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Zakiniaeiz Y, Hillmer AT, Shi H, Pittman B, Nabulsi N, Huang Y, Bonomi R, Matuskey D, Angarita GA, McKee SA, Cosgrove KP. Greater neuroimmune system deficit in women than men with alcohol use disorder. Biol Psychiatry 2025:S0006-3223(25)01196-5. [PMID: 40412787 DOI: 10.1016/j.biopsych.2025.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 05/13/2025] [Accepted: 05/17/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Women who drink are more vulnerable than men to many of the consequences of alcohol use, including alcohol-related cancers, cardiovascular disease, liver cirrhosis, and immune system dysfunction. Acute alcohol triggers neuroimmune cells including microglia, the brain's resident immune cells. Excessive activation can contribute to neuronal dysfunction and alcohol-induced neurodegeneration. Women have a greater vulnerability to alcohol-induced neurodegeneration, thus, there is a critical need to examine sex differences in neuroimmune mechanisms underlying AUD to inform novel treatment strategies for women. METHODS Forty-one individuals with mild-to-moderate AUD (20 women) and 37 sex-matched controls completed one positron emission tomography brain imaging scan with the radiotracer [11C]PBR28, which binds to 18-kDa translocator protein (TSPO), a microglial marker. Volume of distribution was estimated regionally in the cerebellum, hippocampus, striatum, and frontal cortex as a measure of TSPO availability. Neurocognitive function was also assessed. RESULTS People with versus without AUD had significant lower TSPO availability in all brain regions. Women (but not men) with AUD had significantly lower TSPO availability (average of 21%) in all four regions (p=0.022) compared to sex-matched controls. Women with vs. without AUD performed worse on executive function (p=0.020). Lower hippocampal (p=0.059) and cerebellar (p=0.097) TSPO availability were trendingly related to more errors on the executive function task in women with AUD. CONCLUSIONS This study showed lower TSPO levels in people with mild-to-moderate AUD versus controls, and demonstrated that the deficit is significantly greater in women than men with AUD. This suggests that women with AUD may particularly benefit from novel neuroimmune-modulating treatments for AUD.
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Affiliation(s)
| | - Ansel T Hillmer
- Department of Psychiatry, Yale University, New Haven, CT; Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT
| | - Hannah Shi
- Yale College, Yale University, New Haven, CT
| | - Brian Pittman
- Department of Psychiatry, Yale University, New Haven, CT
| | - Nabeel Nabulsi
- Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT
| | - Yiyun Huang
- Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT
| | - Robin Bonomi
- Department of Psychiatry, Yale University, New Haven, CT
| | - David Matuskey
- Department of Psychiatry, Yale University, New Haven, CT; Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT
| | | | - Sherry A McKee
- Department of Psychiatry, Yale University, New Haven, CT
| | - Kelly P Cosgrove
- Department of Psychiatry, Yale University, New Haven, CT; Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT
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Gottlieb S, Zeliff D, O'Rourke B, Rogers WD, Miles MF. GSK3B inhibition partially reverses brain ethanol-induced transcriptomic changes in C57BL/6J mice: Expression network co-analysis with human genome-wide association studies. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.03.647116. [PMID: 40235963 PMCID: PMC11996488 DOI: 10.1101/2025.04.03.647116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Alcohol use disorder (AUD) is a chronic behavioral disease with greater than 50% of its risk due to complex genetic contributions. Existing pharmacological and behavioral treatments for AUD are minimally effective and underutilized. Animal model behavioral genetics and human genome-wide association studies have begun to identify individual genes contributing to the progressive compulsive consumption of ethanol that occurs with AUD, promising possible new therapeutic targets. Our laboratory has previously identified Gsk3b as a central member in a network of ethanol-responsive genes in mouse prefrontal cortex, which altered ethanol consumption with genetic manipulation and was also significantly associated with risk for alcohol dependence in human genome-wide association studies. Here we perform detailed brain RNA sequencing transcriptomic studies to characterize a highly specific and clinically available GSK3B pharmacological inhibitor, tideglusib, as a possible therapeutic for clinical trials on treatment of AUD. A model of chronic intermittent ethanol consumption was used to study gene expression changes in prefrontal cortex and nucleus accumbens in the presence or absence of tideglusib treatment. Multivariate analysis of differentially expressed genes showed that tideglusib largely reversed ethanol- induced expression changes for two prominent clusters of genes in both prefrontal cortex and nucleus accumbens. Bioinformatic analysis showed these genes to have prominent roles in neuronal functioning and synaptic activity. Additionally, mouse brain differential gene expression data was analyzed together with human protein-protein interaction and genome-wide association studies on AUD to derive networks responding to tideglusib and relevant to human genetic risk for alcohol dependence. These studies identified discrete networks significantly enriched with genes provisionally associated with AUD, and provide key information on central hubs of such networks. Together these studies document tideglusib as a major modulator of chronic ethanol consumption-evoked brain gene expression signatures, and identify possible new targets for therapeutic modulation of AUD.
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Quelch D, Lingford-Hughes A, John B, Nutt D, Bradberry S, Roderique-Davies G. Promising strategies for the prevention of alcohol-related brain damage through optimised management of acute alcohol withdrawal: A focussed literature review. J Psychopharmacol 2024:2698811241294005. [PMID: 39529219 DOI: 10.1177/02698811241294005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
There is an increasing awareness of the link between chronic alcohol consumption and the development of cognitive, behavioural and functional deficits. Currently, preventative strategies are limited and require engagement in dedicated long-term rehabilitation and sobriety services, the availability of which is low. The acute alcohol withdrawal syndrome is an episode of neurochemical imbalance leading to autonomic dysregulation, increased seizure risk and cognitive disorientation. In addition to harm from symptoms of alcohol withdrawal (e.g. seizures), the underpinning neurochemical changes may also lead to cytotoxicity through various cellular mechanisms, which long-term, may translate to some of the cognitive impairments observed in Alcohol-Related Brain Damage (ARBD). Here we review some of the pharmacological and neurochemical mechanisms underpinning alcohol withdrawal. We discuss the cellular and pharmacological basis of various potential neuroprotective strategies that warrant further exploration in clinical populations with a view to preventing the development of ARBD. Such strategies, when integrated into the clinical management of acute alcohol withdrawal, may impact large populations of individuals, who currently face limited dedicated service delivery and healthcare resource.
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Affiliation(s)
- Darren Quelch
- Addictions Research Group, Applied Psychology Research and Innovation Group, Faculty of Life Sciences and Education, University of South Wales, Pontypridd, UK
- Alcohol Care Team and Clinical Toxicology Service, Sandwell and West-Birmingham NHS Trust, City Hospital, Birmingham, UK
| | - Anne Lingford-Hughes
- Centre for Neuropsychopharmacology, Division of Psychiatry, Imperial College London, Hammersmith Hospital, London, UK
| | - Bev John
- Addictions Research Group, Applied Psychology Research and Innovation Group, Faculty of Life Sciences and Education, University of South Wales, Pontypridd, UK
| | - David Nutt
- Centre for Neuropsychopharmacology, Division of Psychiatry, Imperial College London, Hammersmith Hospital, London, UK
| | - Sally Bradberry
- Addictions Research Group, Applied Psychology Research and Innovation Group, Faculty of Life Sciences and Education, University of South Wales, Pontypridd, UK
- Alcohol Care Team and Clinical Toxicology Service, Sandwell and West-Birmingham NHS Trust, City Hospital, Birmingham, UK
| | - Gareth Roderique-Davies
- Addictions Research Group, Applied Psychology Research and Innovation Group, Faculty of Life Sciences and Education, University of South Wales, Pontypridd, UK
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4
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Chun MY, An H, Lee HA, Hwang S, Chung S, Kim NY, Lee HW. Clinical characteristics of seizure recurrence and epilepsy development in patients with alcohol-related seizures. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:2113-2125. [PMID: 39333025 DOI: 10.1111/acer.15449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 09/05/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND Alcohol withdrawal is widely recognized as a trigger for acute symptomatic seizures among individuals with chronic alcohol consumption. While most alcohol withdrawal seizures occur shortly after cessation, chronic alcohol consumption can be associated with the development of epilepsy, necessitating anti-epileptic drug (AED) therapy. This study aimed to investigate the clinical characteristics, seizure recurrence, and epilepsy development in patients with alcohol-related seizures and to identify prognostic factors for epilepsy. METHODS In a retrospective analysis at Ewha Womans University Mokdong Hospital, 206 patients with alcohol-related seizures were examined and 15 were excluded due to preexisting epilepsy. Demographic and clinical data, including alcohol withdrawal duration, seizure recurrence, types, and comorbidities, were investigated. Logistic regression models were used to analyze the risk factors for seizure recurrence and epilepsy development. The performance of the final models was evaluated based on the area under the receiver operating characteristic curve (AUC) and validated using calibration plots and leave-one-out cross-validation. RESULTS Of the 191 patients (146 males; mean age 48.3 ± 12.1 years) with alcohol-related seizures, 99 patients (51.8%) experienced seizure recurrence and 79 patients (41.4%) developed epilepsy. Factors associated with seizure recurrence included alcohol consumption levels, occurrence of focal impaired awareness seizure, anxiety, and headache. The number of recurrent seizures, semiology, status epilepticus, electroencephalogram findings, and brain imaging findings was associated with epilepsy development. The predictive models showed strong diagnostic performance, with AUCs of 0.833 for seizure recurrence and 0.939 for epilepsy development. CONCLUSION High alcohol consumption and specific clinical and diagnostic features are significant predictors of seizure recurrence and the development of epilepsy among patients with alcohol-related seizures. These findings underscore the importance of early identification and intervention to prevent seizure recurrence and the onset of epilepsy, emphasizing the importance of AED treatment in managing these conditions.
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Affiliation(s)
- Min Young Chun
- Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, South Korea
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
- Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin, South Korea
| | - Hyungmi An
- Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, South Korea
| | - Hye Ah Lee
- Clinical Trial Center, Ewha Womans University Mokdong Hospital, Seoul, South Korea
| | - Sungeun Hwang
- Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, South Korea
| | - Seungwon Chung
- Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, South Korea
| | - Na-Young Kim
- Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, South Korea
| | - Hyang Woon Lee
- Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, South Korea
- Neurology and Medical Science, Ewha Womans University School of Medicine and Ewha Medical Research Institute, Seoul, South Korea
- Computational Medicine, System Health Science & Engineering, Ewha Womans University, Seoul, South Korea
- Artificial Intelligence Convergence Graduate Programs, Ewha Womans University, Seoul, South Korea
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5
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Kaye AD, Staser AN, Mccollins TS, Zheng J, Berry FA, Burroughs CR, Heisler M, Mouhaffel A, Ahmadzadeh S, Kaye AM, Shekoohi S, Varrassi G. Delirium Tremens: A Review of Clinical Studies. Cureus 2024; 16:e57601. [PMID: 38707114 PMCID: PMC11069634 DOI: 10.7759/cureus.57601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 04/03/2024] [Indexed: 05/07/2024] Open
Abstract
Delirium tremens (DT) is a severe condition resulting from alcohol withdrawal. This review highlights the challenges in diagnosing and managing DT and emphasizes the importance of early recognition and intervention to prevent complications and ensure optimal patient outcomes. The discussion of the pathophysiology of DT, focusing on the neurochemical imbalances involving the neurotransmitters gamma-aminobutyric acid and glutamate, explains how chronic alcohol dependence leads to these imbalances and contributes to the hyperexcitability seen in DT. The management of DT involves ensuring patient safety and alleviating symptoms, primarily through pharmacological approaches, such as benzodiazepines. Closely monitoring vital signs and electrolyte imbalances is necessary due to autonomic dysregulation associated with DT. The mention of the potential complexity of DT when coexisting with other conditions emphasizes the need for additional research to advance comprehension, identify predictive factors, and enhance its management.
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Affiliation(s)
- Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Amanda N Staser
- Department of Medicine, Ross University School of Medicine, Miramar, USA
| | | | - Jackson Zheng
- School of Medicine, American University of the Caribbean, Miramar, USA
| | - Fouad A Berry
- School of Medicine, American University of the Caribbean, Miramar, USA
| | - Caroline R Burroughs
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Michael Heisler
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Aya Mouhaffel
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Shahab Ahmadzadeh
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Adam M Kaye
- Department of Pharmacy Practice, Thomas J. Long School of Pharmacy and Health Sciences University of the Pacific, Stockton, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
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Liang Z, Qiu L, Lou Y, Zheng Z, Guo Q, Zhao Q, Liu S. Causal relationship between addictive behaviors and epilepsy risk: A mendelian randomization study. Epilepsy Behav 2023; 147:109443. [PMID: 37729683 DOI: 10.1016/j.yebeh.2023.109443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/27/2023] [Accepted: 09/05/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND Previous studies have reported inconsistent results regarding the potential relationships between addictive behaviors and the risk of epilepsy. OBJECTIVE To assess whether genetically predicted addictive behaviors are causally associated with the risk of epilepsy outcomes. METHODS The causation between five addictive behaviors (including cigarettes per day, alcoholic drinks per week, tea intake, coffee intake, and lifetime cannabis use) and epilepsy was evaluated by using a two-sample Mendelian Randomization (MR) analysis. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (MR Egger, weighted median, simulation extrapolation corrected MR-Egger, and Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO)) were performed to complement IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis. RESULTS The IVW analysis method indicated an approximately 20% increased risk of epilepsy per standard deviation increase in lifetime cannabis use (odds ratio [OR], 1.20; 95% confidence interval [CI]), 1.02-1.42, P = 0.028). However, there is no causal association between the other four addictive behaviors and the risk of epilepsy (cigarettes per day: OR, 1.04; 95% CI, 0.92-1.18, P = 0.53; alcoholic drinks per week: OR, 1.31; 95% CI, 0.93-1.84, P = 0.13; tea intake: OR, 1.15; 95% CI, 0.84-1.56, P = 0.39; coffee intake: OR, 0.86; 95% CI, 0.59-1.23, P = 0.41). The other MR analysis methods and further leave-one-out sensitivity analysis suggested the results were robust. CONCLUSION This MR study indicated a potential genetically predicted causal association between lifetime cannabis use and higher risk of epilepsy. As for the other four addictive behaviors, no evidence of a causal relationship with the risk of epilepsy was found in this study.
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Affiliation(s)
- Zhen Liang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Lin Qiu
- Department of South Lake Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yingyue Lou
- Department of Rehabilitation, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Zhaoshi Zheng
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Qi Guo
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Qing Zhao
- Department of South Lake Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Songyan Liu
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China.
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Petrie J, Kowallis LR, Kamhout S, Bills KB, Adams D, Fleming DE, Brown BL, Steffensen SC. Gender-Specific Interactions in a Visual Object Recognition Task in Persons with Opioid Use Disorder. Biomedicines 2023; 11:2460. [PMID: 37760905 PMCID: PMC10525754 DOI: 10.3390/biomedicines11092460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/26/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Opioid use disorder (OUD)-associated overdose deaths have reached epidemic proportions worldwide over the past two decades, with death rates for men reported at twice the rate for women. Using a controlled, cross-sectional, age-matched (18-56 y) design to better understand the cognitive neuroscience of OUD, we evaluated the electroencephalographic (EEG) responses of male and female participants with OUD vs. age- and gender-matched non-OUD controls during a simple visual object recognition Go/No-Go task. Overall, women had significantly slower reaction times (RTs) than men. In addition, EEG N200 and P300 event-related potential (ERP) amplitudes for non-OUD controls were significantly larger for men, while their latencies were significantly shorter than for women. However, while N200 and P300 amplitudes were not significantly affected by OUD for either men or women in this task, latencies were also affected differentially in men vs. women with OUD. Accordingly, for both N200 and P300, male OUD participants exhibited longer latencies while female OUD participants exhibited shorter ones than in non-OUD controls. Additionally, robust oscillations were found in all participants during a feedback message associated with performance in the task. Although alpha and beta power during the feedback message were significantly greater for men than women overall, both alpha and beta oscillations exhibited significantly lower power in all participants with OUD. Taken together, these findings suggest important gender by OUD differences in cognitive processing and reflection of performance in this simple visual task.
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Affiliation(s)
- JoAnn Petrie
- Department of Psychology, Brigham Young University, Provo, UT 84602, USA; (J.P.); (K.B.B.)
| | - Logan R. Kowallis
- Department of Psychology, Brigham Young University, Provo, UT 84602, USA; (J.P.); (K.B.B.)
| | - Sarah Kamhout
- Department of Psychology, Brigham Young University, Provo, UT 84602, USA; (J.P.); (K.B.B.)
| | - Kyle B. Bills
- Department of Psychology, Brigham Young University, Provo, UT 84602, USA; (J.P.); (K.B.B.)
- Department of Neuroscience, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA
| | - Daniel Adams
- PhotoPharmics, Inc., 947 So, 500 E, Suite 100, American Fork, UT 84003, USA
| | - Donovan E. Fleming
- Department of Psychology, Brigham Young University, Provo, UT 84602, USA; (J.P.); (K.B.B.)
| | - Bruce L. Brown
- Department of Psychology, Brigham Young University, Provo, UT 84602, USA; (J.P.); (K.B.B.)
| | - Scott C. Steffensen
- Department of Psychology, Brigham Young University, Provo, UT 84602, USA; (J.P.); (K.B.B.)
- Department of Neuroscience, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA
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8
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Day E, Daly C. Clinical management of the alcohol withdrawal syndrome. Addiction 2022; 117:804-814. [PMID: 34288186 DOI: 10.1111/add.15647] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023]
Abstract
Up to half of individuals with a history of long-term, heavy alcohol consumption will experience the alcohol withdrawal syndrome (AWS) when consumption is significantly decreased or stopped. In its most severe form, AWS can be life-threatening. Medically assisted withdrawal (MAW) often forms the first part of a treatment pathway. This clinical review discusses key elements of the clinical management of MAW, necessary adjustments for pregnancy and older adults, likely outcome of an episode of MAW, factors that might prevent completion of the MAW process and ways of overcoming barriers to ongoing treatment of alcohol use disorder. The review also discusses the use of benzodiazepines in MAW. Although there is clear evidence for their use, benzodiazepines have been associated with abuse liability, blunting of cognition, interactions with depressant drugs, craving, delirium, dementia and disrupted sleep patterns. Because glutamatergic activation and glutamate receptor upregulation contribute to alcohol withdrawal, anti-glutamatergic strategies for MAW and other potential treatment innovations are also considered.
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Affiliation(s)
- Ed Day
- Addiction Psychiatry, Institute for Mental Health, School of Psychology, University of Birmingham, Edgbaston, Birmingham, UK
| | - Chris Daly
- Addiction Psychiatry, Greater Manchester Mental Health FT, Chapman Barker Unit, Prestwich Hospital, Manchester, UK
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9
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Steel TL, Afshar M, Edwards S, Jolley SE, Timko C, Clark BJ, Douglas IS, Dzierba AL, Gershengorn HB, Gilpin NW, Godwin DW, Hough CL, Maldonado JR, Mehta AB, Nelson LS, Patel MB, Rastegar DA, Stollings JL, Tabakoff B, Tate JA, Wong A, Burnham EL. Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med 2021; 204:e61-e87. [PMID: 34609257 PMCID: PMC8528516 DOI: 10.1164/rccm.202108-1845st] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.
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10
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Ooms M, Roozen HG, Willering JH, Zijlstra WP, de Waart R, Goudriaan AE. Effects of Multiple Detoxifications on Withdrawal Symptoms, Psychiatric Distress and Alcohol-Craving in Patients with an Alcohol Use Disorder. Behav Med 2021; 47:296-310. [PMID: 32396039 DOI: 10.1080/08964289.2020.1760777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Previous studies have shown an association between the number of withdrawal attempts and increased severity of withdrawal symptoms in patients with an alcohol use disorder (AUD). An underlying allostatic neuroadaptive response may negatively affect the withdrawal pathology after alcohol discontinuation. The objective of the present research is to examine the intensification of psychiatric distress, craving, and post-detoxification drinking outcomes, which may result from these neurobehavioral alternations. Fifty-two AUD inpatients were divided into two groups: <2 previous detoxifications and ≥2 previous detoxifications. Patients completed the Dutch version of the Severity of Withdrawal Scale (SWS), Depression Anxiety Stress Scales (DASS-21), VAS Craving, and Desires for Alcohol Questionnaire (DAQ). Linear mixed effects models were applied, controlling for the number of drinks consumed in the past 30 days and alcohol drinking history (years). Patients who had undergone ≥2 detoxifications reported statistically significantly higher scores on SWS withdrawal and DASS psychiatric symptoms. Also, craving patterns were different between groups, as shown by a statistically significant interaction effect for VAS craving for the time of day factor (morning vs. evening). No statistically significant group differences were found for DAQ scores and post-detoxification drinking outcomes. Due to relatively low 1-month follow-up rates our power was limited to detect such a difference. The present study contributes to the existing body of evidence that multiple detoxifications are associated with aggravated withdrawal/psychiatric pathology, and distinct diurnal patterns of VAS craving. Several clinical implications are discussed and alternative strategies are provided to manage repeated cycles of detoxifications.
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Affiliation(s)
- Martha Ooms
- Centrum voor Transculturele Psychiatrie (CTP) Veldzicht, Balkbrug, ZG, The Netherlands
| | - Hendrik G Roozen
- Center on Alcoholism, Substance Abuse, and Addictions (CASAA), University of New Mexico, The University of New Mexico (UNM), Albuquerque, NM, USA
| | - Juul H Willering
- Altrecht Centrum Psychodiagnostiek, Centrum Psychodiagnostiek, Zeist, WB, The Netherlands
| | - Wobbe P Zijlstra
- CITO, Department of Psychometrics and Research, Arnhem, CM, The Netherlands
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11
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Kipp BT, Nunes PT, Savage LM. Sex differences in cholinergic circuits and behavioral disruptions following chronic ethanol exposure with and without thiamine deficiency. Alcohol Clin Exp Res 2021; 45:1013-1027. [PMID: 33690917 DOI: 10.1111/acer.14594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Few studies have investigated differences in the vulnerabilities of males and females to alcohol use disorder and alcohol-related brain damage (ARBD). According to epidemiological and clinical findings, females appear to be more sensitive to the effects of alcohol and thiamine deficiency and have a worse prognosis in recovery from neurocognitive deficits compared with males. This study aimed to characterize the effects of chronic ethanol (EtOH) toxicity and thiamine deficiency across the sexes using rodent models. METHODS Male and female Sprague Dawley rats were assigned to chronic forced EtOH treatment (CET), pyrithiamine-induced thiamine deficiency (PTD), combined CET-PTD, or pair-fed (PF) control treatment conditions. Following treatments, spatial working memory was assessed during a spontaneous alternation task while measuring acetylcholine (ACh) in the prefrontal cortex (PFC) and the hippocampus (HPC). The animals also underwent an operant-based attentional set-shifting task (ASST) for the analysis of behavioral flexibility. RESULTS Female and male rats did not differ in terms of EtOH consumption; however, the CET and CET-PTD-treated female rats had lower BECs than male rats. Compared with the PF group, the CET, PTD, and CET-PTD groups exhibited spatial working memory impairments with corresponding reductions in ACh efflux in the PFC and HPC. The ASST revealed that CET-PTD-treated males and females displayed impairments marked by increased latency to make decisions. Thalamic shrinkage was prominent only in the CET-PTD and PTD treatment conditions, but no sex-specific effects were observed. CONCLUSIONS Although the CET and CET-PTD-treated females had lower BECs than the males, they demonstrated similar cognitive impairments. These results provide evidence that female rats experience behavioral and neurochemical disruptions at lower levels of alcohol exposure than males and that chronic EtOH and thiamine deficiencies produce a unique behavioral profile.
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Affiliation(s)
- Brian T Kipp
- Department of Psychology, Binghamton University of the State University of New York, New York, NY, USA
| | - Polliana T Nunes
- Department of Psychology, Binghamton University of the State University of New York, New York, NY, USA
| | - Lisa M Savage
- Department of Psychology, Binghamton University of the State University of New York, New York, NY, USA
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12
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Alcohol. Alcohol 2021. [DOI: 10.1016/b978-0-12-816793-9.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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13
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Cui B, Wei L, Sun LY, Qu W, Zeng ZG, Liu Y, Zhu ZJ. Status epilepticus as an initial manifestation of hepatic encephalopathy: A case report. World J Clin Cases 2020; 8:6480-6486. [PMID: 33392334 PMCID: PMC7760455 DOI: 10.12998/wjcc.v8.i24.6480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 09/28/2020] [Accepted: 10/20/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Status epilepticus in patients with hepatic encephalopathy (HE) is a rare but serious condition that is refractory to antiepileptic drugs, and current treatment plans are vague. Diagnosis may be difficult without a clear history of cirrhosis. Liver transplantation (LT) is effective to alleviate symptoms, however, there are few reports about LT in the treatment of status epilepticus with HE. To our knowledge, this is the first report of status epilepticus present as initial manifestation of HE.
CASE SUMMARY A 59-year-old woman with a 20-year history of heavy drinking was hospitalized for generalized tonic-clonic seizures. She reported no history of episodes of HE, stroke, spontaneous bacterial peritonitis, ascites or gastrointestinal bleeding. Neurological examination revealed a comatose patient, without papilledema. Laboratory examination suggested liver cirrhosis. Plasma ammonia levels upon admission were five times normal. Brain computed tomography (CT) was normal, while abdominal CT and ultrasound revealed mild ascites, liver cirrhosis and splenomegaly. Electroencephalography (EEG)showed diffuse slow waves rhythm, consistent with HE, and sharp waves during ictal EEG corresponding to clinical semiology of focal tonic seizures. The symptoms were reversed by continuous antiepileptic treatment and lactulose. She was given oral levetiracetam, and focal aware seizures occasionally affected her 10 mo after LT.
CONCLUSION Status epilepticus could be an initial manifestation of HE. Antiepileptic drugs combined with lactulose are essential for treatment of status epilepticus with HE, and LT is effective to prevent the relapse.
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Affiliation(s)
- Bin Cui
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Lin Wei
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Li-Ying Sun
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Wei Qu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zhi-Gui Zeng
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Ying Liu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zhi-Jun Zhu
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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14
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Rosoff DB, Charlet K, Jung J, Lee J, Muench C, Luo A, Longley M, Lohoff FW. Lipid profile dysregulation predicts alcohol withdrawal symptom severity in individuals with alcohol use disorder. Alcohol 2020; 86:93-101. [PMID: 32335269 PMCID: PMC7486690 DOI: 10.1016/j.alcohol.2020.02.164] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 02/07/2020] [Accepted: 02/13/2020] [Indexed: 12/21/2022]
Abstract
Alcohol withdrawal syndrome (AWS) is a serious medical condition of high variability in alcohol use disorder (AUD) after drinking cessation. Identification of clinical biomarkers capable of detecting severe AWS is needed. While alcohol consumption and withdrawal are linked with lipid profile dysregulation, the relationship between lipid levels (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) and AWS is unknown. Therefore, this study investigated whether HDL-C, LDL-C, and triglycerides conferred risk for moderate-to-severe AWS symptoms in treatment-seeking individuals (n = 732) admitted to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcohol treatment program. Lipid levels were measured upon admission, and the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) assessed AWS severity for generating a three-level AWS typology (none-to-mild, moderate, and severe). Multivariable multinomial logistic regression examined whether lipid levels were associated with risk for moderate-to-severe AWS. We found significant predictive relationships between AWS and HDL-C, LDL-C, and triglycerides. While extremely high HDL-C (≥100 mg/dL) conferred the highest odds for moderate (4.405, 95% CI, 2.572-7.546, p < 0.001) and severe AWS (5.494, 95% CI, 3.541-8.523, p < 0.001), the lowest odds ratios for moderate AWS (0.493, 95% CI, 0.248-0.981, p = 0.044) and severe AWS (0.303, 95% CI, 0.223-0.411, p < 0.001) were associated with high LDL-C (≥160 mg/dL). The present study demonstrates that altered lipid levels, measured upon admission for inpatient AUD treatment, may help to predict which individuals are at risk for medically relevant moderate-to-severe AWS. This suggests that further research into the role of lipid biomarkers in AWS may be beneficial for identifying biologically determined risk profiles in AUD.
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Affiliation(s)
- Daniel B Rosoff
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
| | - Katrin Charlet
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
| | - Jeesun Jung
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
| | - Jisoo Lee
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
| | - Christine Muench
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
| | - Audrey Luo
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
| | - Martha Longley
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
| | - Falk W Lohoff
- Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States.
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15
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Zahr NM, Lenart AM, Karpf JA, Casey KM, Pohl KM, Sullivan EV, Pfefferbaum A. Multi-modal imaging reveals differential brain volumetric, biochemical, and white matter fiber responsivity to repeated intermittent ethanol vapor exposure in male and female rats. Neuropharmacology 2020; 170:108066. [PMID: 32240669 DOI: 10.1016/j.neuropharm.2020.108066] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/09/2020] [Accepted: 03/20/2020] [Indexed: 12/11/2022]
Abstract
A generally accepted framework derived predominately from animal models asserts that repeated cycles of chronic intermittent ethanol (EtOH; CIE) exposure cause progressive brain adaptations associated with anxiety and stress that promote voluntary drinking, alcohol dependence, and further brain changes that contribute to the pathogenesis of alcoholism. The current study used CIE exposure via vapor chambers to test the hypothesis that repeated episodes of withdrawals from chronic EtOH would be associated with accrual of brain damage as quantified using in vivo magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and MR spectroscopy (MRS). The initial study group included 16 male (~325g) and 16 female (~215g) wild-type Wistar rats exposed to 3 cycles of 1-month in vapor chambers + 1 week of abstinence. Half of each group (n = 8) was given vaporized EtOH to blood alcohol levels approaching 250 mg/dL. Blood and behavior markers were also quantified. There was no evidence for dependence (i.e., increased voluntary EtOH consumption), increased anxiety, or an accumulation of pathology. Neuroimaging brain responses to exposure included increased cerebrospinal fluid (CSF) and decreased gray matter volumes, increased Choline/Creatine, and reduced fimbria-fornix fractional anisotropy (FA) with recovery seen after one or more cycles and effects in female more prominent than in male rats. These results show transient brain integrity changes in response to CIE sufficient to induce acute withdrawal but without evidence for cumulative or escalating damage. Together, the current study suggests that nutrition, age, and sex should be considered when modeling human alcoholism.
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Affiliation(s)
- Natalie M Zahr
- Neuroscience Program, SRI International, Menlo Park, CA, 94025, USA; Department of Psychiatry & Behavioral Sciences, Stanford University, School of Medicine, Stanford, CA, 94305, USA.
| | - Aran M Lenart
- Neuroscience Program, SRI International, Menlo Park, CA, 94025, USA
| | - Joshua A Karpf
- Neuroscience Program, SRI International, Menlo Park, CA, 94025, USA
| | - Keriann M Casey
- Department of Comparative Medicine, Stanford University, School of Medicine, Stanford, CA. 94305, USA
| | - Kilian M Pohl
- Neuroscience Program, SRI International, Menlo Park, CA, 94025, USA; Department of Psychiatry & Behavioral Sciences, Stanford University, School of Medicine, Stanford, CA, 94305, USA
| | - Edith V Sullivan
- Department of Psychiatry & Behavioral Sciences, Stanford University, School of Medicine, Stanford, CA, 94305, USA
| | - Adolf Pfefferbaum
- Neuroscience Program, SRI International, Menlo Park, CA, 94025, USA; Department of Psychiatry & Behavioral Sciences, Stanford University, School of Medicine, Stanford, CA, 94305, USA
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16
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Spear LP. Timing Eclipses Amount: The Critical Importance of Intermittency in Alcohol Exposure Effects. Alcohol Clin Exp Res 2020; 44:806-813. [PMID: 32056231 DOI: 10.1111/acer.14307] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 02/06/2020] [Indexed: 12/28/2022]
Abstract
Frequency and duration of ethanol (EtOH) exposures influence the consequences of those experiences, with evidence building from basic science studies in rats and mice that intermittent alcohol access (IAA) typically produces a greater escalation of EtOH intake than more continuous alcohol access (CAA). IAA also better simulates human use patterns where alcohol levels typically clear from the body between periods of use. A variety of mechanisms have been proposed to contribute to the enhanced intake of EtOH induced by IAA, including a possible attenuation in the aversive effects of EtOH, although further studies are needed to address this and other possibilities. Neural differences include indications of an IAA-associated increase in NR2B receptors that is not evident with CAA; although little studied, alterations in other neural and neurotransmitter systems are evident as well. Many gaps in understanding of IAA/CAA effects remain. Further work is needed to characterize neural mechanisms underlying these effects, consequences of IAA/CAA on EtOH effects beyond intake, and the impact of stress and environmental variables on these differences. IAA/CAA studies to date have also largely been limited to males and to adult animals, and hence, more studies examining IAA/CAA across sex and age are needed. Such additional work is essential to determine unique contributors to IAA-induced elevations in EtOH intake that may provide important insights for the development of new prevention/intervention strategies for heavy alcohol use and abuse.
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Affiliation(s)
- Linda Patia Spear
- Behavioral Neuroscience Program, Department of Psychology, Developmental Exposure Alcohol Research Center, Binghamton University, Binghamton, NY
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17
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Harmouche E, Steger C, Mikhaeil M, Hoffman RS. Treatment of Alcohol Withdrawal Syndrome. Am J Crit Care 2019; 28:96. [PMID: 30824508 DOI: 10.4037/ajcc2019147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
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18
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Nipper MA, Jensen JP, Helms ML, Ford MM, Crabbe JC, Rossi DJ, Finn DA. Genotype Differences in Sensitivity to the Anticonvulsant Effect of the Synthetic Neurosteroid Ganaxolone during Chronic Ethanol Withdrawal. Neuroscience 2018; 397:127-137. [PMID: 30513375 DOI: 10.1016/j.neuroscience.2018.11.045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 11/26/2018] [Accepted: 11/28/2018] [Indexed: 01/05/2023]
Abstract
Sensitivity to anticonvulsant effects of the γ-aminobutyric acidA receptor-active neurosteroid allopregnanolone (ALLO) during ethanol withdrawal varies across genotypes, with high sensitivity in genotypes with mild withdrawal and low sensitivity in genotypes with high withdrawal. The present studies determined whether the resistance to ALLO during withdrawal in mouse genotypes with high handling-induced convulsions (HICs) during withdrawal could be overcome with use of ganaxolone (GAN), the metabolically stable derivative of ALLO. In separate studies, male and female Withdrawal Seizure-Prone (WSP-1) and DBA/2J (D2) mice were exposed to air (controls) or 72-h ethanol vapor and then were scored for HICs during withdrawal (hourly for the first 12 h, then at hours 24 and 25). After the HIC scoring at hours 5 and 9, mice were injected with 10 mg/kg GAN or vehicle. Area under the HIC curve (AUC) for hours 5-12 was analyzed. In control WSP-1 mice, GAN significantly reduced AUC by 52% (males) and 63% (females), with effects that were absent or substantially reduced during withdrawal. In contrast, GAN significantly reduced AUC in both control and ethanol-withdrawing male and female D2 mice. AUC was decreased by 81% (males) and 70% (females) in controls and by 35% (males) and 21% (females) during withdrawal. The significant anticonvulsant effect of GAN during withdrawal in D2 but not WSP-1 mice suggests that different mechanisms may contribute to ALLO insensitivity during withdrawal in these two genotypes. Importantly, the results in D2 mice suggest that GAN may be a useful treatment for ethanol withdrawal-induced seizures.
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Affiliation(s)
- Michelle A Nipper
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States.
| | - Jeremiah P Jensen
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States
| | - Melinda L Helms
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States
| | - Matthew M Ford
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States; Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, United States
| | - John C Crabbe
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States; Portland Alcohol Research Center, VA Portland Health Care System, Portland, OR 97239, United States
| | - David J Rossi
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States; Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164, United States
| | - Deborah A Finn
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States; Portland Alcohol Research Center, VA Portland Health Care System, Portland, OR 97239, United States
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19
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Jung ME, Mallet RT. Intermittent hypoxia training: Powerful, non-invasive cerebroprotection against ethanol withdrawal excitotoxicity. Respir Physiol Neurobiol 2018; 256:67-78. [PMID: 28811138 PMCID: PMC5825251 DOI: 10.1016/j.resp.2017.08.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 07/24/2017] [Accepted: 08/08/2017] [Indexed: 12/12/2022]
Abstract
Ethanol intoxication and withdrawal exact a devastating toll on the central nervous system. Abrupt ethanol withdrawal provokes massive release of the excitatory neurotransmitter glutamate, which over-activates its postsynaptic receptors, causing intense Ca2+ loading, p38 mitogen activated protein kinase activation and oxidative stress, culminating in ATP depletion, mitochondrial injury, amyloid β deposition and neuronal death. Collectively, these mechanisms produce neurocognitive and sensorimotor dysfunction that discourages continued abstinence. Although the brain is heavily dependent on blood-borne O2 to sustain its aerobic ATP production, brief, cyclic episodes of moderate hypoxia and reoxygenation, when judiciously applied over the course of days or weeks, evoke adaptations that protect the brain from ethanol withdrawal-induced glutamate excitotoxicity, mitochondrial damage, oxidative stress and amyloid β accumulation. This review summarizes evidence from ongoing preclinical research that demonstrates intermittent hypoxia training to be a potentially powerful yet non-invasive intervention capable of affording robust, sustained neuroprotection during ethanol withdrawal.
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Affiliation(s)
- Marianna E Jung
- Center for Neuroscience Discovery, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA.
| | - Robert T Mallet
- Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA.
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20
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Lee KM, Coelho MA, Class MA, Szumlinski KK. mGlu5-dependent modulation of anxiety during early withdrawal from binge-drinking in adult and adolescent male mice. Drug Alcohol Depend 2018; 184:1-11. [PMID: 29324247 PMCID: PMC6371787 DOI: 10.1016/j.drugalcdep.2017.10.031] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 10/26/2017] [Accepted: 10/29/2017] [Indexed: 10/18/2022]
Abstract
Binge alcohol-drinking elicits symptoms of negative affect such as anxiety upon cessation, which is a source of negative reinforcement for perpetuating this pattern of alcohol abuse. Binge-induced anxiety during early (24 h) withdrawal is associated with increased expression of metabotropic glutamate receptor 5 (mGlu5) within the nucleus accumbens shell (AcbSh) of adult male mice, but was unchanged in anxiety-resilient adolescents. Herein, we determined the role of mGlu5 signaling in withdrawal-induced anxiety via pharmacological manipulation using the mGlu5 negative allosteric modulator MTEP and the positive allosteric modulator CDPPB. Adult (PND 56) and adolescent (PND 28) male C57BL/6J mice binge-drank for 14 days under 3-bottle-choice procedures for 2 h/day; control animals drank water only. Approximately 24 h following the final alcohol presentation, animals were treated with 30 mg/kg IP MTEP, CDPPB, or vehicle and then tested, thirty minutes later, for behavioral signs of anxiety. Vehicle-treated binge-drinking adults exhibited hyperanxiety in all paradigms, while vehicle-treated binge-drinking adolescents did not exhibit withdrawal-induced anxiety. In adults, 30 mg/kg MTEP decreased alcohol-induced anxiety across paradigms, while 3 mg/kg MTEP was anxiolytic in adult water controls. CDPPB was modestly anxiogenic in both alcohol- and water-drinking mice. Adolescent animals showed minimal response to either CDPPB or MTEP, suggesting that anxiety in adolescence may be mGlu5-independent. These results demonstrate a causal role for mGlu5 in withdrawal-induced anxiety in adults and suggest age-related differences in the behavioral pharmacology of the negative reinforcing properties of alcohol.
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Affiliation(s)
- Kaziya M. Lee
- Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA, 93106-9660, USA
| | - Michal A. Coelho
- Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA, 93106-9660, USA
| | - MacKayla A. Class
- Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA, 93106-9660, USA,Department of Molecular, Cellular and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, 93106-9625, USA
| | - Karen K. Szumlinski
- Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA, 93106-9660, USA,Department of Molecular, Cellular and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, 93106-9625, USA,Corresponding author at: University of California Santa Barbara, Santa Barbara, CA, 93106-9660, USA. (K.K. Szumlinski)
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21
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Heckmatt J, Shaikh AA, Swash M, Scott DF. Seizure Induction by Alcohol in Patients with Epilepsy Experience in two Hospital Clinics. J R Soc Med 2018; 83:6-9. [PMID: 2106032 PMCID: PMC1292453 DOI: 10.1177/014107689008300105] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
We surveyed 70 epileptic patients attending a general neurology clinic and 64 patients attending an epilepsy clinic to determine the incidence of alcohol-related seizures. Seven (10%) of the neurology clinic patients and 9 (15%) of the epilepsy clinic patients reported exacerbation of their seizures with alcohol. In the first group, two had been heavy drinkers when under-age, two had features of alcohol dependence, and three had experienced resolution of seizures following cessation of their drinking. In the second group, five drank 4 units/day or more, and one drank more heavily. The importance of alcohol in the causation of these patients' seizures had not previously been appreciated. The relationship of alcoholism to epilepsy has been recognized for many years, but the role of alcohol in the exacerbation of primary epilepsy, and in triggering seizures in epileptic patients is often not recognized. Control of alcohol ingestion is an important factor in the management of epilepsy.
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Affiliation(s)
- J Heckmatt
- Department of Neurology, Newham General Hospital, London
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22
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Lee KM, Coehlo MA, Solton NR, Szumlinski KK. Negative Affect and Excessive Alcohol Intake Incubate during Protracted Withdrawal from Binge-Drinking in Adolescent, But Not Adult, Mice. Front Psychol 2017; 8:1128. [PMID: 28729845 PMCID: PMC5499357 DOI: 10.3389/fpsyg.2017.01128] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 06/19/2017] [Indexed: 01/10/2023] Open
Abstract
Binge-drinking is common in underage alcohol users, yet we know little regarding the biopsychological impact of binge-drinking during early periods of development. Prior work indicated that adolescent male C57BL6/J mice with a 2-week history of binge-drinking (PND28-41) are resilient to the anxiogenic effects of early alcohol withdrawal. Herein, we employed a comparable Drinking-in-the-Dark model to determine how a prior history of binge-drinking during adolescence (EtOHadolescents) influences emotionality (assayed with the light-dark box, marble burying test, and the forced swim test) and the propensity to consume alcohol in later life, compared to animals without prior drinking experience. For additional comparison, adult mice (EtOHadults) with comparable drinking history (PND56-69) were subdivided into groups tested for anxiety/drinking either on PND70 (24 h withdrawal) or PND98 (28 days withdrawal). Tissue from the nucleus accumbens shell (AcbSh) and central nucleus of the amygdala (CeA) was examined by immunoblotting for changes in the expression of glutamate-related proteins. EtOHadults exhibited some signs of hyperanxiety during early withdrawal (PND70), but not during protracted withdrawal (PND98). In contrast, EtOHadolescents exhibited robust signs of anxiety-l and depressive-like behaviors when tested as adults on PND70. While all alcohol-experienced animals subsequently consumed more alcohol than mice drinking for the first time, alcohol intake was greatest in EtOHadolescents. Independent of drinking age, the manifestation of withdrawal-induced hyperanxiety was accompanied by reduced Homer2b expression within the CeA and increased Group1 mGlu receptor expression within the AcbSh. The present data provide novel evidence that binge-drinking during adolescence produces a state characterized by profound negative affect and excessive alcohol consumption that incubates with the passage of time in withdrawal. These data extend our prior studies on the effects of subchronic binge-drinking during adulthood by demonstrating that the increase in alcoholism-related behaviors and glutamate-related proteins observed in early withdrawal dissipate with the passage of time. Our results to date highlight a critical interaction between the age of binge-drinking onset and the duration of alcohol withdrawal in glutamate-related neuroplasticity within the extended amygdala of relevance to the etiology of psychopathology, including pathological drinking, in later life.
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Affiliation(s)
- Kaziya M Lee
- Department of Psychological and Brain Sciences, University of California, Santa BarbaraSanta Barbara, CA, United States
| | - Michal A Coehlo
- Department of Psychological and Brain Sciences, University of California, Santa BarbaraSanta Barbara, CA, United States
| | - Noah R Solton
- Department of Psychological and Brain Sciences, University of California, Santa BarbaraSanta Barbara, CA, United States
| | - Karen K Szumlinski
- Department of Psychological and Brain Sciences, University of California, Santa BarbaraSanta Barbara, CA, United States.,Department of Molecular, Cellular and Developmental Biology and The Neuroscience Research Institute, University of California, Santa Barbara, Santa BarbaraCA, United States
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23
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Rehm J, Gmel GE, Gmel G, Hasan OSM, Imtiaz S, Popova S, Probst C, Roerecke M, Room R, Samokhvalov AV, Shield KD, Shuper PA. The relationship between different dimensions of alcohol use and the burden of disease-an update. Addiction 2017; 112:968-1001. [PMID: 28220587 PMCID: PMC5434904 DOI: 10.1111/add.13757] [Citation(s) in RCA: 737] [Impact Index Per Article: 92.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 12/19/2016] [Accepted: 01/09/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Alcohol use is a major contributor to injuries, mortality and the burden of disease. This review updates knowledge on risk relations between dimensions of alcohol use and health outcomes to be used in global and national Comparative Risk Assessments (CRAs). METHODS Systematic review of reviews and meta-analyses on alcohol consumption and health outcomes attributable to alcohol use. For dimensions of exposure: volume of alcohol use, blood alcohol concentration and patterns of drinking, in particular heavy drinking occasions were studied. For liver cirrhosis, quality of alcohol was additionally considered. For all outcomes (mortality and/or morbidity): cause of death and disease/injury categories based on International Classification of Diseases (ICD) codes used in global CRAs; harm to others. RESULTS In total, 255 reviews and meta-analyses were identified. Alcohol use was found to be linked causally to many disease and injury categories, with more than 40 ICD-10 three-digit categories being fully attributable to alcohol. Most partially attributable disease categories showed monotonic relationships with volume of alcohol use: the more alcohol consumed, the higher the risk of disease or death. Exceptions were ischaemic diseases and diabetes, with curvilinear relationships, and with beneficial effects of light to moderate drinking in people without heavy irregular drinking occasions. Biological pathways suggest an impact of heavy drinking occasions on additional diseases; however, the lack of medical epidemiological studies measuring this dimension of alcohol use precluded an in-depth analysis. For injuries, except suicide, blood alcohol concentration was the most important dimension of alcohol use. Alcohol use caused marked harm to others, which has not yet been researched sufficiently. CONCLUSIONS Research since 2010 confirms the importance of alcohol use as a risk factor for disease and injuries; for some health outcomes, more than one dimension of use needs to be considered. Epidemiological studies should include measurement of heavy drinking occasions in line with biological knowledge.
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Affiliation(s)
- Jürgen Rehm
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
- Campbell Family Mental Health Research Institute, CAMHTorontoOntarioCanada
- Institute of Medical Science (IMS)University of TorontoTorontoOntarioCanada
- Department of PsychiatryUniversity of TorontoTorontoOntarioCanada
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
- Institute for Clinical Psychology and Psychotherapy, TU DresdenDresdenGermany
| | - Gerhard E. Gmel
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
- Alcohol Treatment CenterLausanne University HospitalLausanneSwitzerland
- Addiction SwitzerlandLausanneSwitzerland
- University of the West of EnglandBristolUK
| | - Gerrit Gmel
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
| | - Omer S. M. Hasan
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
| | - Sameer Imtiaz
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
- Institute of Medical Science (IMS)University of TorontoTorontoOntarioCanada
| | - Svetlana Popova
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
- Institute of Medical Science (IMS)University of TorontoTorontoOntarioCanada
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
- Factor‐Inwentash Faculty of Social WorkUniversity of TorontoOntarioCanada
| | - Charlotte Probst
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
- Institute for Clinical Psychology and Psychotherapy, TU DresdenDresdenGermany
| | - Michael Roerecke
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
| | - Robin Room
- Centre for Alcohol Policy ResearchLa Trobe UniversityMelbourneVictoriaAustralia
- Centre for Social Research on Alcohol and DrugsStockholm UniversityStockholmSweden
| | - Andriy V. Samokhvalov
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
- Institute of Medical Science (IMS)University of TorontoTorontoOntarioCanada
- Department of PsychiatryUniversity of TorontoTorontoOntarioCanada
| | - Kevin D. Shield
- Section of Cancer SurveillanceInternational Agency for Research on CancerLyonFrance
| | - Paul A. Shuper
- Institute for Mental Health Policy Research, CAMHTorontoOntarioCanada
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
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Ryou MG, Mallet RT, Metzger DB, Jung ME. Intermittent hypoxia training blunts cerebrocortical presenilin 1 overexpression and amyloid-β accumulation in ethanol-withdrawn rats. Am J Physiol Regul Integr Comp Physiol 2017; 313:R10-R18. [PMID: 28490448 DOI: 10.1152/ajpregu.00050.2017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 05/03/2017] [Accepted: 05/04/2017] [Indexed: 01/08/2023]
Abstract
Abrupt cessation of chronic alcohol consumption triggers signaling cascades that harm vulnerable brain regions and produce neurobehavioral deficits. We have demonstrated that a program of intermittent, normobaric hypoxia training (IHT) in rats prevents brain damage and neurobehavioral impairment resulting from abrupt ethanol withdrawal (EW). Moreover, EW induced expression of stress-activated protein kinase p38 and presenilin 1 (PS1), the catalytic subunit of γ-secretase that produces the neurotoxic amyloid-β (Aβ) peptides Aβ40 and Aβ42. We tested the hypotheses that 1) IHT limits EW-induced activation of the p38-PS1 axis, thereby attenuating γ-secretase activation and Aβ accumulation, and 2) EW disables heat shock protein 25 (HSP25), a p38 substrate, molecular chaperone, and antioxidant, and provokes protein carbonylation in a manner suppressed by IHT. Adult male rats completed two cycles of a 4-wk ethanol diet (6.5% wt/vol) and a 3-wk EW or an isocaloric, dextrin-based control diet. A 20-day IHT program (5-8 daily cycles of 5-10 min of 9.5-10% fractional inspired O2 + 4 min of 21% fractional inspired O2) was administered during the first EW phase. After the second EW phase, the brain was excised and the prefrontal cortex extracted. PS1, phosphorylated p38 (p-p38), and HSP25 were analyzed by immunoblot, PS1 messenger RNA by quantitative polymerase chain reaction, protein carbonyl content by spectrometry, and Aβ40 and Aβ42 contents by enzyme-linked immunosorbent assay. IHT attenuated the EW-associated increases in PS1, p-p38, Aβ40, Aβ42, and protein carbonyl contents, but not that of PS1 messenger RNA, while preserving functionally competent HSP25 dimers in EW rats. Collectively, these findings suggest that IHT may attenuate EW-induced γ-secretase overactivation by suppressing activation of the p38-PS1 axis and by preventing oxidative protein damage.
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Affiliation(s)
- Myoung-Gwi Ryou
- Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, Texas.,Department of Medical Laboratory Science and Public Health, Tarleton State University, Fort Worth, Texas
| | - Robert T Mallet
- Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, Texas
| | - Daniel B Metzger
- Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, Texas; and
| | - Marianna E Jung
- Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, Texas; and
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Hwa L, Besheer J, Kash T. Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective. F1000Res 2017; 6:298. [PMID: 28413623 PMCID: PMC5365217 DOI: 10.12688/f1000research.9609.1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/13/2017] [Indexed: 12/18/2022] Open
Abstract
Glutamate signaling in the brain is one of the most studied targets in the alcohol research field. Here, we report the current understanding of how the excitatory neurotransmitter glutamate, its receptors, and its transporters are involved in low, episodic, and heavy alcohol use. Specific animal behavior protocols can be used to assess these different drinking levels, including two-bottle choice, operant self-administration, drinking in the dark, the alcohol deprivation effect, intermittent access to alcohol, and chronic intermittent ethanol vapor inhalation. Importantly, these methods are not limited to a specific category, since they can be interchanged to assess different states in the development from low to heavy drinking. We encourage a circuit-based perspective beyond the classic mesolimbic-centric view, as multiple structures are dynamically engaged during the transition from positive- to negative-related reinforcement to drive alcohol drinking. During this shift from lower-level alcohol drinking to heavy alcohol use, there appears to be a shift from metabotropic glutamate receptor-dependent behaviors to N-methyl-D-aspartate receptor-related processes. Despite high efficacy of the glutamate-related pharmaceutical acamprosate in animal models of drinking, it is ineffective as treatment in the clinic. Therefore, research needs to focus on other promising glutamatergic compounds to reduce heavy drinking or mediate withdrawal symptoms or both.
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Affiliation(s)
- Lara Hwa
- Department of Pharmacology, University of North Carolina School of Medicine, Bowles Center for Alcohol Studies, Chapel Hill, NC, 27599, USA
| | - Joyce Besheer
- Department of Psychiatry, University of North Carolina School of Medicine, Bowles Center for Alcohol Studies, Chapel Hill, NC, 27599, USA
| | - Thomas Kash
- Department of Pharmacology, University of North Carolina School of Medicine, Bowles Center for Alcohol Studies, Chapel Hill, NC, 27599, USA
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26
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Rehm J, Gmel GE, Gmel G, Hasan OSM, Imtiaz S, Popova S, Probst C, Roerecke M, Room R, Samokhvalov AV, Shield KD, Shuper PA. The relationship between different dimensions of alcohol use and the burden of disease-an update. ADDICTION (ABINGDON, ENGLAND) 2017. [PMID: 28220587 DOI: 10.1111/add.13757.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND AIMS Alcohol use is a major contributor to injuries, mortality and the burden of disease. This review updates knowledge on risk relations between dimensions of alcohol use and health outcomes to be used in global and national Comparative Risk Assessments (CRAs). METHODS Systematic review of reviews and meta-analyses on alcohol consumption and health outcomes attributable to alcohol use. For dimensions of exposure: volume of alcohol use, blood alcohol concentration and patterns of drinking, in particular heavy drinking occasions were studied. For liver cirrhosis, quality of alcohol was additionally considered. For all outcomes (mortality and/or morbidity): cause of death and disease/injury categories based on International Classification of Diseases (ICD) codes used in global CRAs; harm to others. RESULTS In total, 255 reviews and meta-analyses were identified. Alcohol use was found to be linked causally to many disease and injury categories, with more than 40 ICD-10 three-digit categories being fully attributable to alcohol. Most partially attributable disease categories showed monotonic relationships with volume of alcohol use: the more alcohol consumed, the higher the risk of disease or death. Exceptions were ischaemic diseases and diabetes, with curvilinear relationships, and with beneficial effects of light to moderate drinking in people without heavy irregular drinking occasions. Biological pathways suggest an impact of heavy drinking occasions on additional diseases; however, the lack of medical epidemiological studies measuring this dimension of alcohol use precluded an in-depth analysis. For injuries, except suicide, blood alcohol concentration was the most important dimension of alcohol use. Alcohol use caused marked harm to others, which has not yet been researched sufficiently. CONCLUSIONS Research since 2010 confirms the importance of alcohol use as a risk factor for disease and injuries; for some health outcomes, more than one dimension of use needs to be considered. Epidemiological studies should include measurement of heavy drinking occasions in line with biological knowledge.
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Affiliation(s)
- Jürgen Rehm
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada.,Campbell Family Mental Health Research Institute, CAMH, Toronto, Ontario, Canada.,Institute of Medical Science (IMS), University of Toronto, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.,Institute for Clinical Psychology and Psychotherapy, TU Dresden, Dresden, Germany
| | - Gerhard E Gmel
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada.,Alcohol Treatment Center, Lausanne University Hospital, Lausanne, Switzerland.,Addiction Switzerland, Lausanne, Switzerland.,University of the West of England, Bristol, UK
| | - Gerrit Gmel
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada
| | - Omer S M Hasan
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada
| | - Sameer Imtiaz
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada.,Institute of Medical Science (IMS), University of Toronto, Toronto, Ontario, Canada
| | - Svetlana Popova
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada.,Institute of Medical Science (IMS), University of Toronto, Toronto, Ontario, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.,Factor-Inwentash Faculty of Social Work, University of Toronto, Ontario, Canada
| | - Charlotte Probst
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada.,Institute for Clinical Psychology and Psychotherapy, TU Dresden, Dresden, Germany
| | - Michael Roerecke
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Robin Room
- Centre for Alcohol Policy Research, La Trobe University, Melbourne, Victoria, Australia.,Centre for Social Research on Alcohol and Drugs, Stockholm University, Stockholm, Sweden
| | - Andriy V Samokhvalov
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada.,Institute of Medical Science (IMS), University of Toronto, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Kevin D Shield
- Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France
| | - Paul A Shuper
- Institute for Mental Health Policy Research, CAMH, Toronto, Ontario, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
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27
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Zahr NM, Rohlfing T, Mayer D, Luong R, Sullivan EV, Pfefferbaum A. Transient CNS responses to repeated binge ethanol treatment. Addict Biol 2016; 21:1199-1216. [PMID: 26283309 DOI: 10.1111/adb.12290] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 05/14/2015] [Accepted: 06/30/2015] [Indexed: 12/12/2022]
Abstract
The effects of ethanol (EtOH) on in vivo magnetic resonance (MR)-detectable brain measures across repeated exposures have not previously been reported. Of 28 rats weighing 340.66 ± 21.93 g at baseline, 15 were assigned to an EtOH group and 13 to a control group. Animals were exposed to five cycles of 4 days of intragastric (EtOH or dextrose) treatment and 10 days of recovery. Rats in both groups had structural MR imaging and whole-brain MR spectroscopy (MRS) scans at baseline, immediately following each binge period and after each recovery period (total = 11 scans per rat). Blood alcohol level at each of the five binge periods was ~300 mg/dl. Blood drawn at the end of the experiment did not show group differences for thiamine or its phosphate derivatives. Postmortem liver histopathology provided no evidence for hepatic steatosis, alcoholic hepatitis or alcoholic cirrhosis. Cerebrospinal fluid volumes of the lateral ventricles and cisterns showed enlargement with each binge EtOH exposure but recovery with each abstinence period. Similarly, changes in MRS metabolite levels were transient: levels of N-acetylaspartate and total creatine decreased, while those of choline-containing compounds and the combined resonance from glutamate and glutamine increased with each binge EtOH exposure cycle and then recovered during each abstinence period. Changes in response to EtOH were in expected directions based on previous single-binge EtOH exposure experiments, but the current MR findings do not provide support for accruing changes with repeated binge EtOH exposure.
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Affiliation(s)
- Natalie M. Zahr
- Psychiatry and Behavioral Sciences; Stanford University School of Medicine; Stanford CA USA
- Neuroscience Program; SRI International; Menlo Park CA USA
| | | | - Dirk Mayer
- Neuroscience Program; SRI International; Menlo Park CA USA
- Diagnostic Radiology and Nuclear Medicine; University of Maryland School of Medicine; Baltimore MD USA
| | - Richard Luong
- Department of Comparative Medicine; Stanford University; Stanford CA USA
| | - Edith V. Sullivan
- Psychiatry and Behavioral Sciences; Stanford University School of Medicine; Stanford CA USA
| | - Adolf Pfefferbaum
- Psychiatry and Behavioral Sciences; Stanford University School of Medicine; Stanford CA USA
- Neuroscience Program; SRI International; Menlo Park CA USA
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28
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Rasmussen DD, Kincaid CL, Froehlich JC. Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations. Alcohol Alcohol 2016; 52:5-11. [PMID: 27797712 DOI: 10.1093/alcalc/agw082] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 10/06/2016] [Accepted: 10/14/2016] [Indexed: 11/13/2022] Open
Abstract
AIMS Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active α1-adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations. METHODS Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles. Prazosin (1.0 or 1.5 mg/kg, IP) or vehicle was administered before each restraint stress. Anxiety-like behavior during alcohol deprivation following the third 5-day cycle of alcohol drinking (7 days after the most recent restraint stress ± prazosin treatment) was measured by performance in an elevated plus-maze and in social approach/avoidance testing. RESULTS Rats that received constant alcohol access, or alcohol access and deprivations without stress or prazosin treatments in the first two alcohol deprivations did not exhibit augmented anxiety-like behavior during the third deprivation. In contrast, rats that had been stressed during the first two alcohol deprivations exhibited increased anxiety-like behavior (compared with control rats) in both anxiety tests during the third deprivation. Prazosin given before stresses in the first two cycles of alcohol withdrawal prevented increased anxiety-like behavior during the third alcohol deprivation. CONCLUSION Prazosin treatment before stresses experienced during alcohol deprivations may prevent the increased anxiety during subsequent deprivation/abstinence that is a risk factor for relapse to alcohol drinking. SHORT SUMMARY Administration of prazosin before stresses during repetitive alcohol deprivations in male alcohol-preferring (P) rats prevents increased anxiety during a subsequent deprivation without further prazosin treatment. Prazosin treatment during repeated alcohol deprivations may prevent the increased anxiety that is a risk factor for relapse to alcohol drinking.
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Affiliation(s)
- Dennis D Rasmussen
- VISN 20 Mental Illness Research, Education and Clinical Center (MIRECC), Mental Health Service, VA Puget Sound Health Care System, Seattle, WA, USA .,Department of Psychiatry, University of Washington, Seattle, WA 98108, USA
| | - Carrie L Kincaid
- VISN 20 Mental Illness Research, Education and Clinical Center (MIRECC), Mental Health Service, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Janice C Froehlich
- Department of Medicine, Indiana University School of Medicine, Indinapolis, IN 46202, USA
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29
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Jung ME, Metzger DB, Das HK. The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal. J Pharmacol Exp Ther 2016; 358:516-26. [PMID: 27278235 PMCID: PMC4998674 DOI: 10.1124/jpet.116.233361] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 05/27/2016] [Indexed: 01/02/2023] Open
Abstract
Presenilin-1 (PS1) is a core component of γ-secretase that is involved in neurodegeneration. We have previously shown that PS1 interacts with a mitogen-activated protein kinase [(MAPK) jun-NH2-terminal-kinase], and another MAPK (p38) is activated by ethanol withdrawal (EW), abrupt termination from chronic ethanol exposure. EW is excitotoxic in nature, induces glutamate upregulation, and provokes neuronal damage. Here, we explored a potential mechanistic pathway involving glutamate, p38 (p38α isozyme), and PS1 that may mediate EW-induced excitotoxic stress. We used the prefrontal cortex of male rats withdrawn from a chronic ethanol diet. Additionally, we used ethanol-withdrawn HT22 cells (mouse hippocampal) treated with the inhibitor of glutamate receptors [dizocilpine (MK-801)], p38α (SB203580; 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine), or γ-secretase [N-[N- (3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT)] during EW. Separately, ethanol-free HT22 cells were exposed to glutamate with or without SB203580 or DAPT. Protein levels, mRNA levels, and cell viability were assessed using immunoblotting, qualitative polymerase chain reaction, and calcein assay, respectively. The prefrontal cortex of ethanol-withdrawn rats or HT22 cells showed an increase in PS1 and p38α, which was attenuated by MK-801 and SB203580, but mimicked by glutamate treatment to ethanol-free HT22 cells. DAPT attenuated the toxic effect of EW or glutamate on HT22 cells. These results suggest that PS1 expression is triggered by glutamate through p38α, contributing to the excitotoxic stimulus of EW.
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Affiliation(s)
- Marianna E Jung
- Institute for Health Aging, Center for Neuroscience Discovery (M.E.J., D.B.M., H.K.D.), and Institute of Cancer Research (H.K.D.), University of North Texas Health Science Center, Fort Worth, Texas
| | - Daniel B Metzger
- Institute for Health Aging, Center for Neuroscience Discovery (M.E.J., D.B.M., H.K.D.), and Institute of Cancer Research (H.K.D.), University of North Texas Health Science Center, Fort Worth, Texas
| | - Hriday K Das
- Institute for Health Aging, Center for Neuroscience Discovery (M.E.J., D.B.M., H.K.D.), and Institute of Cancer Research (H.K.D.), University of North Texas Health Science Center, Fort Worth, Texas
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30
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Czynniki ryzyka majaczenia alkoholowego u osób leczonych stacjonarnie w Polsce z powodu uzależnienia od alkoholu. ALCOHOLISM AND DRUG ADDICTION 2016. [DOI: 10.1016/j.alkona.2016.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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31
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Kumar MA, Patnaik SG, Lakshminarayanan V, Ramamurthy SS. Elecrochemical Determination of Ethanol by a Palladium Modified Graphene Nanocomposite Glassy Carbon Electrode. ANAL LETT 2016. [DOI: 10.1080/00032719.2016.1179746] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Manne Anupam Kumar
- Department of Chemistry, Sri Sathya Sai Institute of Higher Learning, Anantapur, Andhra Pradesh, India
| | - Sai Gourang Patnaik
- Department of Chemistry, Sri Sathya Sai Institute of Higher Learning, Anantapur, Andhra Pradesh, India
| | - V. Lakshminarayanan
- Soft Condensed Matter Laboratory, Raman Research Institute, Bangalore, India
| | - Sai Sathish Ramamurthy
- Department of Chemistry, Sri Sathya Sai Institute of Higher Learning, Anantapur, Andhra Pradesh, India
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32
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Reynolds AR, Saunders MA, Prendergast MA. Ethanol Stimulates Endoplasmic Reticulum Inositol Triphosphate and Sigma Receptors to Promote Withdrawal-Associated Loss of Neuron-Specific Nuclear Protein/Fox-3. Alcohol Clin Exp Res 2016; 40:1454-61. [PMID: 27177604 DOI: 10.1111/acer.13097] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/01/2016] [Indexed: 02/02/2023]
Abstract
BACKGROUND Prior studies demonstrate that ethanol (EtOH) exposure induces the release of intracellular calcium (CA(2+) ) in modulation of γ-aminobutyric acid-ergic tone and produces concomitant alterations in sigma (σ)-1 protein expression that may contribute to the development EtOH dependence. However, the influence of CA(2+) released from endoplasmic reticulum (ER)-bound inositol triphosphate (IP3) and σ-1 receptors in regulating hippocampal function has yet to be delineated. METHODS Rat hippocampal explants were subjected to chronic intermittent EtOH (CIE) exposure with or without the addition of IP3 inhibitor xestospongin C (0 to 0.5 μM) or σ-1 receptor antagonist BD-1047 (0 to 80 μM). Hippocampal viability was assessed via immunohistochemical labeling of neuron-specific nuclear protein (NeuN)/Fox-3 in CA1, CA3, and dentate gyrus (DG) subregions. RESULTS Exposure to CIE produced consistent and significant decreases of NeuN/Fox-3 in each primary cell layer of the hippocampal formation. Co-exposure to xestospongin reversed these effects in the CA1 subregion and significantly attenuated these effects in the CA3 and DG regions. Xestospongin application also significantly increased NeuN/Fox-3 immunofluorescence in EtOH-naïve hippocampi. Co-exposure to 20 μM BD-1047 also reversed the loss of NeuN/Fox-3 during CIE exposure in each hippocampal cell layer, whereas exposure to 80 μM BD-1047 did not alter NeuN/Fox-3 in EtOH-treated hippocampi. By contrast, 80 μM BD-1047 application significantly increased NeuN/Fox-3 immunofluorescence in EtOH-naïve hippocampi in each subregion. CONCLUSIONS These data suggest that EtOH stimulates ER IP3 and σ-1 receptors to promote hippocampal loss of NeuN/Fox-3 during CIE.
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Affiliation(s)
- Anna R Reynolds
- Department of Behavioral Science, University of Kentucky, Lexington, Kentucky
| | - Meredith A Saunders
- Department of Psychology, University of Kentucky, Lexington, Kentucky.,Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
| | - Mark A Prendergast
- Department of Psychology, University of Kentucky, Lexington, Kentucky.,Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
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33
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Breese GR, Knapp DJ. Persistent adaptation by chronic alcohol is facilitated by neuroimmune activation linked to stress and CRF. Alcohol 2016; 52:9-23. [PMID: 27139233 PMCID: PMC4855305 DOI: 10.1016/j.alcohol.2016.01.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 12/10/2015] [Accepted: 01/24/2016] [Indexed: 01/11/2023]
Abstract
This review updates the conceptual basis for the association of alcohol abuse with an insidious adaptation that facilitates negative affect during withdrawal from chronic intermittent alcohol (CIA) exposure - a change that later supports sensitization of stress-induced anxiety following alcohol abstinence. The finding that a CRF1-receptor antagonist (CRF1RA) minimized CIA withdrawal-induced negative affect supported an association of alcohol withdrawal with a stress mechanism. The finding that repeated stresses or multiple CRF injections into selected brain sites prior to a single 5-day chronic alcohol (CA) exposure induced anxiety during withdrawal provided critical support for a linkage of CIA withdrawal with stress. The determination that CRF1RA injection into positive CRF-sensitive brain sites prevented CIA withdrawal-induced anxiety provided support that neural path integration maintains the persistent CIA adaptation. Based upon reports that stress increases neuroimmune function, an effort was undertaken to test whether cytokines would support the adaptation induced by stress/CA exposure. Twenty-four hours after withdrawal from CIA, cytokine mRNAs were found to be increased in cortex as well as other sites in brain. Further, repeated cytokine injections into previously identified brain sites substituted for stress and CRF induction of anxiety during CA withdrawal. Discovery that a CRF1RA prevented the brain cytokine mRNA increase induced by CA withdrawal provided critical evidence for CRF involvement in this neuroimmune induction after CA withdrawal. However, the CRF1RA did not block the stress increase in cytokine mRNA increases in controls. The latter data supported the hypothesis that distinct mechanisms linked to stress and CA withdrawal can support common neuroimmune functions within a brain site. As evidence evolves concerning neural involvement in brain neuroimmune function, a better understanding of the progressive adaptation associated with CIA exposure will advance new knowledge that could possibly lead to strategies to combat alcohol abuse.
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Affiliation(s)
- George R Breese
- Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA; Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA; Curriculum in Neurobiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA; The UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA.
| | - Darin J Knapp
- Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA; Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7178, USA
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Sukhenko O. Alcohol withdrawal management in adult patients in a high acuity medical surgical transitional care unit: a best practice implementation project. ACTA ACUST UNITED AC 2016; 13:314-34. [PMID: 26767821 DOI: 10.11124/jbisrir-2015-2529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 10/08/2015] [Indexed: 10/31/2022]
Abstract
BACKGROUND Excessive alcohol consumption, a major health problem worldwide, affects about 6% of the United States population. Caring for patients with alcohol withdrawal syndrome in a hospital ward presents complex physiologic and psycho-social challenges which are best met with evidence-based practices. An academic medical center in the United States has been experiencing an increase in patients with alcohol withdrawal syndrome. However, gaps in clinician knowledge and infrastructure supporting the management of these patients still existed. OBJECTIVES The aim of this project was to improve the continuity of care of patients undergoing alcohol withdrawal in a medical surgical high acuity transitional care unit by incorporating evidence-based practices, and thereby to positively impact on patient outcomes. Specific objectives were related to standardized assessments and pharmacologic management strategies. METHODS The project used the Joanna Briggs Institute's Practical Application of Clinical Evidence System and Getting Research into Practice audit tool for promoting change in health practice. A baseline clinical audit was conducted to assess compliance with best practices for managing alcohol withdrawal syndrome, which was followed by several interventions targeted at nurses and providers. A follow-up audit was conducted to assess compliance with the implemented strategies. The follow-up audit used the same evidence-based audit criteria as those used for the baseline audit. A non-probabilistic, convenience sampling approach was used. A sample size of 15 patients was used for both the baseline and follow-up audits. RESULTS The baseline audit revealed a high compliance rate for four of the five audit criteria concerning risk assessment and pharmacologic strategies. There was sub-optimal compliance (53%) with the criterion regarding use of the Clinical Institute Withdrawal Assessment of Alcohol Scale (revised) (CIWA-Ar) scale to assess patients with alcohol withdrawal. After the interventions were implemented this criterion recorded an improvement to 100% compliance. None of the patients in the pilot were transferred to the intensive care unit (ICU) for reasons relating to alcohol withdrawal. CONCLUSIONS The outcomes of this project demonstrated alcohol withdrawal management can be safely undertaken outside the ICU when the patients are appropriately assessed and treated for the severity of their withdrawal symptoms. This new clinical program significantly impacted on continuity of care. Challenges were resolved using an interdisciplinary team approach. The project resulted in plans for further areas of work concerning alcohol withdrawal management, including adoption of similar approaches by other acute and transitional care units.
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Laghi F, Baumgartner E, Baiocco R, Kotzalidis GD, Piacentino D, Girardi P, Angeletti G. Alcohol intake and binge drinking among Italian adolescents: The role of drinking motives. J Addict Dis 2015; 35:119-127. [PMID: 26670483 DOI: 10.1080/10550887.2015.1129703] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Binge drinking, a pattern associated with worse outcome, is becoming increasingly popular among youths, thus negatively impacting social life. To investigate drinking patterns and their underlying motives in Italian adolescents, the Alcohol Use Questionnaire and the Drinking Motive Questionnaire Revised Short Form were administered to 332 school-age teenagers (16-19 years; 139 girls, 193 boys) from a single Roman school, recruited at their classrooms through the intermediation of their teachers. Boys scored higher than girls on all drinking and binge measures. They also scored higher on the Enhancement, Social, and Conformity Drinking Motive Questionnaire-Revised Short Form subscales. Binge drinking scores positively correlated with gender, alcohol consumption, and with all Drinking Motive Questionnaire Revised Short Form subscales. In the two-step hierarchical model, Drinking Motive Questionnaire-Revised Short Form enhancement and conformity predicted alcohol use and Drinking Motive Questionnaire-Revised Short Form coping motives significantly predicted binge drinking. Binge drinking is prevalent among Italian adolescents, who mainly drink to enhance perceived positive effects of alcohol, conform to their social groups, and face their problems. Boys binge more than girls.
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Affiliation(s)
- Fiorenzo Laghi
- a Department of Developmental and Social Psychology , School of Medicine and Psychology, Sapienza University , Rome , Italy
| | - Emma Baumgartner
- a Department of Developmental and Social Psychology , School of Medicine and Psychology, Sapienza University , Rome , Italy
| | - Roberto Baiocco
- a Department of Developmental and Social Psychology , School of Medicine and Psychology, Sapienza University , Rome , Italy
| | - Georgios D Kotzalidis
- b NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department , School of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University , Rome , Italy
| | - Daria Piacentino
- b NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department , School of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University , Rome , Italy
| | - Paolo Girardi
- b NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department , School of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University , Rome , Italy
| | - Gloria Angeletti
- b NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department , School of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University , Rome , Italy
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Harper KM, Knapp DJ, Breese GR. Withdrawal from Chronic Alcohol Induces a Unique CCL2 mRNA Increase in Adolescent But Not Adult Brain--Relationship to Blood Alcohol Levels and Seizures. Alcohol Clin Exp Res 2015; 39:2375-85. [PMID: 26556523 DOI: 10.1111/acer.12898] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 09/02/2015] [Indexed: 11/29/2022]
Abstract
BACKGROUND The role of neuroimmune activation in withdrawal from chronic alcohol (ethanol) has been established in both adolescent and adult models, but direct comparisons across age are sparse. Studies need to elucidate age-dependent neuroimmune effects of alcohol and to focus research attention on age-dependent mechanisms and outcomes. METHODS Adult and adolescent rats from 2 commonly used strains, Wistar and Sprague Dawley (SD), were maintained on continuous 7%, 5.35%, 4.5% alcohol diet (CAD) or cycled 7% w/v alcohol diet for 15 days. Cortical tissue was collected at 0, 8, 16, and 24 hours postwithdrawal followed by measurement of chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor alpha, and interleukin 1 beta mRNA with quantitative real-time polymerase chain reaction. RESULTS Both age groups and strains showed a strong cytokine mRNA response at 7% CAD. Further, a greater increase in CCL2 mRNA was observed in the cortex of adolescents at 7% CAD, which correlated with higher blood alcohol levels (BALs). Adolescents exposed to 5.35% CAD exhibited similar blood levels and cytokine responses as adults exposed to 7% CAD. Substantial variability in CCL2 mRNA responses was found only in adolescent rats exposed to 7% CAD. In this group, data could be segregated into high-responding and low-responding groups. Moreover, the data from the high-responding group were associated with seizures. CONCLUSIONS Relative to other cytokine mRNAs, CCL2 exhibits a unique response profile during withdrawal from CAD. This profile is shown in adolescents, where CCL2 is uniquely influenced by the effects of seizures. Additionally, this profile is shown by the fact that only CCL2 expression correlated with BAL that transcended age groups. These data emphasize the importance of BALs and treatment regimen on developmental neuroimmune responses and suggest that select components of the neuroimmune system are more responsive to CAD withdrawal and that neurobiological mechanisms differentiating these responses should be further explored.
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Affiliation(s)
- Kathryn M Harper
- Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Darin J Knapp
- Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.,Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - George R Breese
- Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.,Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.,Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.,Curriculum in Neurobiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.,The UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Sachdeva A, Choudhary M, Chandra M. Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond. J Clin Diagn Res 2015; 9:VE01-VE07. [PMID: 26500991 DOI: 10.7860/jcdr/2015/13407.6538] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 07/03/2015] [Indexed: 11/24/2022]
Abstract
Alcohol dependence is an increasing and pervasive problem. Alcohol withdrawal symptoms are a part of alcohol dependence syndrome and are commonly encountered in general hospital settings, in most of the departments. Alcohol withdrawal syndrome ranges from mild to severe. The severe complicated alcohol withdrawal may present with hallucinations, seizures or delirium tremens. Benzodiazepines have the largest and the best evidence base in the treatment of alcohol withdrawal, and are considered the gold standard. Others, such as anticonvulsants, barbiturates, adrenergic drugs, and GABA agonists have been tried and have evidence. Supportive care and use of vitamins is essential in the management. Symptom triggered regime is favoured over fixed tapering dose regime, although monitoring through scales is cumbersome. This article aims to review the evidence base for appropriate clinical management of the alcohol withdrawal syndrome. We searched Pubmed for articles published in English on 'Alcohol withdrawal syndrome' in humans during the last 10 years. A total of 1182 articles came up. Articles not relevant to clinical utility and management were excluded based on the titles and abstract available. Full text articles, meta-analyses, systematic reviews and randomized controlled trials were obtained from this list and were considered for review.
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Affiliation(s)
- Ankur Sachdeva
- Assistant Professor, Department of Psychiatry, ESIC Medical College and Hospital , Faridabad, Haryana, India
| | - Mona Choudhary
- Senior Resident, Department of Psychiatry and Drug De-addiction, Post Graduate Institute of Medical Education and Research, Dr Ram Manohar Lohia Hospital , New Delhi, India
| | - Mina Chandra
- Chief Medical Officer (NFSG), Department of Psychiatry and Drug De-addiction, Post Graduate Institute of Medical Education and Research, Dr Ram Manohar Lohia Hospital , New Delhi, India
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Hwa LS, Nathanson AJ, Shimamoto A, Tayeh JK, Wilens AR, Holly EN, Newman EL, DeBold JF, Miczek KA. Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice. Psychopharmacology (Berl) 2015; 232:2889-902. [PMID: 25899790 PMCID: PMC4515187 DOI: 10.1007/s00213-015-3925-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/20/2015] [Indexed: 12/14/2022]
Abstract
RATIONALE Disrupted social behavior, including occasional aggressive outbursts, is characteristic of withdrawal from long-term alcohol (EtOH) use. Heavy EtOH use and exaggerated responses during withdrawal may be treated using glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonists. OBJECTIVES The current experiments explore aggression and medial prefrontal cortex (mPFC) glutamate as consequences of withdrawal from intermittent access to EtOH and changes in aggression and mPFC glutamate caused by NMDAR antagonists memantine and ketamine. METHODS Swiss male mice underwent withdrawal following 1-8 weeks of intermittent access to 20 % EtOH. Aggressive and nonaggressive behaviors with a conspecific were measured 6-8 h into EtOH withdrawal after memantine or ketamine (0-30 mg/kg, i.p.) administration. In separate mice, extracellular mPFC glutamate after memantine was measured during withdrawal using in vivo microdialysis. RESULTS At 6-8 h withdrawal from EtOH, mice exhibited more convulsions and aggression and decreased social contact compared to age-matched water controls. Memantine, but not ketamine, increased withdrawal aggression at the 5-mg/kg dose in mice with a history of 8 weeks of EtOH but not 1 or 4 weeks of EtOH or in water drinkers. Tonic mPFC glutamate was higher during withdrawal after 8 weeks of EtOH compared to 1 week of EtOH or 8 weeks of water. Five milligrams per kilogram of memantine increased glutamate in 8-week EtOH mice, but also in 1-week EtOH and water drinkers. CONCLUSIONS These studies reveal aggressive behavior as a novel symptom of EtOH withdrawal in outbred mice and confirm a role of NMDARs during withdrawal aggression and for disrupted social behavior.
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Affiliation(s)
- Lara S. Hwa
- Tufts University Department of Psychology, Medford, MA 02155
| | | | - Akiko Shimamoto
- Tufts University Department of Psychology, Medford, MA 02155
| | | | | | | | - Emily L. Newman
- Tufts University Department of Psychology, Medford, MA 02155
| | | | - Klaus A. Miczek
- Tufts University Department of Psychology, Medford, MA 02155
- Tufts University Department of Neuroscience, Boston, MA 02111
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Wong A, Smithburger PL, Kane-Gill SL. Review of adjunctive dexmedetomidine in the management of severe acute alcohol withdrawal syndrome. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2015; 41:382-91. [DOI: 10.3109/00952990.2015.1058390] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Adrian Wong
- Department of Pharmacy, University of Pittsburgh Medical Center Presbyterian, Pittsburgh, PA and
| | - Pamela L. Smithburger
- Department of Pharmacy, University of Pittsburgh Medical Center Presbyterian, Pittsburgh, PA and
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
| | - Sandra L. Kane-Gill
- Department of Pharmacy, University of Pittsburgh Medical Center Presbyterian, Pittsburgh, PA and
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
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Reynolds AR, Berry JN, Sharrett-Field L, Prendergast MA. Ethanol withdrawal is required to produce persisting N-methyl-D-aspartate receptor-dependent hippocampal cytotoxicity during chronic intermittent ethanol exposure. Alcohol 2015; 49:219-27. [PMID: 25746220 PMCID: PMC4414743 DOI: 10.1016/j.alcohol.2015.01.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 01/23/2015] [Accepted: 01/23/2015] [Indexed: 11/03/2022]
Abstract
Chronic intermittent ethanol consumption is associated with neurodegeneration and cognitive deficits in preclinical laboratory animals and in the clinical population. While previous work suggests a role for neuroadaptations in the N-methyl-D-aspartate (NMDA) receptor in the development of ethanol dependence and manifestation of withdrawal, the relative roles of ethanol exposure and ethanol withdrawal in producing these effects have not been fully characterized. To examine underlying cytotoxic mechanisms associated with CIE exposure, organotypic hippocampal slices were exposed to 1–3 cycles of ethanol (50 mM) in cell culture medium for 5 days, followed by 24-hours of ethanol withdrawal in which a portion of slices were exposed to competitive NMDA receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV; 40 µM). Cytotoxicity was assessed using immunohistochemical labeling of neuron specific nuclear protein (NeuN; Fox-3), a marker of mature neurons, and thionine (2%) staining of Nissl bodies. Multiple cycles of CIE produced neurotoxicity, as reflected in persisting losses of neuron NeuN immunoreactivity and thionine staining in each of the primary cell layers of the hippocampal formation. Hippocampi aged in vitro were significantly more sensitive to the toxic effects of multiple CIEs than were non-aged hippocampi. This effect was not demonstrated in slices exposed to continuous ethanol, in the absence of withdrawal, or to a single exposure/withdrawal regimen. Exposure to APV significantly attenuated the cytotoxicity observed in the primary cell layers of the hippocampus. The present findings suggest that ethanol withdrawal is required to produce NMDA receptor-dependent hippocampal cytotoxicity, particularly in the aging hippocampus in vitro.
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Riegle MA, Masicampo ML, Shan HQ, Xu V, Godwin DW. Ethosuximide Reduces Mortality and Seizure Severity in Response to Pentylenetetrazole Treatment During Ethanol Withdrawal. Alcohol Alcohol 2015; 50:501-8. [PMID: 25870316 DOI: 10.1093/alcalc/agv033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 03/12/2015] [Indexed: 11/13/2022] Open
Abstract
AIMS We recently demonstrated that T-type calcium channels are affected by alcohol abuse and withdrawal. Treatment with ethosuximide, an antiepileptic drug that blocks T-type calcium channels, reduces seizure activity induced by intermittent ethanol exposures and withdrawals. Here, we expand on these findings to test whether ethosuximide can reduce the sensitivity to pentylenetetrazole-induced seizures during ethanol withdrawal. METHODS We used an intermittent ethanol exposure model to produce withdrawal-induced hyperexcitability in DBA/2J mice. RESULTS Ethosuximide (250 mg/kg) reduced seizure severity in mice undergoing ethanol withdrawal with concurrent PTZ treatment (20 mg/kg). Importantly, ethosuximide did not produce rebound excitability and protected against ethanol withdrawal-induced mortality produced by concurrent PTZ treatment (40 mg/kg). CONCLUSION These results, in addition to previous preclinical findings, suggest that ethosuximide should be further evaluated as a safe, effective alternative to benzodiazepines for the treatment of alcohol withdrawal.
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Affiliation(s)
- Melissa A Riegle
- Neuroscience Program, Wake Forest School of Medicine Department of Neurobiology and Anatomy, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
| | - Melissa L Masicampo
- Department of Neurobiology and Anatomy, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
| | - Hong Qu Shan
- Department of Neurobiology and Anatomy, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
| | - Victoria Xu
- Department of Neurobiology and Anatomy, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
| | - Dwayne W Godwin
- Neuroscience Program, Wake Forest School of Medicine Department of Neurobiology and Anatomy, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157, USA
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42
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Stafford LD, Whittle A. Obese Individuals Have Higher Preference and Sensitivity to Odor of Chocolate. Chem Senses 2015; 40:279-84. [DOI: 10.1093/chemse/bjv007] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
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Jung ME, Metzger DB. Aberrant histone acetylation promotes mitochondrial respiratory suppression in the brain of alcoholic rats. J Pharmacol Exp Ther 2015; 352:258-66. [PMID: 25406171 PMCID: PMC4293440 DOI: 10.1124/jpet.114.219311] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Accepted: 11/17/2014] [Indexed: 11/22/2022] Open
Abstract
The acetylation of histone proteins in the core of DNA regulates gene expression, including those affecting mitochondria. Both histone acetylation and mitochondrial deficit have been implicated in neuronal damage associated with drinking problems. Many alcoholics will repeat unsuccessful attempts at abstaining, developing a pattern of repeated drinking and withdrawal. We investigated whether aberrant histone acetylation contributes to mitochondrial and cellular damage induced by repeated ethanol withdrawal (EW). We also investigated whether this effect of histone acetylation involves let-7f, a small noncoding RNA (microRNA). Male rats received two cycles of an ethanol/control diet (7.5%, 4 weeks) and withdrawal. Their prefrontal cortex was collected to measure the mitochondrial respiration and histone acetylation using extracellular flux (XF) real-time respirometry and gold immunostaining, respectively. Separately, HT22 (mouse hippocampal) cells received two cycles of ethanol exposure (100 mM, 20 hours) and withdrawal. Trichostatin A (TSA) as a histone acetylation promoter and let-7f antagomir were applied during withdrawal. The mitochondrial respiration, let-7f level, and cell viability were assessed using XF respirometry, quantitative polymerase chain reaction, TaqMan let-7f primers, and a calcein-acetoxymethyl assay, respectively. Repeated ethanol withdrawn rats showed a more than 2-fold increase in histone acetylation, accompanied by mitochondrial respiratory suppression. EW-induced mitochondrial respiratory suppression was exacerbated by TSA treatment in a manner that was attenuated by let-7f antagomir cotreatment. TSA treatment did not alter the increasing effect of EW on the let-7f level but dramatically exacerbated the cell death induced by EW. These data suggest that the multiple episodes of withdrawal from chronic ethanol impede mitochondrial and cellular integrity through upregulating histone acetylation, independent of or additively with let-7f.
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Affiliation(s)
- Marianna E Jung
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas
| | - Daniel B Metzger
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas
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Trick L, Kempton MJ, Williams SCR, Duka T. Impaired fear recognition and attentional set-shifting is associated with brain structural changes in alcoholic patients. Addict Biol 2014; 19:1041-54. [PMID: 25123156 PMCID: PMC4282104 DOI: 10.1111/adb.12175] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Alcoholic patients with multiple detoxifications/relapses show cognitive and emotional deficits. We performed structural magnetic resonance imaging and examined performance on a cognitive flexibility task (intra-extradimensional set shift and reversal; IED). We also presented subjects with fearful, disgust and anger facial emotional expressions. Participants were abstaining, multiply detoxified (MDTx; n = 12) or singly detoxified patients (SDTx; n = 17) and social drinker controls (n = 31). Alcoholic patients were less able than controls to change their behavior in accordance with the changing of the rules in the IED and they were less accurate in recognizing fearful expressions in particular. They also showed lower gray matter volume compared with controls in frontal brain areas, including inferior frontal cortex (IFC) and insula that mediate emotional processing, inferior parietal lobule and medial frontal cortex that mediate attentional and motor planning processes, respectively. Impairments in performance and some of the regional decreases in gray matter were greater in MDTx. Gray matter volume in IFC in patients was negatively correlated with the number of detoxifications, whereas inferior parietal lobule was negatively correlated with the control over drinking score (impaired control over drinking questionnaire). Performance in IED was also negatively correlated with gray matter volume in IFC/BA47, whereas recognition of fearful faces was positively correlated with the IFC gray matter. Repeated episodes of detoxification from alcohol, related to severity of dependency, are coupled with altered brain structure in areas of emotional regulation, attention and motor planning. Such changes may confer increased inability to switch behavior according to environmental demands and social incompetence, contributing to relapse.
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Affiliation(s)
| | - Matthew J. Kempton
- Department of Neuroimaging; Institute of Psychiatry; King's College London; UK
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Rosenwasser AM, McCulley WD, Fecteau M. Circadian activity rhythms and voluntary ethanol intake in male and female ethanol-preferring rats: effects of long-term ethanol access. Alcohol 2014; 48:647-55. [PMID: 25281289 DOI: 10.1016/j.alcohol.2014.07.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 06/12/2014] [Accepted: 07/01/2014] [Indexed: 01/13/2023]
Abstract
Chronic alcohol (ethanol) intake alters fundamental properties of the circadian clock. While previous studies have reported significant alterations in free-running circadian period during chronic ethanol access, these effects are typically subtle and appear to require high levels of intake. In the present study we examined the effects of long-term voluntary ethanol intake on ethanol consumption and free-running circadian period in male and female, selectively bred ethanol-preferring P and HAD2 rats. In light of previous reports that intermittent access can result in escalated ethanol intake, an initial 2-week water-only baseline was followed by either continuous or intermittent ethanol access (i.e., alternating 15-day epochs of ethanol access and ethanol deprivation) in separate groups of rats. Thus, animals were exposed to either 135 days of continuous ethanol access or to five 15-day access periods alternating with four 15-day periods of ethanol deprivation. Animals were maintained individually in running-wheel cages under continuous darkness throughout the experiment to allow monitoring of free-running activity and drinking rhythms, and 10% (v/v) ethanol and plain water were available continuously via separate drinking tubes during ethanol access. While there were no initial sex differences in ethanol drinking, ethanol preference increased progressively in male P and HAD2 rats under both continuous and intermittent-access conditions, and eventually exceeded that seen in females. Free-running period shortened during the initial ethanol-access epoch in all groups, but the persistence of this effect showed complex dependence on sex, breeding line, and ethanol-access schedule. Finally, while females of both breeding lines displayed higher levels of locomotor activity than males, there was little evidence for modulation of activity level by ethanol access. These results are consistent with previous findings that chronic ethanol intake alters free-running circadian period, and show further that the development of chronobiological tolerance to ethanol may vary by sex and genotype.
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Affiliation(s)
- Alan M Rosenwasser
- Department of Psychology, University of Maine, Orono, ME 04469, USA; School of Biology and Ecology, University of Maine, Orono, ME 04469, USA; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA.
| | | | - Matthew Fecteau
- Department of Psychology, University of Maine, Orono, ME 04469, USA
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Goodson CM, Clark BJ, Douglas IS. Predictors of Severe Alcohol Withdrawal Syndrome: A Systematic Review and Meta-Analysis. Alcohol Clin Exp Res 2014; 38:2664-77. [DOI: 10.1111/acer.12529] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 07/15/2014] [Indexed: 11/30/2022]
Affiliation(s)
- Carrie M. Goodson
- University of Colorado School of Medicine; Denver Colorado
- Denver Health Medical Center, Department of Medicine; Denver Colorado
| | | | - Ivor S. Douglas
- University of Colorado School of Medicine; Denver Colorado
- Denver Health Medical Center, Department of Medicine; Denver Colorado
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Levetiracetam results in increased and decreased alcohol drinking with different access procedures in C57BL/6J mice. Behav Pharmacol 2014; 25:61-70. [PMID: 24322822 DOI: 10.1097/fbp.0000000000000019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The antiepileptic levetiracetam (LEV) has been investigated for the treatment of alcohol abuse. However, little is known about how LEV alters the behavioral effects of alcohol in laboratory animals. The acute effects of LEV on alcohol drinking by male C57BL/6J mice were investigated using two different drinking procedures, limited access [drinking-in-the-dark (DID)] and intermittent access (IA) drinking. In the first experiment (DID), mice had access to a single bottle containing alcohol or sucrose for 4 h every other day. In the second experiment (IA), mice had IA to two bottles, one containing alcohol or sucrose and one containing water, for 24 h on Monday, Wednesday, and Friday. In both experiments, mice were administered LEV (0.3-100 mg/kg intraperitoneally) or vehicle 30 min before access to the drinking solutions. In the DID mice, LEV increased alcohol intake from 4.3 to 5.4 g/kg, whereas in the IA mice LEV decreased alcohol intake from 4.8 to 3.0 g/kg in the first 4 h of access and decreased 24 h alcohol intake from 20 to ∼15 g/kg. These effects appear specific to alcohol, as LEV did not affect sucrose intake in either experiment. LEV appears to differentially affect drinking in animal models of moderate and heavier alcohol consumption.
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Maldonado JR, Sher Y, Ashouri JF, Hills-Evans K, Swendsen H, Lolak S, Miller AC. The "Prediction of Alcohol Withdrawal Severity Scale" (PAWSS): systematic literature review and pilot study of a new scale for the prediction of complicated alcohol withdrawal syndrome. Alcohol 2014; 48:375-90. [PMID: 24657098 DOI: 10.1016/j.alcohol.2014.01.004] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Revised: 01/22/2014] [Accepted: 01/23/2014] [Indexed: 01/10/2023]
Abstract
BACKGROUND To date, no screening tools for alcohol withdrawal syndromes (AWS) have been validated in the medically ill. Although several tools quantify the severity of AWS (e.g., Clinical Institute Withdrawal Assessment for Alcohol [CIWA]), none identify subjects at risk of AWS, thus missing the opportunity for timely prophylaxis. Moreover, there are no validated tools for the prediction of complicated (i.e., moderate to severe) AWS in the medically ill. OBJECTIVES Our goals were (1) to conduct a systematic review of the published literature on AWS to identify clinical factors associated with the development of AWS, (2) to use the identified factors to develop a tool for the prediction of alcohol withdrawal among patients at risk, and (3) to conduct a pilot study to assess the validity of the tool. METHODS For the creation of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS), we conducted a systematic literature search using PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines for clinical factors associated with the development of AWS, using PubMed, PsychInfo, MEDLINE, and Cochrane Databases. Eligibility criteria included: (i) manuscripts dealing with human subjects, age 18 years or older, (ii) manuscripts directly addressing descriptions of AWS or its predisposing factors, including case reports, naturalistic case descriptions, and all types of clinical trials (e.g., randomized, single-blind, or open label studies), (iii) manuscripts describing characteristics of alcohol use disorder (AUD), and (iv) manuscripts dealing with animal data (which were considered only if they directly dealt with variables described in humans). Obtained data were used to develop the Prediction of Alcohol Withdrawal Severity Scale, in order to assist in the identification of patients at risk for complicated AWS. A pilot study was conducted to assess the new tool's psychometric qualities on patients admitted to a general inpatient medicine unit over a 2-week period, who agreed to participate in the study. Blind to PAWSS results, a separate group of researchers retrospectively examined the medical records for evidence of AWS. RESULTS The search produced 2802 articles describing factors potentially associated with increased risk for AWS, increased severity of withdrawal symptoms, and potential characteristics differentiating subjects with various forms of AWS. Of these, 446 articles met inclusion criteria and underwent further scrutiny, yielding a total of 233 unique articles describing factors predictive of AWS. A total of 10 items were identified as correlated with complicated AWS (i.e., withdrawal hallucinosis, withdrawal-related seizures, and delirium tremens) and used to construct the PAWSS. During the pilot study, a total of 68 subjects underwent evaluation with PAWSS. In this pilot sample the sensitivity, specificity, and positive and negative predictive values of PAWSS were 100%, using the threshold score of 4. DISCUSSION The results of the literature search identified 10 items which may be correlated with risk for complicated AWS. These items were assembled into a tool to assist in the identification of patients at risk: PAWSS. The results of this pilot study suggest that PAWSS may be useful in identifying risk of complicated AWS in medically ill, hospitalized individuals. PAWSS is the first validated tool for the prediction of severe AWS in the medically ill and its use may aid in the early identification of patients at risk for complicated AWS, allowing for prophylaxis against AWS before severe alcohol withdrawal syndromes develop.
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Affiliation(s)
- José R Maldonado
- Psychiatry, Internal Medicine, Surgery, & Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
| | - Yelizaveta Sher
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Judith F Ashouri
- Internal Medicine (Rheumatology), University of California, San Francisco, CA, USA
| | | | - Heavenly Swendsen
- Psychosomatic Medicine, Department of Psychiatry, Stanford University School of Medicine, Stanford, CA, USA
| | - Sermsak Lolak
- Psychiatry, George Washington University School of Medicine & Health Sciences, Washington, DC, USA
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Association of recent incarceration with traumatic injury, substance use-related health consequences, and health care utilization. J Addict Med 2014; 8:66-72. [PMID: 24365804 DOI: 10.1097/adm.0000000000000009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The higher risk of death among recently released inmates relative to the general population may be because of the higher prevalence of substance dependence among inmates or an independent effect of incarceration. We explored the effects of recent incarceration on health outcomes that may be intermediate markers for mortality. METHODS Longitudinal multivariable regression analyses were conducted on interview data (baseline, 3-, 6-, and 12-month follow-up) from alcohol- and/or drug-dependent individuals (n = 553) participating in a randomized clinical trial to test the effectiveness of chronic disease management for substance dependence in primary care. The main independent variable was recent incarceration (spending ≥1 night in jail or prison in the past 3 months). The 3 main outcomes of this study were any traumatic injury, substance use-related health consequences, and health care utilization--defined as hospitalization (excluding addiction treatment or detoxification) and/or emergency department visit. RESULTS Recent incarceration was not significantly associated with traumatic injury (adjusted odds ratio [AOR] = 0.98; 95% confidence interval [CI]: 0.65-1.49) or health care utilization (AOR = 0.88; 95% CI: 0.64-1.20). However, recent incarceration was associated with higher odds for substance use-related health consequences (AOR = 1.42; 95% CI: 1.02-1.98). CONCLUSIONS Among people with alcohol and/or drug dependence, recent incarceration was significantly associated with substance use-related health consequences but not injury or health care utilization after adjustment for covariates. These findings suggest that substance use-related health consequences may be part of the explanation for the increased risk of death faced by former inmates.
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Nejad SH, Chuang K, Hirschberg R, Aquino PR, Fricchione GL. The Use of Antiepileptic Drugs in Acute Neuropsychiatric Conditions: Focus on Traumatic Brain Injury, Pain, and Alcohol Withdrawal. ACTA ACUST UNITED AC 2014. [DOI: 10.4236/ijcm.2014.512099] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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