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Wlaź P, Fitzgerald PJ, Żmudzki P, Socała K. Investigating whether alcohol is transformed to norepinephrine or dopamine in the mouse brain. Pharmacol Rep 2025; 77:703-715. [PMID: 40069538 DOI: 10.1007/s43440-025-00708-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/22/2025] [Accepted: 02/24/2025] [Indexed: 05/13/2025]
Abstract
BACKGROUND A number of rodent studies have investigated the effects of alcohol (ethanol) administration on the catecholaminergic neurotransmitters, norepinephrine (NE) and dopamine (DA). These studies suggest that presentation of alcohol to mice or rats can alter brain levels of NE and DA, in various subregions. Other studies have presented the hypothesis that there may be an unidentified pathway in rodents, and other organisms, that actually transforms ethanol to NE or DA. Here, this paper investigates the hypothesis in male CD-1 mice. METHODS Experimental mice were systemically injected with an intoxicating dose of stable isotope-labeled carbon 13 (C13) ethanol (ethanol-1-13C, 20% v/v, 1.5 g/kg, ip), and brain samples (hippocampus and brainstem) were collected two hours post-injection. Two other groups of mice received normal unlabeled carbon 12 (C12) ethanol or a water (Control) injection, respectively. RESULTS Although we had difficulty detecting the two neurotransmitters (especially C13 NE) due to their very low concentrations, high-resolution mass spectrometry analysis suggests that C12 ethanol selectively boosted hippocampal C12 NE, and C13 ethanol likewise boosted hippocampal C13 NE. We did not observe effects on DA. CONCLUSIONS These data provide preliminary information on whether there is a novel biosynthetic pathway in mice that converts alcohol to catecholamines in select brain regions, where the ethanol molecule would presumably help form the ethanolamine side chain of NE. There are, however, alternative interpretations of these findings, including that acute alcohol administration modulates catecholamine release, reuptake, metabolism, or canonical biosynthesis.
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Affiliation(s)
- Piotr Wlaź
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland
| | | | - Paweł Żmudzki
- Department of Medicinal Chemistry, Medical College, Jagiellonian University, Medyczna 9, 30-688, Kraków, Poland
| | - Katarzyna Socała
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland.
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2
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Pich EM, Tarnanas I, Brigidi P, Collo G. Gut Microbiome-Liver-Brain axis in Alcohol Use Disorder. The role of gut dysbiosis and stress in alcohol-related cognitive impairment progression: possible therapeutic approaches. Neurobiol Stress 2025; 35:100713. [PMID: 40092632 PMCID: PMC11909761 DOI: 10.1016/j.ynstr.2025.100713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 01/20/2025] [Accepted: 02/07/2025] [Indexed: 03/19/2025] Open
Abstract
The Gut Microbiome-Liver-Brain Axis is a relatively novel construct with promising potential to enhance our understanding of Alcohol Use Disorder (AUD), and its therapeutic approaches. Significant alterations in the gut microbiome occur in AUD even before any other systemic signs or symptoms manifest. Prolonged and inappropriate alcohol consumption, by affecting the gut microbiota and gut mucosa permeability, is thought to contribute to the development of behavioral and cognitive impairments, leading to Alcohol-Related Liver Disorders and potentially progressing into alcoholic cirrhosis, which is often associated with severe cognitive impairment related to neurodegeneration, such as hepatic encephalopathy and alcoholic dementia. The critical role of the gut microbiota is further supported by the efficacy of FDA-approved treatments for hepatic encephalopathy in alcoholic cirrhosis (i.e., lactulose and rifaximin). To stimulate new research, we hypothesize that interactions between a maladaptive stress response and a constitutional predisposition to neurodegeneration underlie the progression of AUD to conditions of Alcohol-Related Clinical Concerns with severe cognitive impairment, which represent a significant and costly burden to society. Early identification of AUD individuals at risk for developing these conditions could help to prioritize integrated therapeutic interventions targeting different substrates of the Gut Microbiome-Liver-Brain axis. Specifically, addiction medications, microbiome modulators, stress-reducing interventions, and, possibly soon, novel agents that reduce hepatic steatosis/fibrosis will be discussed in the context of digitally supported integrated therapeutic approaches. The explicit goal of this AUD treatment performed on the early stage of the disorder would be to reduce the transition from AUD to those conditions of Alcohol-Related Common Clinical Concerns associated with severe cognitive impairment, a strategy recommended for most neurological neurodegenerative disorders.
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Affiliation(s)
| | - Ioannis Tarnanas
- Trinity College Dublin, Global Brain Health Institute, Dublin, Ireland
- Altoida Inc., Washington DC, USA
| | - Patrizia Brigidi
- Human Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Ginetta Collo
- Human Neuropharmacology Unit, Department of Molecular & Translational Medicine, University of Brescia, Italy
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3
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Nippert KE, Rowland CP, Vazey EM, Moorman DE. Alcohol, flexible behavior, and the prefrontal cortex: Functional changes underlying impaired cognitive flexibility. Neuropharmacology 2024; 260:110114. [PMID: 39134298 PMCID: PMC11694314 DOI: 10.1016/j.neuropharm.2024.110114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 08/22/2024]
Abstract
Cognitive flexibility enables individuals to alter their behavior in response to changing environmental demands, facilitating optimal behavior in a dynamic world. The inability to do this, called behavioral inflexibility, is a pervasive behavioral phenotype in alcohol use disorder (AUD), driven by disruptions in cognitive flexibility. Research has repeatedly shown that behavioral inflexibility not only results from alcohol exposure across species but can itself be predictive of future drinking. Like many high-level executive functions, flexible behavior requires healthy functioning of the prefrontal cortex (PFC). The scope of this review addresses two primary themes: first, we outline tasks that have been used to investigate flexibility in the context of AUD or AUD models. We characterize these based on the task features and underlying cognitive processes that differentiate them from one another. We highlight the neural basis of flexibility measures, focusing on the PFC, and how acute or chronic alcohol in humans and non-human animal models impacts flexibility. Second, we consolidate findings on the molecular, physiological and functional changes in the PFC elicited by alcohol, that may contribute to cognitive flexibility deficits seen in AUD. Collectively, this approach identifies several key avenues for future research that will facilitate effective treatments to promote flexible behavior in the context of AUD, to reduce the risk of alcohol related harm, and to improve outcomes following AUD. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".
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Affiliation(s)
- Kathryn E Nippert
- Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, 01003, USA
| | - Courtney P Rowland
- Department of Biology, University of Massachusetts Amherst, Amherst, MA, 01003, USA
| | - Elena M Vazey
- Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, 01003, USA; Department of Biology, University of Massachusetts Amherst, Amherst, MA, 01003, USA.
| | - David E Moorman
- Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, 01003, USA; Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA, 01003, USA.
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4
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Liu M, Mu S, Han W, Tan X, Liu E, Hang Z, Zhu S, Yue Q, Sun J. Dopamine D1 receptor in orbitofrontal cortex to dorsal striatum pathway modulates methamphetamine addiction. Biochem Biophys Res Commun 2023; 671:96-104. [PMID: 37300946 DOI: 10.1016/j.bbrc.2023.06.005] [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: 05/02/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023]
Abstract
The orbitofrontal cortex (OFC)-dorsal striatum (DS) is an important neural circuit that contributes to addictive behavior, including compulsive reinforcement, yet the specific types of neurons that play a major role still need to be further elucidated. Here, we used a place conditioning paradigm to measure the conditioned responses to methamphetamine (MA). The results demonstrated that MA increases the expression of c-Fos, synaptic plasticity in OFC and DS. Patch-clamp recording showed that MA activated projection neurons from the OFC to the DS, and chemogenetic manipulation of neuronal activity in OFC-DS projection neurons affects conditioned place preference (CPP) scores. And the combined patch-electrochemical technique was used to detect the DA release in OFC, the data indicated that the DA release was increased in MA group. Additionally, SCH23390, a D1R antagonist, was used to verify the function of D1R projection neurons, showing that SCH23390 reversed MA addiction-like behavior. Collectively, these findings provide evidence for the D1R neuron is sufficient to regulate MA addiction in the OFC-DS pathway, and the study provides new insight into the underlying mechanism of pathological changes in MA addiction.
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Affiliation(s)
- Min Liu
- Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Shouhong Mu
- Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Weikai Han
- Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xu Tan
- Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - E Liu
- Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Zhaofang Hang
- Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Shaowei Zhu
- Department of Neurology, Qilu Hospital, Shandong University, Jinan, China
| | - Qingwei Yue
- Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jinhao Sun
- Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, China.
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5
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Haun HL, Lebonville CL, Solomon MG, Griffin WC, Lopez MF, Becker HC. Dynorphin/Kappa Opioid Receptor Activity Within the Extended Amygdala Contributes to Stress-Enhanced Alcohol Drinking in Mice. Biol Psychiatry 2022; 91:1019-1028. [PMID: 35190188 PMCID: PMC9167153 DOI: 10.1016/j.biopsych.2022.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND While there is high comorbidity of stress-related disorders and alcohol use disorder, few effective treatments are available and elucidating underlying neurobiological mechanisms has been hampered by a general lack of reliable animal models. Here, we use a novel mouse model demonstrating robust and reproducible stress-enhanced alcohol drinking to examine the role of dynorphin/kappa opioid receptor (DYN/KOR) activity within the extended amygdala in mediating this stress-alcohol interaction. METHODS Mice received repeated weekly cycles of chronic intermittent ethanol exposure alternating with weekly drinking sessions ± forced swim stress exposure. Pdyn messenger RNA expression was measured in the central amygdala (CeA), and DYN-expressing CeA neurons were then targeted for chemogenetic inhibition. Finally, a KOR antagonist was microinjected into the CeA or bed nucleus of the stria terminalis to examine the role of KOR signaling in promoting stress-enhanced drinking. RESULTS Stress (forced swim stress) selectively increased alcohol drinking in mice with a history of chronic intermittent ethanol exposure, and this was accompanied by elevated Pdyn messenger RNA levels in the CeA. Targeted chemogenetic silencing of DYN-expressing CeA neurons blocked stress-enhanced drinking, and KOR antagonism in the CeA or bed nucleus of the stria terminalis significantly reduced stress-induced elevated alcohol consumption without altering moderate intake in control mice. CONCLUSIONS Using a novel and robust model of stress-enhanced alcohol drinking, a significant role for DYN/KOR activity within extended amygdala circuitry in mediating this effect was demonstrated, thereby providing further evidence that the DYN/KOR system may be a valuable target in the development of more effective treatments for individuals presenting with comorbidity of stress-related disorders and alcohol use disorder.
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Affiliation(s)
- Harold L Haun
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Christina L Lebonville
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Matthew G Solomon
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - William C Griffin
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Marcelo F Lopez
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Howard C Becker
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina; Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina.
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6
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Rodberg EM, Vazey EM. Individual differences in behavioral flexibility predict future volitional ethanol consumption in mice. Alcohol 2022; 101:37-43. [PMID: 35395359 DOI: 10.1016/j.alcohol.2022.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 03/01/2022] [Accepted: 03/14/2022] [Indexed: 11/18/2022]
Abstract
Cognitive control is key to regulating alcohol intake and preventing relapse. Behavioral inflexibility can prevent adaptive strategies such as mindfulness or other relapse-prevention behaviors. In a mouse model we investigated whether individual variability in behavioral flexibility (using attentional set-shifting task; ASST) predicts future alcohol intake. Adult male and female C57BL/6J mice were subjected to ASST using a bowl-digging paradigm where mice identify a baited bowl based on compound odor and textural cues. This was completed prior to any alcohol exposure. Individual performance across mice varied within the group. We integrated several metrics, specifically ASST stage completed, trials to completion, and errors performed to produce an individual performance index measure of behavioral flexibility. Afterward, ASST mice were trained to drink ethanol (15%, v/v, 1 h/day) for 3-4 weeks until intake stabilized. Using this prospective approach, we identified an inverse relationship between behavioral flexibility and drinking-less-flexible mice had a propensity to consume more alcohol. Similar relationships have been identified previously in non-human primates and rats. Our results show that the relationship between alcohol and behavioral flexibility is a robust trait that is conserved across species and can be used in mice to study neural substrates underlying these behaviors.
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Affiliation(s)
- Ellen M Rodberg
- Neuroscience and Behavior Program and Department of Biology, University of Massachusetts Amherst, 611 North Pleasant St., Amherst, MA 01003, United States
| | - Elena M Vazey
- Neuroscience and Behavior Program and Department of Biology, University of Massachusetts Amherst, 611 North Pleasant St., Amherst, MA 01003, United States.
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7
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Bagheri F, Goudarzi I, Lashkarbolouki T, Elahdadi Salmani M, Goudarzi A, Morley-Fletcher S. The Combined Effects of Perinatal Ethanol and Early-Life Stress on Cognition and Risk-Taking Behavior through Oxidative Stress in Rats. Neurotox Res 2022; 40:925-940. [PMID: 35507233 DOI: 10.1007/s12640-022-00506-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 04/07/2022] [Accepted: 04/09/2022] [Indexed: 11/29/2022]
Abstract
Both prenatal ethanol and early-life stress have been shown to induce reduced risk-taking and explorative behavior as well as cognitive dysfunction in the offspring. In this study, we examined the effect of combined exposure to ethanol and early stress on maternal care, exploratory behavior, memory performances, and oxidative stress in male offspring. Pregnant rats were exposed to ethanol (4 g/kg) from gestational day (GD) 6-to postnatal day (PND) 14 and limited nesting material (LNS) from PND0-PND14 individually or in combination. Maternal behavior was evaluated during diurnal cycle. The level of corticosterone hormone and markers of oxidative stress were evaluated in the pups. Risk-taking and explorative behavior were assessed with the elevated-plus maze (EPM) test and cognitive behavior with the Morris water maze (MWM), novel object recognition (NORT), and object location memory (OLM) tests. In the mothers, perinatal alcohol or LNS either alone or in combination decreased maternal behavior. In the offspring, the combination of the two factors significantly increased the pup's plasma corticosterone concentration in comparison with ethanol and LNS alone. Reduced risk-taking behavior was observed in the ethanol, LNS and ethanol + LNS groups compared with the control group, and this was amplified in the co-exposure of ethanol and LNS groups. The MWM, NORT, and OLM tests revealed spatial and recognition memory impairment in the ethanol and LNS groups. This impairment was more profound in the co-exposure of ethanol and LNS. Also, we observed a significant decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and an increase in malondialdehyde (MDA) level in the hippocampus of ethanol and LNS co-exposed animals as compared with individual exposure of ethanol and LNS. While each factor independently produced similar outcomes, the results indicate that the dual exposure paradigm could significantly strengthen the outcomes.
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Affiliation(s)
| | - Iran Goudarzi
- School of Biology, Damghan University, Damghan, Iran.
| | | | | | - Afsaneh Goudarzi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Morley-Fletcher
- UMR 8576, Univ. Lille, CNRS, UGSF - Unité de Glycobiologie Structurale Et Fonctionnelle, 59000, Lille, France
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8
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Bloch S, Holleran KM, Kash TL, Vazey EM, Rinker JA, Lebonville CL, O'Hara K, Lopez MF, Jones SR, Grant KA, Becker HC, Mulholland PJ. Assessing negative affect in mice during abstinence from alcohol drinking: Limitations and future challenges. Alcohol 2022; 100:41-56. [PMID: 35181404 PMCID: PMC8983487 DOI: 10.1016/j.alcohol.2022.02.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 01/09/2023]
Abstract
Alcohol use disorder (AUD) is frequently comorbid with mood disorders, and these co-occurring neuropsychiatric disorders contribute to the development and maintenance of alcohol dependence and relapse. In preclinical models, mice chronically exposed to alcohol display anxiety-like and depressive-like behaviors during acute withdrawal and protracted abstinence. However, in total, results from studies using voluntary alcohol-drinking paradigms show variable behavioral outcomes in assays measuring negative affective behaviors. Thus, the main objective of this review is to summarize the literature on the variability of negative affective behaviors in mice after chronic alcohol exposure. We compare the behavioral phenotypes that emerge during abstinence across different exposure models, including models of alcohol and stress interactions. The complicated outcomes from these studies highlight the difficulties of assessing negative affective behaviors in mouse models designed for the study of AUD. We discuss new behavioral assays, comprehensive platforms, and unbiased machine-learning algorithms as promising approaches to better understand the interaction between alcohol and negative affect in mice. New data-driven approaches in the understanding of mouse behavior hold promise for improving the identification of mechanisms, cell subtypes, and neurocircuits that mediate negative affect. In turn, improving our understanding of the neurobehavioral basis of alcohol-associated negative affect will provide a platform to test hypotheses in mouse models that aim to improve the development of more effective strategies for treating individuals with AUD and co-occurring mood disorders.
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Affiliation(s)
- Solal Bloch
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Katherine M Holleran
- Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States
| | - Thomas L Kash
- Bowles Center for Alcohol Studies, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Elena M Vazey
- Department of Biology, University of Massachusetts Amherst, Amherst, MA 01003, United States
| | - Jennifer A Rinker
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Christina L Lebonville
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Krysten O'Hara
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Marcelo F Lopez
- Department of Psychiatry & Behavioral Sciences, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Sara R Jones
- Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States
| | - Kathleen A Grant
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, United States
| | - Howard C Becker
- Department of Psychiatry & Behavioral Sciences, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Patrick J Mulholland
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC 29425, United States.
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Charlton AJ, Perry CJ. The Effect of Chronic Alcohol on Cognitive Decline: Do Variations in Methodology Impact Study Outcome? An Overview of Research From the Past 5 Years. Front Neurosci 2022; 16:836827. [PMID: 35360176 PMCID: PMC8960615 DOI: 10.3389/fnins.2022.836827] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/27/2022] [Indexed: 11/24/2022] Open
Abstract
Excessive alcohol use is often associated with accelerated cognitive decline, and extensive research using animal models of human alcohol consumption has been conducted into potential mechanisms for this relationship. Within this literature there is considerable variability in the types of models used. For example, alcohol administration style (voluntary/forced), length and schedule of exposure and abstinence period are often substantially different between studies. In this review, we evaluate recent research into alcohol-induced cognitive decline according to methodology of alcohol access, as well as cognitive behavioral task employed. Our aim was to query whether the nature and severity of deficits observed may be impacted by the schedule and type of alcohol administration. We furthermore examined whether there is any apparent relationship between the amount of alcohol consumed and the severity of the deficit, as well as the potential impact of abstinence length, and other factors such as age of administration, and sex of subject. Over the past five years, researchers have overwhelmingly used non-voluntary methods of intake, however deficits are still found where intake is voluntary. Magnitude of intake and type of task seem most closely related to the likelihood of producing a deficit, however even this did not follow a consistent pattern. We highlight the importance of using systematic and clear reporting styles to facilitate consistency across the literature in this regard. We hope that this analysis will provide important insights into how experimental protocols might influence findings, and how different patterns of consumption are more or less likely to produce an addiction-vulnerable cognitive phenotype in animal models.
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Affiliation(s)
- Annai J. Charlton
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Christina J. Perry
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- School of Psychological Sciences, Centre for Emotional Health, Macquarie University, North Ryde, NSW, Australia
- *Correspondence: Christina J. Perry,
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10
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Schuh KM, Sneddon EA, Nader AM, Muench MA, Radke AK. Orbitofrontal cortex subregion inhibition during binge-like and aversion-resistant alcohol drinking. Alcohol 2022; 99:1-8. [PMID: 34863917 PMCID: PMC8844094 DOI: 10.1016/j.alcohol.2021.11.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/29/2021] [Accepted: 11/28/2021] [Indexed: 01/10/2023]
Abstract
Two important contributors to alcohol-related problems and alcohol use disorder (AUD) are binge- and compulsive-like drinking. The orbitofrontal cortex (OFC), a brain region implicated in outcome valuation and behavioral flexibility, is functionally altered by alcohol exposure. Data from animal models also suggest that both the medial (mOFC) and lateral (lOFC) subregions of the OFC regulate alcohol-related behaviors. The current study was designed to examine the contributions of mOFC and lOFC using a model of binge-like and aversion-resistant ethanol drinking in C57BL/6J male and female mice. The inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) hM4Di were used to inhibit neurons in either the mOFC or the lOFC in mice drinking 15% ethanol in a two-bottle, limited-access, modified drinking in the dark paradigm. The effects of chemogenetic inhibition on consumption of quinine-adulterated ethanol, water, and water + quinine were also assessed. Inhibiting the mOFC did not alter consumption of ethanol or aversion-resistant drinking of ethanol + quinine. In contrast, inhibition of neurons in the lOFC increased consumption, but not preference, of ethanol alone. mOFC and lOFC inhibition did not alter water or quinine-adulterated water intake, indicating the effects shown here are specific to ethanol drinking. These data support the role of the lOFC in regulating alcohol consumption but fail to find a similar role for mOFC.
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Affiliation(s)
| | | | | | | | - Anna K. Radke
- Correspondence to: Anna K. Radke, Ph.D., 90 N. Patterson Ave., Oxford, OH, USA 45056, , Phone: 513-529-6941, Fax: 513-529-2420
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11
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Hosseini-Sharifabad A, Alaei Z, Rabbani M, Seyedabadi M. The Role of Cyclooxygenase 2 in the Cognitive Impairment Induced by Alcohol or Stress in Rats. Adv Biomed Res 2022; 10:44. [PMID: 35071112 PMCID: PMC8744420 DOI: 10.4103/abr.abr_287_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/12/2021] [Accepted: 02/13/2021] [Indexed: 11/20/2022] Open
Abstract
Background: Cognitive impairment is an unpleasant and progressive mental disorder characterized by learning and memory disabilities. Stress and alcohol are two known environmental factors that increase cognitive impairment. This study was designed to evaluate the relative role of cyclooxygenase 2 in alcohol or stress-induced cognitive impairment. Materials and Methods: Male Wistar rats were randomly divided into groups with six rats in each. The groups included sham, control, alcohol (15% ethanol in drinking water), and restraint stress (restraint 6 h per day). Three separated groups received celecoxib at a dose of 20 mg/kg in addition to those listed above. The treatments continued daily for 28 days. The object recognition task (ORT) and Morris water maze (MWM) are used to evaluate the learning and memory. Results: Alcohol or restrain stress significantly increased the time and distance needed to find the hidden platform in MWM. Furthermore, they decreased the recognition index in ORT compared to the control group. Administration of celecoxib significantly decreased the required time and traveled distance to reach the platform in alcohol-treated animals but not in the stress-exposed rats. Celecoxib also significantly increased the recognition index both in alcohol- or restraint stress-exposed animals. Conclusion: We found that either alcohol or restraint stress impairs memory in rats. In MWM, celecoxib improved the alcohol-induced memory impairment but could not show a reduction in memory deterioration due to restraint stress. In ORT, celecoxib reversed memory impairment due to both alcohol and restraint stress.
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Affiliation(s)
- Ali Hosseini-Sharifabad
- Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Alaei
- Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Rabbani
- Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Seyedabadi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.,Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran
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12
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Sep MSC, Vellinga M, Sarabdjitsingh RA, Joëls M. The rodent object-in-context task: A systematic review and meta-analysis of important variables. PLoS One 2021; 16:e0249102. [PMID: 34270575 PMCID: PMC8284613 DOI: 10.1371/journal.pone.0249102] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/24/2021] [Indexed: 12/15/2022] Open
Abstract
Environmental information plays an important role in remembering events. Information about stable aspects of the environment (here referred to as 'context') and the event are combined by the hippocampal system and stored as context-dependent memory. In rodents (such as rats and mice), context-dependent memory is often investigated with the object-in-context task. However, the implementation and interpretation of this task varies considerably across studies. This variation hampers the comparison between studies and-for those who design a new experiment or carry out pilot experiments-the estimation of whether observed behavior is within the expected range. Also, it is currently unclear which of the variables critically influence the outcome of the task. To address these issues, we carried out a preregistered systematic review (PROSPERO CRD42020191340) and provide an up-to-date overview of the animal-, task-, and protocol-related variations in the object-in-context task for rodents. Using a data-driven explorative meta-analysis we next identified critical factors influencing the outcome of this task, such as sex, testbox size and the delay between the learning trials. Based on these observations we provide recommendations on sex, strain, prior arousal, context (size, walls, shape, etc.) and timing (habituation, learning, and memory phase) to create more consensus in the set-up, procedure, and interpretation of the object-in-context task for rodents. This could contribute to a more robust and evidence-based design in future animal experiments.
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Affiliation(s)
- Milou S. C. Sep
- Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
- Brain Research and Innovation Centre, Ministry of Defence, Utrecht, The Netherlands
| | - Marijn Vellinga
- Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - R. Angela Sarabdjitsingh
- Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Marian Joëls
- Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
- University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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13
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Wang JY, Zhang L, Liu J, Yang W, Ma LN. Metabolic syndrome, ApoE genotype, and cognitive dysfunction in an elderly population: A single-center, case-control study. World J Clin Cases 2021; 9:1005-1015. [PMID: 33644164 PMCID: PMC7896651 DOI: 10.12998/wjcc.v9.i5.1005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/12/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is related to poor cognitive function. However, the results of previous studies were inconsistent, and whether the ApoEε4 allele modifies the association remains unclear.
AIM To elucidate the relationships among MetS, ApoEε4, and cognitive dysfunction in an elderly population in China.
METHODS One hundred elderly patients with MetS and 102 age- and gender-matched controls were included in the study. Baseline clinical characteristics and biochemical index for glucose and lipid metabolism were obtained. The distribution of ApoEε4 was assessed with PCR restriction fragment length polymorphism analysis. Cognitive function was evaluated by mini-mental status examination at the 1-year follow-up examination.
RESULTS Compared with controls, MetS patients had worse cognitive function and decreased ability to participate in activities of daily life (P = 0.001 and 0.046, respectively). Patients with cognitive dysfunction had higher prevalence of MetS (62.1% vs 36.4%, P < 0.001) and were more likely to carry the ApoEε4 allele (22.3% vs 10.1%, P = 0.019). Multivariate logistic regression analyses showed that diagnosis with MetS, severe insulin resistance, status as an ApoEε4 carrier, higher systolic blood pressure, and larger waist circumference were risk factors for cognitive dysfunction (P < 0.05). Repeated-measures analysis of variance, performed with data collected at the 1-year follow-up, revealed continuous influences of MetS and ApoEε4 on the deterioration of cognitive function (time × team, P < 0.001 for both).
CONCLUSION Diagnosis of MetS and ApoEε4 carrier status were persistently associated with cognitive dysfunction among an elderly population in China.
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Affiliation(s)
- Jie-Yu Wang
- Department of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Medicine, Beijing 100053, China
| | - Li Zhang
- Department of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Medicine, Beijing 100053, China
| | - Jia Liu
- Department of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Medicine, Beijing 100053, China
| | - Wei Yang
- Department of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Medicine, Beijing 100053, China
| | - Li-Na Ma
- Department of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Medicine, Beijing 100053, China
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Jensen BE, Townsley KG, Grigsby KB, Metten P, Chand M, Uzoekwe M, Tran A, Firsick E, LeBlanc K, Crabbe JC, Ozburn AR. Ethanol-Related Behaviors in Mouse Lines Selectively Bred for Drinking to Intoxication. Brain Sci 2021; 11:189. [PMID: 33557285 PMCID: PMC7915226 DOI: 10.3390/brainsci11020189] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 11/18/2022] Open
Abstract
Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Angela R. Ozburn
- Department of Behavioral Neuroscience, Oregon Health & Science University, and VA Portland Health Care System, Portland, OR 97239, USA; (B.E.J.); (K.G.T.); (K.B.G.); (P.M.); (M.C.); (M.U.); (A.T.); (E.F.); (K.L.); (J.C.C.)
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15
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Cannady R, Nguyen T, Padula AE, Rinker JA, Lopez MF, Becker HC, Woodward JJ, Mulholland PJ. Interaction of chronic intermittent ethanol and repeated stress on structural and functional plasticity in the mouse medial prefrontal cortex. Neuropharmacology 2021; 182:108396. [PMID: 33181147 PMCID: PMC7942177 DOI: 10.1016/j.neuropharm.2020.108396] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/05/2020] [Accepted: 11/06/2020] [Indexed: 01/27/2023]
Abstract
Stress is a risk factor that plays a considerable role in the development and maintenance of alcohol (ethanol) abuse and relapse. Preclinical studies examining ethanol-stress interactions have demonstrated elevated ethanol drinking, cognitive deficits, and negative affective behaviors in mice. However, the neural adaptations in prefrontal cortical regions that drive these aberrant behaviors produced by ethanol-stress interactions are unknown. In this study, male C57BL/6J mice were exposed to chronic intermittent ethanol (CIE) and repeated forced swim stress (FSS). After two cycles of CIE x FSS, brain slices containing the prelimbic (PrL) and infralimbic (IfL) cortex were prepared for analysis of adaptations in dendritic spines and synaptic plasticity. In the PrL cortex, total spine density was increased in mice exposed to CIE. Immediately following induction of long-term potentiation (LTP), the fEPSP slope was increased in the PrL of CIE x FSS treated mice, indicative of a presynaptic adaptation on post-tetanic potentiation (PTP). In the IfL cortex, CIE exposure regardless of FSS experience resulted in an increase in spine density. FSS alone or when combined with CIE exposure increased PTP following LTP induction. Repeated FSS episodes increased IfL cortical paired-pulse facilitation, a second measure of presynaptic plasticity. In summary, CIE exposure resulted in structural adaptations while repeated stress exposure drove metaplastic changes in presynaptic function, demonstrating distinct morphological and functional changes in PrL and IfL cortical neurons. Thus, the structural and functional adaptations may be one mechanism underlying the development of excessive drinking and cognitive deficits associated with ethanol-stress interactions.
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Affiliation(s)
- Reginald Cannady
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA; Department of Biology, College of Science and Technology, North Carolina Agricultural & Technical State University, 1601 East Market Street, Barnes Hall 215, Greensboro, NC, 27411, USA
| | - Tiffany Nguyen
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA
| | - Audrey E Padula
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA
| | - Jennifer A Rinker
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA
| | - Marcelo F Lopez
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA
| | - Howard C Becker
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA
| | - John J Woodward
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA
| | - Patrick J Mulholland
- Department of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA.
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16
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Padula AE, Rinker JA, Lopez MF, Mulligan MK, Williams RW, Becker HC, Mulholland PJ. Bioinformatics identification and pharmacological validation of Kcnn3/K Ca2 channels as a mediator of negative affective behaviors and excessive alcohol drinking in mice. Transl Psychiatry 2020; 10:414. [PMID: 33247097 PMCID: PMC7699620 DOI: 10.1038/s41398-020-01099-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/16/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Mood disorders are often comorbid with alcohol use disorder (AUD) and play a considerable role in the development and maintenance of alcohol dependence and relapse. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy drinking and negative affective behaviors. In order to identify novel pharmacogenetic targets, a bioinformatics analysis was used to quantify the expression of amygdala K+ channel genes that covary with anxiety-related phenotypes in the well-phenotyped and fully sequenced family of BXD strains. We used a model of stress-induced escalation of drinking in alcohol-dependent mice to measure negative affective behaviors during abstinence. A pharmacological approach was used to validate the key bioinformatics findings in alcohol-dependent, stressed mice. Amygdalar expression of Kcnn3 correlated significantly with 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors and negative correlations with binge-like and voluntary alcohol drinking. Mice treated with chronic intermittent alcohol exposure and repeated swim stress consumed more alcohol in their home cages and showed hypophagia on the novelty-suppressed feeding test during abstinence. Pharmacologically targeting Kcnn gene products with the KCa2 (SK) channel-positive modulator 1-EBIO decreased drinking and reduced feeding latency in alcohol-dependent, stressed mice. Collectively, these validation studies provide central nervous system links into the covariance of stress, negative affective behaviors, and AUD in the BXD strains. Further, the bioinformatics discovery tool is effective in identifying promising targets (i.e., KCa2 channels) for treating alcohol dependence exacerbated by comorbid mood disorders.
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Affiliation(s)
- Audrey E Padula
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA
- Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Jennifer A Rinker
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA
- Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Marcelo F Lopez
- Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Megan K Mulligan
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA
| | - Robert W Williams
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA
| | - Howard C Becker
- Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Patrick J Mulholland
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA.
- Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
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17
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Shields CN, Gremel CM. Review of Orbitofrontal Cortex in Alcohol Dependence: A Disrupted Cognitive Map? Alcohol Clin Exp Res 2020; 44:1952-1964. [PMID: 32852095 PMCID: PMC8261866 DOI: 10.1111/acer.14441] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 08/13/2020] [Indexed: 12/18/2022]
Abstract
Alcoholism is a persistent worldwide problem associated with long-lasting impairments to decision making processes. Some aspects of dysfunction are thought to reflect alcohol-induced changes to relevant brain areas such as the orbitofrontal cortex (OFC). In this review, we will examine how chronic alcohol exposure alters OFC function to potentially contribute to maladaptive decision making, and explore experimental behavioral approaches that may be better suited to test whether alcohol dependence disrupts OFC's function. We argue that although past works suggest impairments in aspects of OFC function, more information may be gained by specifically targeting tasks to the broader function of OFC as put forth by the recent hypothesis of OFC as a "cognitive map" of task space. Overall, we suggest that such a focus could provide a better understanding of how OFC function changes in alcohol dependence, and could inform better assessment tools and treatment options for clinicians working with this population.
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Affiliation(s)
- Chloe N. Shields
- Department of Psychology, University of California San Diego, La Jolla, CA 92093, USA
| | - Christina M. Gremel
- Department of Psychology, University of California San Diego, La Jolla, CA 92093, USA
- The Neurosciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA
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18
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den Hartog CR, Blandino KL, Nash ML, Sjogren ER, Grampetro MA, Moorman DE, Vazey EM. Noradrenergic tone mediates marble burying behavior after chronic stress and ethanol. Psychopharmacology (Berl) 2020; 237:3021-3031. [PMID: 32588079 PMCID: PMC7529922 DOI: 10.1007/s00213-020-05589-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 06/11/2020] [Indexed: 12/27/2022]
Abstract
RATIONALE Stress plays a major role in the development of alcohol use disorder (AUD)-a history of chronic stress contributes to alcohol misuse, and withdrawal from alcohol elevates stress, perpetuating cycles of problematic drinking. Recent studies have shown that, in male mice, repeated chronic intermittent ethanol (CIE) and stress elevates alcohol use above either manipulation alone and impacts cognitive functions such as behavioral flexibility. OBJECTIVE Here, we investigated the impact of CIE and stress on anxiety in both sexes, and whether the norepinephrine (NE) system via locus coeruleus, which is implicated in both stress and alcohol motivation, is involved. RESULTS Male and female mice received multiple cycles of CIE and/or repeated forced swim stress (FSS), producing elevated drinking in both sexes. CIE/FSS treatment increased anxiety, which was blocked by treatment with the α1-AR inverse agonist prazosin. In contrast, administration of the corticotropin releasing factor receptor antagonist CP376395 into locus coeruleus did not reduce CIE/FSS-elevated anxiety. We also observed sex differences in behavioral responses to a history of CIE or FSS alone as well as differential behavioral consequences of prazosin treatment. CONCLUSIONS These data indicate that NE contributes to the development of anxiety following a history of alcohol and/or stress, and that the influence of both treatment history and NE signaling is sex dependent. These results argue for further investigation of the NE system in relation to disrupted behavior following chronic alcohol and stress, and support the assertion that treatments may differ across sex based on differential neural system engagement.
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Affiliation(s)
| | | | - McKenzie L. Nash
- Department of Biology, University of Massachusetts Amherst, MA, 01003, USA
| | - Emily R. Sjogren
- Department of Biology, University of Massachusetts Amherst, MA, 01003, USA
| | | | - David E. Moorman
- Department of Psychological and Brain Sciences, University of Massachusetts Amherst, MA, 01003, USA
| | - Elena M. Vazey
- Department of Biology, University of Massachusetts Amherst, MA, 01003, USA
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19
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Piggott VM, Lloyd SC, Perrine SA, Conti AC. Chronic Intermittent Ethanol Exposure Increases Ethanol Consumption Following Traumatic Stress Exposure in Mice. Front Behav Neurosci 2020; 14:114. [PMID: 32694985 PMCID: PMC7338656 DOI: 10.3389/fnbeh.2020.00114] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/08/2020] [Indexed: 01/15/2023] Open
Abstract
Individuals with post-traumatic stress disorder (PTSD) often use alcohol to cope with their distress. This aberrant use of alcohol often develops into alcohol use disorder (AUD) leading to high rates of PTSD-AUD co-occurrence. Individuals with comorbid PTSD-AUD have more intense alcohol cravings and increased relapse rates during withdrawal than those with AUD alone. Also, individuals with PTSD or AUD alone often show similar psychological behaviors, such as impulsivity and anhedonia. Extensive clinical studies on the behavioral effects of PTSD-AUD comorbidity, namely alcohol use, have been performed. However, these effects have not been well studied or mechanistically explored in animal models. Therefore, the present study evaluated the effects of traumatic stress comorbid with alcohol exposures on ethanol intake, impulsivity, and anhedonia in mice. Adult male C57Bl/6 mice were first exposed to either mouse single-prolonged stress (mSPS), an animal model that has been validated for characteristics akin to PTSD symptoms, or control conditions. Baseline two-bottle choice ethanol consumption and preference tests were conducted after a 7-day isolation period, as part of the mSPS exposure. Next, mice were exposed to air or chronic intermittent ethanol (CIE), a vapor-induced ethanol dependence and withdrawal model, for 4 weeks. Two-bottle choice ethanol drinking was used to measure dependence-induced ethanol consumption and preference during periods intervening CIE cycles. The novelty suppressed feeding (NSF) test was used to evaluate impulsivity and anhedonia behaviors 48 h after mSPS and/or repeated CIE exposure. Results showed that, compared to control conditions, mSPS did not affect baseline ethanol consumption and preference. However, mSPS-CIE mice increased Post-CIE ethanol consumption compared to Control-Air mice. Mice exposed to mSPS had a shorter latency to feed during the NSF, whereas CIE-exposed mice consumed less palatable food reward in their home cage after the NSF. These results demonstrate that mice exposed to both mSPS and CIE are more vulnerable to ethanol withdrawal effects, and those exposed to mSPS have increased impulsivity, while CIE exposure increases anhedonia. Future studies to examine the relationship between behavioral outcomes and the molecular mechanisms in the brain after PTSD-AUD are warranted.
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Affiliation(s)
- Veronica M Piggott
- Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, United States.,Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States.,Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States
| | - Scott C Lloyd
- Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, United States.,Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States.,Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States
| | - Shane A Perrine
- Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, United States.,Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States
| | - Alana C Conti
- Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, United States.,Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States.,Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States
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20
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Farris SP, Tiwari GR, Ponomareva O, Lopez MF, Mayfield RD, Becker HC. Transcriptome Analysis of Alcohol Drinking in Non-Dependent and Dependent Mice Following Repeated Cycles of Forced Swim Stress Exposure. Brain Sci 2020; 10:E275. [PMID: 32370184 PMCID: PMC7288165 DOI: 10.3390/brainsci10050275] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/22/2020] [Accepted: 04/27/2020] [Indexed: 01/01/2023] Open
Abstract
Chronic stress is a known contributing factor to the development of drug and alcohol addiction. Animal models have previously shown that repeated forced swim stress promotes escalated alcohol consumption in dependent animals. To investigate the underlying molecular adaptations associated with stress and chronic alcohol exposure, RNA-sequencing and bioinformatics analyses were conducted on the prefrontal cortex (CTX) of male C57BL/6J mice that were behaviorally tested for either non-dependent alcohol consumption (CTL), chronic intermittent ethanol (CIE) vapor dependent alcohol consumption, repeated bouts of forced swim stress alone (FSS), and chronic intermittent ethanol with forced swim stress (CIE + FSS). Brain tissue from each group was collected at 0-h, 72-h, and 168-h following the final test to determine long-lasting molecular changes associated with maladaptive behavior. Our results demonstrate unique temporal patterns and persistent changes in coordinately regulated gene expression systems with respect to the tested behavioral group. For example, increased expression of genes involved in "transmitter-gated ion channel activity" was only determined for CIE + FSS. Overall, our results provide a summary of transcriptomic adaptations across time within the CTX that are relevant to understanding the neurobiology of chronic alcohol exposure and stress.
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Affiliation(s)
- Sean P. Farris
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA;
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15206, USA
| | - Gayatri R. Tiwari
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA; (G.R.T.); (O.P.); (R.D.M.)
| | - Olga Ponomareva
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA; (G.R.T.); (O.P.); (R.D.M.)
| | - Marcelo F. Lopez
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 28425, USA;
| | - R. Dayne Mayfield
- Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA; (G.R.T.); (O.P.); (R.D.M.)
- Department of Neuroscience, The University of Texas at Austin, Austin, TX 78712, USA
| | - Howard C. Becker
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 28425, USA;
- Department of Neuroscience, Medical University of South, Charleston, SC 29425, USA
- Department of Veterans Affairs Medical Center, Charleston, SC 20401, USA
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21
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Arinze I, Moorman DE. Selective impact of lateral orbitofrontal cortex inactivation on reinstatement of alcohol seeking in male Long-Evans rats. Neuropharmacology 2020; 168:108007. [PMID: 32092436 PMCID: PMC10373069 DOI: 10.1016/j.neuropharm.2020.108007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 02/05/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022]
Abstract
The orbitofrontal cortex (OFC) plays a fundamental role in motivated behavior and decision-making. In humans, OFC structure and function is significantly disrupted in drug using and dependent individuals, including those exhibiting chronic alcohol use and alcoholism. In animal models, the OFC has been shown to significantly influence the seeking of non-alcohol drugs of abuse. However direct investigations of the OFC during alcohol seeking and use have been more limited. In the studies reported here, we inactivated lateral (lOFC) or medial OFC (mOFC) subregions in rats during multiple stages of alcohol seeking. After one month of intermittent access to homecage 20% ethanol (EtOH), rats were trained to self-administer EtOH under an FR3 schedule and implanted with cannulae directed to lOFC or mOFC. We inactivated OFC subregions with baclofen/muscimol during EtOH self-administration, extinction, cue-induced reinstatement, and progressive ratio testing to broadly characterize the influence of these subregions on alcohol seeking. There were no significant effects of mOFC or lOFC inactivation during FR3 self-administration, extinction, or progressive ratio self-administration. However, lOFC, and not mOFC, inactivation significantly decreased cue-induced reinstatement of EtOH seeking. These findings contribute new information to the specific impact of OFC manipulation on operant alcohol seeking, support previous studies investigating the role of OFC in seeking and consumption of alcohol and other drugs of abuse, and indicate a specific role for lOFC vs. mOFC in reinstatement.
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22
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Charlton AJ, May C, Luikinga SJ, Burrows EL, Hyun Kim J, Lawrence AJ, Perry CJ. Chronic voluntary alcohol consumption causes persistent cognitive deficits and cortical cell loss in a rodent model. Sci Rep 2019; 9:18651. [PMID: 31819151 PMCID: PMC6901469 DOI: 10.1038/s41598-019-55095-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 11/18/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation. Despite this, addiction therapy does not address cognitive deficits, and there is poor understanding regarding the mechanisms that underlie this decline. We established a rodent model of chronic voluntary alcohol use to measure ensuing cognitive effects and underlying pathology. Rats had intermittent access to alcohol or an isocaloric solution in their home cage under voluntary 2-bottle choice conditions. In Experiments 1 and 2 cognition was assessed using operant touchscreen chambers. We examined performance in a visual discrimination and reversal task (Experiment 1), and a 5-choice serial reaction time task (Experiment 2). For Experiment 3, rats were perfused immediately after cessation of alcohol access period, and volume, cell density and microglial populations were assessed in the prefrontal cortex and striatum. Volume was assessed using the Cavalieri probe, while cell and microglial counts were estimated using unbiased stereology with an optical fractionator. Alcohol-exposed and control rats showed comparable acquisition of pairwise discrimination; however, performance was impaired when contingencies were reversed indicating reduced behavioral flexibility. When tested in a 5-choice serial reaction time task alcohol-exposed rats showed increased compulsivity and increased attentional bias towards a reward associated cue. Consistent with these changes, we observed decreased cell density in the prefrontal cortex. These findings confirm a detrimental effect of chronic alcohol and establish a model of alcohol-induced cognitive decline following long-term voluntary intake that may be used for future intervention studies.
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Affiliation(s)
- Annai J Charlton
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
| | - Carlos May
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
| | - Sophia J Luikinga
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
| | - Emma L Burrows
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
| | - Jee Hyun Kim
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
| | - Andrew J Lawrence
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia
| | - Christina J Perry
- Mental Health Theme, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia.
- Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia.
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23
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Solomon MG, Griffin WC, Lopez MF, Becker HC. Brain Regional and Temporal Changes in BDNF mRNA and microRNA-206 Expression in Mice Exposed to Repeated Cycles of Chronic Intermittent Ethanol and Forced Swim Stress. Neuroscience 2019; 406:617-625. [PMID: 30790666 DOI: 10.1016/j.neuroscience.2019.02.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 02/07/2019] [Accepted: 02/10/2019] [Indexed: 12/11/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) expression and signaling activity in brain are influenced by chronic ethanol and stress. We previously demonstrated reduced Bdnf mRNA levels in the medial prefrontal cortex (mPFC) following chronic ethanol treatment and forced swim stress (FSS) enhanced escalated drinking associated with chronic ethanol exposure. The present study examined the effects of chronic ethanol and FSS exposure, alone and in combination, on Bdnf mRNA expression in different brain regions, including mPFC, central amygdala (CeA), and hippocampus (HPC). Additionally, since microRNA-206 has been shown to negatively regulate BDNF expression, the effects of chronic ethanol and FSS on its expression in the target brain regions were examined. Mice received four weekly cycles of chronic intermittent ethanol (CIE) vapor or air exposure and then starting 72-h later, the mice received either a single or 5 daily 10-min FSS sessions (or left undisturbed). Brain tissue samples were collected 4-h following final FSS testing and Bdnf mRNA and miR-206 levels were determined by qPCR assay. Results indicated dynamic brain regional and time-dependent changes in Bdnf mRNA and miR-206 expression. In general, CIE and FSS exposure reduced Bdnf mRNA expression while miR-206 levels were increased in the mPFC, CeA, and HPC. Further, in many instances, these effects were more robust in mice that experienced both CIE and FSS treatments. These results have important implications for the potential link between BDNF signaling in the brain and ethanol consumption related to stress interactions with chronic ethanol experience.
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Affiliation(s)
- Matthew G Solomon
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
| | - William C Griffin
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Marcelo F Lopez
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Howard C Becker
- Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA; RHJ Department of Veterans Affairs Medical Center, Charleston, SC 20401, USA.
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24
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Scarlata MJ, Lee SH, Lee D, Kandigian SE, Hiller AJ, Dishart JG, Mintz GE, Wang Z, Coste GI, Mousley AL, Soler I, Lawson K, Ng AJ, Bezek JL, Bergstrom HC. Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization. Sci Rep 2019; 9:6730. [PMID: 31040357 PMCID: PMC6491487 DOI: 10.1038/s41598-019-43159-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/16/2019] [Indexed: 01/28/2023] Open
Abstract
Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often comorbid. Drinking tends to increase following trauma, which may exacerbate PTSD-related symptoms. Despite a clear relationship between excessive alcohol use and PTSD, how alcohol impacts the expression of traumatic fear remains unclear. This study aims to determine the neurobehavioral impact of chronic alcohol (ethanol; EtOH) on the expression of established fear memories in C57BL/6 N mice. We show that chronic EtOH selectively augments cued fear memory generalization and impairs fear extinction retrieval, leaving the expression of the original cued response intact. Immunohistochemistry for Arc/arg3.1 (Arc) revealed EtOH-induced decreases in Arc expression in the infralimbic cortex (IL) and basolateral amygdala complex (BLA) that were associated with cued fear memory overgeneralization. Chemogenetic stimulation of IL pyramidal neurons reversed EtOH-driven fear memory overgeneralization, identifying a role for the IL in cued fear memory precision. Considering the modulatory influence of the IL over conditioned fear expression, these data suggest a model whereby chronic EtOH-driven neuroadaptations in the IL promote fear memory overgeneralization. These findings provide new mechanistic insight into how excessive alcohol use, following exposure to a traumatic event, can exacerbate symptoms of traumatic fear.
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Affiliation(s)
- M J Scarlata
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - S H Lee
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - D Lee
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - S E Kandigian
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - A J Hiller
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - J G Dishart
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - G E Mintz
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - Z Wang
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - G I Coste
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - A L Mousley
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - I Soler
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - K Lawson
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - A J Ng
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - J L Bezek
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA
| | - H C Bergstrom
- Vassar College, Department of Psychological Science, Program in Neuroscience and Behavior, Poughkeepsie, NY, 12604, USA.
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25
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Moorman DE. The role of the orbitofrontal cortex in alcohol use, abuse, and dependence. Prog Neuropsychopharmacol Biol Psychiatry 2018; 87:85-107. [PMID: 29355587 PMCID: PMC6072631 DOI: 10.1016/j.pnpbp.2018.01.010] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 12/22/2017] [Accepted: 01/13/2018] [Indexed: 12/21/2022]
Abstract
One of the major functions of the orbitofrontal cortex (OFC) is to promote flexible motivated behavior. It is no surprise, therefore, that recent work has demonstrated a prominent impact of chronic drug use on the OFC and a potential role for OFC disruption in drug abuse and addiction. Among drugs of abuse, the use of alcohol is particularly salient with respect to OFC function. Although a number of studies in humans have implicated OFC dysregulation in alcohol use disorders, animal models investigating the association between OFC and alcohol use are only beginning to be developed, and there is still a great deal to be revealed. The goal of this review is to consider what is currently known regarding the role of the OFC in alcohol use and dependence. I will first provide a brief, general overview of current views of OFC function and its contributions to drug seeking and addiction. I will then discuss research to date related to the OFC and alcohol use, both in human clinical populations and in non-human models. Finally I will consider issues and strategies to guide future study that may identify this brain region as a key player in the transition from moderated to problematic alcohol use and dependence.
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Affiliation(s)
- David E. Moorman
- Department of Psychological and Brain Sciences, Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst MA 01003 USA
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26
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Farris SP, Riley BP, Williams RW, Mulligan MK, Miles MF, Lopez MF, Hitzemann R, Iancu OD, Colville A, Walter NAR, Darakjian P, Oberbeck DL, Daunais JB, Zheng CL, Searles RP, McWeeney SK, Grant KA, Mayfield RD. Cross-species molecular dissection across alcohol behavioral domains. Alcohol 2018; 72:19-31. [PMID: 30213503 PMCID: PMC6309876 DOI: 10.1016/j.alcohol.2017.11.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 11/17/2017] [Accepted: 11/28/2017] [Indexed: 12/14/2022]
Abstract
This review summarizes the proceedings of a symposium presented at the "Alcoholism and Stress: A Framework for Future Treatment Strategies" conference held in Volterra, Italy on May 9-12, 2017. Psychiatric diseases, including alcohol-use disorders (AUDs), are influenced through complex interactions of genes, neurobiological pathways, and environmental influences. A better understanding of the common neurobiological mechanisms underlying an AUD necessitates an integrative approach, involving a systematic assessment of diverse species and phenotype measures. As part of the World Congress on Stress and Alcoholism, this symposium provided a detailed account of current strategies to identify mechanisms underlying the development and progression of AUDs. Dr. Sean Farris discussed the integration and organization of transcriptome and postmortem human brain data to identify brain regional- and cell type-specific differences related to excessive alcohol consumption that are conserved across species. Dr. Brien Riley presented the results of a genome-wide association study of DSM-IV alcohol dependence; although replication of genetic associations with alcohol phenotypes in humans remains challenging, model organism studies show that COL6A3, KLF12, and RYR3 affect behavioral responses to ethanol, and provide substantial evidence for their role in human alcohol-related traits. Dr. Rob Williams expanded upon the systematic characterization of extensive genetic-genomic resources for quantifying and clarifying phenotypes across species that are relevant to precision medicine in human disease. The symposium concluded with Dr. Robert Hitzemann's description of transcriptome studies in a mouse model selectively bred for high alcohol ("binge-like") consumption and a non-human primate model of long-term alcohol consumption. Together, the different components of this session provided an overview of systems-based approaches that are pioneering the experimental prioritization and validation of novel genes and gene networks linked with a range of behavioral phenotypes associated with stress and AUDs.
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Affiliation(s)
- Sean P Farris
- University of Texas at Austin, Austin, TX, United States
| | - Brien P Riley
- Virginia Commonwealth University, Richmond, VA, United States
| | - Robert W Williams
- University of Tennessee Health Science Center, Memphis, TN, United States
| | - Megan K Mulligan
- University of Tennessee Health Science Center, Memphis, TN, United States
| | - Michael F Miles
- University of Tennessee Health Science Center, Memphis, TN, United States
| | - Marcelo F Lopez
- University of Tennessee Health Science Center, Memphis, TN, United States
| | - Robert Hitzemann
- Oregon Health and Science University, Portland, OR, United States
| | - Ovidiu D Iancu
- Oregon Health and Science University, Portland, OR, United States
| | | | | | | | | | - James B Daunais
- Wake Forest School of Medicine, Winston-Salem, NC, United States
| | | | - Robert P Searles
- Oregon Health and Science University, Portland, OR, United States
| | | | - Kathleen A Grant
- Oregon Health and Science University, Portland, OR, United States
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27
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Anderson RI, Moorman DE, Becker HC. Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol. Handb Exp Pharmacol 2018. [PMID: 29526023 DOI: 10.1007/164_2018_100] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The dynorphin and orexin/hypocretin neuropeptide systems are particularly relevant with respect to alcohol use and misuse. Both systems are strongly associated with alcohol-seeking behaviors, particularly in cases of high levels of alcohol use as seen in dependence. Furthermore, both systems also play a role in stress and anxiety, indicating that disruption of these systems may underlie long-term homeostatic dysregulation seen in alcohol use disorders. These systems are also closely interrelated with one another - dynorphin/kappa opioid receptors and orexin/hypocretin receptors are found in similar regions and hypocretin/orexin neurons also express dynorphin - suggesting that these two systems may work together in the regulation of alcohol seeking and may be mutually disrupted in alcohol use disorders. This chapter reviews studies demonstrating a role for each of these systems in motivated behavior, with a focus on their roles in regulating alcohol-seeking and self-administration behaviors. Consideration is also given to evidence indicating that these neuropeptide systems may be viable targets for the development of potential treatments for alcohol use disorders.
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Affiliation(s)
- Rachel I Anderson
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.,Science and Technology Policy Fellowships, American Association for the Advancement of Science, Washington, DC, USA
| | - David E Moorman
- Department of Psychological and Brain Sciences, Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, USA
| | - Howard C Becker
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA. .,Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC, USA. .,Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. .,Department of Veterans Affairs, Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
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28
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Vazey EM, den Hartog CR, Moorman DE. Central Noradrenergic Interactions with Alcohol and Regulation of Alcohol-Related Behaviors. Handb Exp Pharmacol 2018; 248:239-260. [PMID: 29687164 DOI: 10.1007/164_2018_108] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Alcohol use disorder (AUD) results from disruption of a number of neural systems underlying motivation, emotion, and cognition. Patients with AUD exhibit not only elevated motivation for alcohol but heightened stress and anxiety, and disruptions in cognitive domains such as decision-making. One system at the intersection of these functions is the central norepinephrine (NE) system. This catecholaminergic neuromodulator, produced by several brainstem nuclei, plays profound roles in a wide range of behaviors and functions, including arousal, attention, and other aspects of cognition, motivation, emotional regulation, and control over basic physiological processes. It has been known for some time that NE has an impact on alcohol seeking and use, but the mechanisms of its influence are still being revealed. This chapter will discuss the influence of NE neuron activation and NE release at alcohol-relevant targets on behaviors and disruptions underlying alcohol motivation and AUD. Potential NE-based pharmacotherapies for AUD treatment will also be discussed. Given the basic properties of NE function, the strong relationship between NE and alcohol use, and the effectiveness of current NE-related treatments, the studies presented here indicate an encouraging direction for the development of precise and efficacious future therapies for AUD.
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Affiliation(s)
- Elena M Vazey
- Department of Biology & Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, USA.
| | - Carolina R den Hartog
- Department of Biology & Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, USA
| | - David E Moorman
- Department of Psychological and Brain Sciences & Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, USA
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