochemistry of various markers along with Bromo-deoxy-Uridine (BrdU) injections were used to examine different aspects of neurogenesis. After 4 days of binge alcohol exposure, neurogenesis was decreased by 33 and 28% at 0 and 2 days after the last dose according to doublecortin expression. To determine whether this decrease in neurogenesis was due to effects on neural stem cell proliferation, quantification of BrdU-labeled cells revealed a 21% decrease in the dentate gyrus of alcohol-exposed brains. Cell survival and phenotype of BrdU-labeled cells were assessed 28 days after alcohol exposure and revealed a significant, 50% decrease in the number of surviving cells in the alcohol-exposed group. Reduced survival was supported by significant increases in the number of pyknotic-, FluoroJade B positive-, and TUNEL-positive cells. However, so few cells were TUNEL-positive that cell death is likely necrotic in this model. Although alcohol decreased the number of newborn cells, it did not affect the percentage of cells that matured into neurons (differentiation). Thus, our data support that in a model of an adolescent alcohol use disorder, neurogenesis is impaired by two mechanisms: alcohol-inhibition of neural stem cell proliferation and alcohol effects on new cell survival. Remarkably, alcohol inhibition of neurogenesis may outweigh the few dying cells per section, which implies that alcohol inhibition of neurogenesis contributes to hippocampal neurodegeneration in alcohol use disorders.