Abstract
Alcohol use disorder (AUD) is a global health concern associated with several comorbidities. Various health problems related to AUD, such as cognitive deficits, have been linked to neuroinflammation. Alcohol use has been associated with changes in neuroimmune activity, although current literature has yielded mixed results. For example, markers of gliosis, including translocator protein 18-kDa (TSPO), pro-inflammatory cytokines, glutamate (Glu), and myo-inositol (mI), are disrupted in the alcohol-dependent brain. Further, neuroinflammatory-related phenomena including membrane turnover, blood brain barrier (BBB) permeability, and adenosine release have also shown alterations in AUD. However, current literature remains inconclusive about the directionality of these changes. Both in vivo and in vitro studies have provided insight on the relationship between alcohol use and neuroinflammatory processes, suggesting considerable treatment potential for alcohol use disorder and its inflammatory comorbidities. Here, we review current neuroimaging literature assessing the impacts of alcohol use on neuroimmune activity in the brain.
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References
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington: APA, 2013
Griswold M G, Fullman N, Hawley C, et al. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet, 2018, 392: 1015–1035
Brust J. Ethanol and cognition: indirect effects, neurotoxicity and neuroprotection: a review. J Environ Res Public Health, 2010, 7: 1540–1557
Crews F T, Lawrimore C J, Walter T J, et al. The role of neuroimmune signaling in alcoholism. Neuropharmacology, 2017, 122: 56–73
Kohno M, Link J, Dennis L E, et al. Neuroinflammation in addiction: a review of neuroimaging studies and potential immunotherapies. Pharmacol Biochem Behav, 2019, 179: 34–42
Stavro K, Pelletier J, Potvin S. Widespread and sustained cognitive deficits in alcoholism: a meta-analysis. Addiction Biol, 2013, 18: 203–213
Gupta S, Warner J. Alcohol-related dementia: a 21st-century silent epidemic? British J Psychiatry, 2008, 193: 351–353
Davies S J, Pandit S A, Feeney A, et al. Is there cognitive impairment in clinically ‘healthy’ abstinent alcohol dependence? Alcohol Alcoholism, 2005, 40: 498–503
Coleman J L G, Zou J, Crews F T. Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J Neuroinflammation, 2017, 14: 22
Kane C J M, Drew P D. Inflammatory responses to alcohol in the CNS: nuclear receptors as potential therapeutics for alcohol-induced neuropathologies. J Leukoc Biol, 2016, 100: 951–959
Tiwari V, Chopra K. Protective effect of curcumin against chronic alcohol-induced cognitive deficits and neuroinflam-mation in the adult rat brain. Neuroscience, 2013, 244: 147–158
Robinson G M, Orrego H, Israel Y, et al. Low-molecular-weight polyethylene glycol as a probe of gastrointestinal permeability after alcohol ingestion. Digest Dis Sci, 1981, 26: 971–977
Bjarnason I, Ward K, Peters T J. The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet, 1984, 323: 179–182
Keshavarz´ıan A F, Jeremy Z, Vaeth J, et al. The differing effects of acute and chronic alcohol on gastric and intestinal permeability. Am J Gastroenterol, 1994, 89: 2205–2211
Leclercq S, Cani P D, Neyrinck A M, et al. Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain Behav Immun, 2012, 26: 911–918
Ellis F W. Effect of ethanol on plasma corticosterone levels. J Pharmacol Exp Ther, 1966, 153: 121–127
Frank M G, Miguel Z D, Watkins L R, et al. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. Coli Lipopolysaccharide. Brain Behav Immun, 2010, 24: 19–30
Woodcock E A, Hillmer A T, Mason G F, et al. Imaging biomarkers of the neuroimmune system among substance use disorders: a systematic review. Mol Neuropsychiatry, 2019, 5: 125–146
Tyler R E, Kim S W, Guo M, et al. Detecting neuroinflammation in the brain following chronic alcohol exposure in rats: a comparison between in vivo and in vitro TSPO radioligand binding. Eur J Neurosci, 2019, 50: 1831–1842
Saba W, Goutal S, Auvity S, et al. Imaging the neuroimmune response to alcohol exposure in adolescent baboons: a TSPO PET study using (18) F-DPA-714. Addiction Biol, 2018, 23: 1000–1009
Hillmer A T, Sandiego C M, Hannestad J, et al. In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence. Mol Psychiatry, 2017, 22: 1759–1766
Kalk N J, Guo Q, Owen D, et al. Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a PBR28 PET study. Transl Psychiatry, 2017, 7: 996
Kim S W, Wiers C E, Tyler R, et al. Influence of alcoholism and cholesterol on TSPO binding in brain: PET PBR28 studies in humans and rodents. Neuropsychopharmacol, 2018, 43: 1832–1839
Gundersen H, van Wageningen H, Grüner R. Alcohol-induced changes in cerebral blood flow and cerebral blood volume in social drinkers. Alcohol Alcoholism, 2012, 48: 160–165
Ende G, Hermann D, Demirakca T, et al. Loss of control of alcohol use and severity of alcohol dependence in non-treatment-seeking heavy drinkers are related to lower glutamate in frontal white matter. Alcoholism: Clinical Exp Res, 2013, 37: 1643–1649
Cheng H, Kellar D, Lake A, et al. Effects of alcohol cues on MRS glutamate levels in the anterior cingulate. Alcohol Alcoholism, 2018, 53: 209–215
Bagga D, Khushu S, Modi S, et al. Impaired visual information processing in alcohol-dependent subjects: a proton magnetic resonance spectroscopy study of the primary visual cortex. J Stud Alcohol Drugs, 2014, 75: 817–826
Mon A, Durazzo T C, Meyerhoff D J. Glutamate, GABA, and other cortical metabolite concentrations during early abstinence from alcohol and their associations with neurocognitive changes. Drug Alcohol Dependence, 2012, 125: 27–36
Thoma R, Mullins P, Ruhl D, et al. Perturbation of the glutamate-glutamine system in alcohol dependence and remission. Neuropsychopharmacol, 2011, 36: 1359–1365
Valenta J P, Gonzales R A. Chronic intracerebroventricular infusion of monocyte chemoattractant protein-1 leads to a persistent increase in sweetened ethanol consumption during operant self-administration but does not influence sucrose consumption in long-evans rats. Alcohol Clin Exp Res, 2016, 40: 187–195
Hermann D, Weber-Fahr W, Sartorius A, et al. Translational magnetic resonance spectroscopy reveals excessive central glutamate levels during alcohol withdrawal in humans and rats. Biol Psychiatry, 2012, 71: 1015–1021
Zahr N M, Mayer D, Rohlfing T, et al. Imaging neuroinflammation? A perspective from MR spectroscopy. Brain Pathol, 2014, 24: 654–664
Meyerhoff D J, Blumenfeld R, Truran D, et al. Effects of heavy drinking, binge drinking, and family history of alcoholism on regional brain metabolites. Alcoholism-Clin Exp Res, 2004, 28: 650–661
Schweinsburg B C, Taylor M J, Alhassoon O M, et al. Chemical pathology in brain white matter of recently detoxified alcoholics: a 1H magnetic resonance spectroscopy investigation of alcohol-associated frontal lobe injury. Alcoholism Clin Exp Res, 2001, 25: 924–934
Quarantelli M. MRI/MRS in neuroinflammation: methodology and applications. Clin Transl Imag, 2015, 3: 475–489
Bendszus M, Weijers H G, Wiesbeck G, et al. Sequential MR imaging and proton MR spectroscopy in patients who underwent recent detoxification for chronic alcoholism: correlation with clinical and neuropsychological data. Am J Neuroradiol, 2001, 22: 1926–1932
Parks M H, Dawant B M, Riddle W R, et al. Longitudinal brain metabolic characterization of chronic alcoholics with proton magnetic resonance spectroscopy. Alcoholism Clin Exp Res, 2002, 26: 1368–1380
de Souza R S M, Rosa M, Rodrigues T M, et al. Lower choline rate in the left prefrontal cortex is associated with higher amount of alcohol use in alcohol use disorder. Front Psychiatry, 2018, 9: 563
Ende G, Welzel H, Walter S, et al. Monitoring the effects of chronic alcohol consumption and abstinence on brain metabolism: a longitudinal proton magnetic resonance spectroscopy study. Biol Psychiatry, 2005, 58: 974–980
Haorah J, Schall K, Ramirez S H, et al. Activation of protein tyrosine kinases and matrix metalloproteinases causes blood-brain barrier injury: novel mechanism for neurodegeneration associated with alcohol abuse. Glia, 2008, 56: 78–88
Monnig M A, Caprihan A, Yeo R A, et al. Diffusion tensor imaging of white matter networks in individuals with current and remitted alcohol use disorders and comorbid conditions. Psychol Addictive Behavs, 2013, 27: 455–465
Volkow N D, Kim S W, Wang G J, et al. Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain. Neuroimage, 2013, 64: 277–283
Tanabe J, Yamamoto D J, Sutton B, et al. Effects of alcohol and acetate on cerebral blood flow: a pilot study. Alcohol Clin Exp Res, 2019, 43: 2070–2078
Courtney K E, Infante M A, Brown G G, et al. The relationship between regional cerebral blood flow estimates and alcohol problems at 5-year follow-up: the role of level of response. Alcohol Clin Exp Re, 2019, 43: 812–821
Brand A, Richter-Landsberg C, Leibfritz D. Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci, 1993, 15: 289–298
Chang L, Munsaka S M, Kraft-Terry S, et al. Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. J Neuroimmune Pharmacol, 2013, 8: 576–593
Meyerhoff D J. Effects of alcohol and HIV infection on the central nervous system. Alcohol Res Health, 2001, 25: 288–298
Fawcett J W, Asher R A. The glial scar and central nervous system repair. Brain Res Bull, 1999, 49: 377–391
Hoogland I C M, Houbolt C, van Westerloo D J, et al. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation, 2015, 12: 114
Perry V H. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurode-generative disease. Brain Behav Immun, 2004, 18: 407–413
Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol, 2016, 53: 1181–1194
Block M L, Zecca L, Hong J S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci, 2007, 8: 57–69
Yawata I, Takeuchi H, Doi Y, et al. Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors. Life Sci, 2008, 82: 1111–1116
Freeman K, Brureau A, Vadigepalli R, et al. Temporal changes in innate immune signals in a rat model of alcohol withdrawal in emotional and cardiorespiratory homeostatic nuclei. J Neuroinflammation, 2012, 9: 97
Sweet M J, Hume D A. Endotoxin signal transduction in macrophages. J Leukocyte Biol, 1996, 60: 8–26
Breese G R, Knapp D J, Overstreet D H, et al. Repeated lipopolysaccharide (LPS) or cytokine treatments sensitize ethanol withdrawal-induced anxiety-like behavior. Neuropsychopharmacol, 2008, 33: 867–876
Heberlein A, Kaser M, Lichtinghagen R, et al. TNF-alpha and IL-6 serum levels: Neurobiological markers of alcohol consumption in alcohol-dependent patients? Alcohol, 2014, 48: 671–676
Leclercq S, de Saeger C, Delzenne N, et al. Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry, 2014, 76: 725–733
Nishiyama A, Komitova M, Suzuki R, et al. Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nature Rev Neurosci, 2009, 10: 9–22
Harper C. The neuropathology of alcohol-related brain damage. Alcohol Alcoholism, 2009, 44: 136–140
Gallucci M, Amicarelli I, Rossi A, et al. MR imaging of white matter lesions in uncomplicated chronic alcoholism. J Comput Assisted Tomography, 1989, 13: 395–398
He J, Overstreet D H, Crews F T. Abstinence from moderate alcohol self-administration alters progenitor cell proliferation and differentiation in multiple brain regions of male and female P rats. Alcoholism-Clin Exp Res, 2009, 33: 129–138
Helfer J L, Calizo L H, Dong W K, et al. Binge-like postnatal alcohol exposure triggers cortical gliogenesis in adolescent rats. J Comp Neurol, 2009, 514: 259–271
Albrecht D S, Granziera C, Hooker J M, et al. In vivo imaging of human neuroinflammation. ACS Chem Neurosci, 2016, 7: 470–483
Colombo E, Farina C. Astrocytes: key regulators of neuroinflammation. Trends Immunol, 2016, 37: 608–620
Adermark L, Bowers M S. Disentangling the role of astrocytes in alcohol use disorder. Alcohol Clin Exp Res, 2016, 40: 1802–1816
Blanco A M, Vallés S L, Pascual M, et al. Involvement of TLR4/Type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes. J Immunol, 2005, 175: 6893–6899
Bull C, Freitas K C, Zou S, et al. Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence. Neuropsychopharmacol, 2014, 39: 2835–2845
Korbo L. Glial cell loss in the hippocampus of alcoholics. Alcoholism Clinical Exp Res, 1999, 23: 164–168
Miguel-Hidalgo J J, Overholser J C, Meltzer H Y, et al. Reduced glial and neuronal packing density in the orbitofrontal cortex in alcohol dependence and its relationship with suicide and duration of alcohol dependence. Alcoholism Clin Exp Res, 2006, 30: 1845–1855
Miguel-Hidalgo J J, Overholser J C, Meltzer H Y, et al. Glia pathology in the prefrontal cortex in alcohol dependence with and without depressive symptoms. Alcoholism Clin Exp Res, 2002, 30: 1845–1855
Chen M K, Guilarte T R. Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Therapeutics, 2008, 118: 1–17
Gulyás B, Makkai B, Kása P, et al. A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system. NeuroChem Int, 2009, 54: 28–36
Marshall S A, McClain J A, Kelso M L, et al. Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: the importance of microglia phenotype. Neurobiol Dis, 2013, 54: 239–251
Kreisl W C, Jenko K J, Hines C S, et al. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cerebral Blood Flow Metabolism, 2013, 33: 53–58
Gavish M, Veenman L. Regulation of mitochondrial, cellular, and organismal functions by TSPO. Adv Pharmacol, 2018, 82: 103–136
Jaipuria G, Leonov A, Giller K, et al. Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure. Nat Commun, 2017, 8: 14893
Brien S E, Ronksley P E, Turner B J, et al. Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies. Biomed J, 2011, 342: d636
Kahl K G, Greggersen W, Schweiger U, et al. Prevalence of the metabolic syndrome in men and women with alcohol dependence: results from a cross-sectional study during behavioural treatment in a controlled environment. Addiction, 2010, 105: 1921–1927
Owen D R, Fan J, Campioli E, et al. TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis. Biochem J, 2017, 474: 3985–3999
Wiers C E, de Carvalho L M, Hodgkinson C A, et al. TSPO polymorphism in individuals with alcohol use disorder: association with cholesterol levels and withdrawal severity. Addiction Biol, 2019. doi: 10.1111/adb.12838
Ikawa M, Lohith T G, Shrestha S, et al. 11C-ER176, a radioligand for 18-kDa translocator protein, has adequate sensitivity to robustly image all three affinity genotypes in human brain. J Nucl Med, 2017, 58: 320–325
Chakraborty S, Bhattacharyya R, Banerjee D. Infections: a possible risk factor for type 2 diabetes. Adv Clin Chem, 2017, 80: 227–251
Harrison N A, Cooper E, Dowell N G, et al. Quantitative magnetization transfer imaging as a biomarker for effects of systemic inflammation on the brain. Biol Psychiatry, 2015, 78: 49–57
He J, Crews F T. Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol, 2008, 210: 349–358
Coleman J L G, Zou J, Qin L, et al. HMGB1/IL-1β complexes regulate neuroimmune responses in alcoholism. Brain Behav Immun, 2018, 72: 61–77
Crews F T, Vetreno R P. Neuroimmune basis of alcoholic brain damage. Int Rev Neurobiol, 2014, 118: 315–357
Neupane S P, Skulberg A, Skulberg K R, et al. Cytokine changes following acute ethanol intoxication in healthy men: a crossover study. Mediators Inflamm, 2016, 2016: 3758590
Serres S, Anthony D C, Jiang Y, et al. Systemic inflammatory response reactivates immune-mediated lesions in rat brain. J Neurosci, 2009, 29: 4820–4828
Sankar S B, Pybus A F, Liew A, et al. Low cerebral blood flow is a non-invasive biomarker of neuroinflammation after repetitive mild traumatic brain injury. Neurobiol Dis, 2019, 124: 544–554
Haroon E, Miller A H, Sanacora G. Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacol, 2017, 42: 193–215
Bauer J, Pedersen A, Scherbaum N, et al. Craving in alcohol-dependent patients after detoxification is related to glutamatergic dysfunction in the nucleus accumbens and the anterior cingulate cortex. Neuropsychopharmacol, 2013, 38: 1401–1408
de Witte P. Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol. Addictive Behavs, 2004, 29: 1325–1339
Lee E, Jang D P, Kim J J, et al. Alteration of brain metabolites in young alcoholics without structural changes. Neuroreport, 2007, 18: 1511–1514
Licata S C, Renshaw P F. Neurochemistry of drug action: insights from proton magnetic resonance spectroscopic imaging and their relevance to addiction. Ann New York Acad Sci, 2010, 1187: 148–171
Ramadan S, Lin A, Stanwell P. Glutamate and glutamine: a review of in vivo MRS in the human brain. NMR Biomed, 2013, 26: 1630–1646
Umhau J C, Momenan R, Schwandt M L, et al. Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. JAMA Psychiatry, 2010, 67: 1069–1077
Yeo R A, Thoma R J, Gasparovic C, et al. Neurometabolite concentration and clinical features of chronic alcohol use: a proton magnetic resonance spectroscopy study. Psychiatry Res-Neuroimag, 2013, 211: 141–147
Chang L, Ernst T, Poland R E, et al. In vivo proton magnetic resonance spectroscopy of the normal aging human brain. Life Sci, 1996, 58: 2049–2056
Chang L, Ernst T, Witt M D, et al. Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naïve HIV patients. Neuroimage, 2002, 17: 1638–1648
Schneider J R, Bandiera S, Souza D G, et al. N-acetylcysteine prevents alcohol related neuroinflammation in rats. Neurochem Res, 2017, 42: 2135–2141
Ross B D. Biochemical considerations in 1H spectroscopy. Glutamate and glutamine; Myo-inositol and related metabolites. NMR Biomedicine, 1991, 4: 59–63
Schweinsburg B C, Taylor M J, Videen J S, et al. Elevated myo-inositol in gray matter of recently detoxified but not long-term abstinent alcoholics: a preliminary MR spectroscopy study. Alcoholism Clin Exp Res, 2000, 24: 699–705
de Groot N S, Burgas M T. Is membrane homeostasis the missing link between inflammation and neurodegenerative diseases? Cellular Molecular Life Sci, 2015, 72: 4795–4805
Chang L, Ernst T, Leonido-Yee M, et al. Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology, 1999, 53: 782–782
Chang L, Ernst T, Leonido-Yee M, et al. Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex. Neurology, 1999, 52: 100
Mader I, Rauer S, Gall P, et al. (1)H MR spectroscopy of inflammation, infection and ischemia of the brain. Eur J Rad, 2008, 67: 250–257
S¨amann P G, Schlegel J, Müller G, et al. Serial proton MR spectroscopy and diffusion imaging findings in HIV-related herpes simplex encephalitis. Am J Neuroradiol, 2003, 24: 2015
Lee N M, Friedman H J, Loh H H. Effect of acute and chronic ethanol treatment on rat brain phospholipid turnover. Biochem Pharmacol, 1980, 29: 2815–2818
Obermeier B, Daneman R, Ransohoff R M. Development, maintenance and disruption of the blood-brain barrier. Nat Med, 2013, 19: 1584–1596
Banks W A, Kastin A J, Gutierrez E G. Penetration of interleukin-6 across the murine blood-brain barrier. Neurosci Lett, 1994, 179: 53–56
Banks W A, Kastin A J, Broadwell R D. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation, 1995, 2: 241–248
Estes M L, McAllister A K. Alterations in immune cells and mediators in the brain: it’s not always neuroinflammation! Brain Pathol, 2014, 24: 623–630
Rebeles F, Fink J, Anzai Y, et al. Blood-brain barrier imaging and therapeutic potentials. Top Magn Reson Imag, 2006, 17: 107–116
Runge V M, Schoerner W, Niendorf H P, et al. Initial clinical evaluation of gadolinium DTPA for contrast-enhanced magnetic resonance imaging. Magn Reson Imag, 1985, 3: 27–35
Ivanidze J, Mackay M, Hoang A, et al. Dynamic contrast-enhanced MRI reveals unique blood-brain barrier permeability characteristics in the hippocampus in the normal brain. Am J Neuroradiol, 2019, 40: 408–411
Alexander A L, Lee J E, Lazar M, et al. Diffusion tensor imaging of the brain. Neurotherapeutics, 2007, 4: 316–329
Abbott N J, Patabendige A A K, Dolman D E M, et al. Structure and function of the blood-brain barrier. NeuroBiol Dis, 2010, 37: 13–25
Le Bihan D, Mangin J F, Poupon C, et al. Diffusion tensor imaging: concepts and applications. J Magn Reson Imag, 2001, 13: 534–546
Assaf Y, Pasternak O. Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review. J Mol Neurosci, 2008, 34: 51–61
Pierpaoli C, Jezzard P, Basser P J, et al. Diffusion tensor MR imaging of the human brain. Radiology, 1996, 201: 637–648
Inglese M, Bester M. Diffusion imaging in multiple sclerosis: research and clinical implications. NMR Biomed, 2010, 23: 865–872
Smith S M, Jenkinson M, Woolrich M W, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage, 2004, 23: 208–219
Smith S M, Jenkinson M, Johansen-Berg H, et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage, 2006, 31: 1487–1505
Shiu C, Barbier E, Cello F D, et al. HIV-1 gp120 as well as alcohol affect blood-brain barrier permeability and stress fiber formation: involvement of reactive oxygen species. Alcoholism Clin Exp Res, 2007, 31: 130–137
Toborek M, Lee Y W, Flora G, et al. Mechanisms of the blood-brain barrier disruption in HIV-1 infection. Cell Mol Neurobiol, 2005, 25: 181–199
Petrache I, Birukova A, Ramirez S I, et al. The role of the microtubules in tumor necrosis factor-alpha-induced endothelial cell permeability. Am J Respir Cell Mol Biol, 2003, 28: 574–581
Schwartz J A, Speed N M, Gross M D, et al. Acute effects of alcohol administration on regional cerebral blood flow: the role of acetate. Alcoholism Clin Exp Res, 1993, 17: 1119–1123
Beamer E, Gölöncsér F, Horváth G, et al. Purinergic mechanisms in neuroinflammation: an update from molecules to behavior. Neuropharmacology, 2016, 104: 94–104
Dai S S, Zhou Y G, Li W, et al. Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci, 2010, 30: 5802–5810
Ferrante A, de Simone R, Ajmone-Cat M A, et al. Adenosine receptors and neuroinflammation. In: The Adenosine Receptors. Cham: Humana Press, 2018. 217–237
Boison D. Adenosine dysfunction in epilepsy. Glia, 2012, 60: 1234–1243
da Rocha Lapa F, Jünior S J M, Cerutti M L, et al. Pharmacology of adenosine receptors and their signaling role in immunity and inflammation. In: Pharmacology and Therapeutics. New York: IntechOpen, 2014
Nagy L E, Diamond I, Casso D J, et al. Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the nucleoside transporter. J Biol Chem, 1990, 265: 1946–1951
Clasadonte J, McIver S R, Schmitt L I, et al. Chronic sleep restriction disrupts sleep homeostasis and behavioral sensitivity to alcohol by reducing the extracellular accumulation of adenosine. J Neurosci, 2014, 34: 1879–1891
Sharma R, Sahota P, Thakkar M M. Role of adenosine and the orexinergic perifornical hypothalamus in sleep-promoting effects of ethanol. Sleep, 2014, 37: 525–533
Wiers C E. Adenosine sheds light on the relationship between alcohol and sleep. J Neurosci, 2014, 34: 7733–7734
Ishibashi K, Tago T, Wagatsuma K, et al. Type 1 metabotropic glutamate receptors measured with a novel PET ligand, 11C-ITMM, in patients with cerebellar ataxia. J Nuclear Med, 2018, 59: 1696
Guo M, Gao Z G, Tyler R, et al. Preclinical evaluation of the first adenosine A1 receptor partial agonist radioligand for Positron Emission Tomography imaging. J Med Chem, 2018, 61: 9966–9975
Vuorimaa A, Rissanen E, Airas L. In vivo PET imaging of adenosine 2A receptors in neuroinflammatory and neu-rodegenerative disease. Contrast Media Molecular Imag, 2017, 2017: 6975841
Kreft S, Bier D, Holschbach M H, et al. New potent A1 adenosine receptor radioligands for positron emission tomography. Nucl Med Biol, 2017, 44: 69–77
Elmenhorst E M, Elmenhorst D, Benderoth S, et al. Cognitive impairments by alcohol and sleep deprivation indicate trait characteristics and a potential role for adenosine A1 receptors. Proc Natl Acad Sci USA, 2018, 115: 8009–8014
Carmichael F, Salvida V, Varghese G, et al. Ethanol-induced increase in portal blood flow: role of acetate A1 and A2-adenosine receptors. Am J Physiol, 1988, 255: 417–423
Orrego H, Carmichael F, Saldiva V, et al. Ethanol-induced increase in portal blood flow: Role of adenosine. Am J Physiol, 1988, 254: 495–501
Fan J, Yang J, Jiang Z. Prediction of central nervous system side effects through drug permeability to blood-brain barrier and recommendation algorithm. J Comput Biol, 2018, 25: 435–443
Dirchwolf M. Role of systemic inflammation in cirrhosis: from pathogenesis to prognosis. World J Hepatol, 2015, 7: 1974–1981
Huang J V, Schooling C M. Inflammation and bone mineral density: a mendelian randomization study. Sci Rep, 2017, 7: 8666
Schuckit M A. Alcohol-use disorders. Lancet, 2009, 373: 492–501
Yudkin J S, Kumari M, Humphries S E, et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis, 2000, 48: 209–214
Barton E A, Baker C, Leasure J L. Investigation of sex differences in the microglial response to binge ethanol and exercise. Brain Sci, 2017, 7: 139
Landolt H P. Sleep homeostasis: a role for adenosine in humans? Biochem Pharmacol, 2008, 75: 2070–2079
Huang Z L, Urade Y, Hayaishi O. The role of adenosine in the regulation of sleep. Current Top Med Chem, 2011, 11: 1047–1057
Huang Z L, Zhang Z, Qu W M. Roles of adenosine and its receptors in sleep-wake regulation. Int Rev Neurobiol, 2014, 119: 349–371
Angarita G A, Emadi N, Hodges S, et al. Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: a comprehensive review. Addict Sci Clin Pract, 2016, 11: 9
Colrain I M, Turlington S, Baker F C. Impact of alcoholism on sleep architecture and EEG power spectra in men and women. Sleep, 2009, 32: 1341–1352
Hasler B P, Pedersen S L. Sleep and circadian risk factors for alcohol problems: a brief overview and proposed mechanisms. Current Opinion Psychol, 2019, 34: 57–62
Hasler B P, Soehner A M, Clark D B. Sleep and circadian contributions to adolescent alcohol use disorder. Alcohol, 2015, 49: 377–387
Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and abuse. Sleep Med Rev, 2001, 5: 287–297
Dinges D F, Douglas S D, Hamarman S, et al. Sleep deprivation and human immune function. Adv Neuroimmunol, 1995, 5: 97–110
Manchanda S, Singh H, Kaur T, et al. Low-grade neuroinflammation due to chronic sleep deprivation results in anxiety and learning and memory impairments. Mol Cell Biochem, 2018, 449: 63–72
Shearer W T, Reuben J M, Mullington J M, et al. Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight. J Allergy Clin Immunol, 2001, 107: 165–170
Wisor J P, Schmidt M A, Clegern W C. Evidence for neuroinflammatory and microglial changes in the cerebral response to sleep loss. Sleep, 2011, 34: 261–272
Zhu B, Dong Y, Xu Z, et al. Sleep disturbance induces neuroinflammation and impairment of learning and memory. Neurobiol Dis, 2012, 48: 348–355
Sharma R, Engemann S C, Sahota P, et al. Effects of ethanol on extracellular levels of adenosine in the basal forebrain: an in vivo microdialysis study in freely behaving rats. Alcoholism-Clin Exp Res, 2010, 34: 813–818
Thakkar M M, Engemann S C, Sharma R, et al. Role of wake-promoting basal forebrain and adenosinergic mechanisms in sleep-promoting effects of ethanol. Alcoholism-Clin Exp Res, 2010, 34: 997–1005
Nam H W, McIver S R, Hinton D J, et al. Adenosine and glutamate signaling in neuron-glial interactions: implications in alcoholism and sleep disorders. Alcohol Clin Exp Res, 2012, 36: 1117–1125
Sharma R, Sahota P, Thakkar M M. Alcoholism and sleep. In: The Behavioral, Molecular, Pharmacological, and Clinical Basis of the Sleep-Wake Cycle. London: Academic Press, 2019. 159–192
Knapp C M, Ciraulo D A, Datta S. Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum. Behavioural Brain Res, 2014, 274: 291–301
Ruby C L, Vadnie C A, Hinton D J, et al. Adenosinergic regulation of striatal clock gene expression and ethanol intake during constant light. Neuropsychopharmacol, 2014, 39: 2432–2440
Garland E L, Froeliger B, Howard M O. Mindfulness training targets neurocognitive mechanisms of addiction at the attention-appraisal-emotion interface. Front Psychiatry, 2014, 4: 173
Stevens F L, Hurley R A, Taber K H. Anterior cingulate cortex: unique role in cognition and emotion. J Neuropsy-chiatry Clinical Neurosci, 2011, 23: 121–125
Cheetham A, Allen N B, Whittle S, et al. Volumetric differences in the anterior cingulate cortex prospectively predict alcohol-related problems in adolescence. Psychopharmacology, 2014, 231: 1731–1742
Cardenas V A, Studholme C, Gazdzinski S, et al. Deformation-based morphometry of brain changes in alcohol dependence and abstinence. Neuroimage, 2007, 34: 879–887
Vollst¨adt-Klein S, Hermann D, Rabinstein J, et al. Increased activation of the ACC during a spatial working memory task in alcohol-dependence versus heavy social drinking. Alcoholism-Clin Exp Res, 2010, 34: 771–776
Dev S I, Moore R C, Soontornniyomkij B, et al. Peripheral inflammation related to lower fMRI activation during a working memory task and resting functional connectivity among older adults: a preliminary study. Int J Geriatr Psychiatry, 2017, 32: 341–349
Passamonti L, Tsvetanov K A, Jones P S, et al. Neuroinflammation and functional connectivity in alzheimer’s disease: interactive influences on cognitive performance. J Neurosci, 2019, 39: 7218–7226
O’Neill J, Cardenas V A, Meyerhoff D J. Effects of abstinence on the brain: quantitative magnetic resonance imaging and magnetic resonance spectroscopic imaging in chronic alcohol abuse. Alcoholism Clin Exp Res, 2001, 25: 1673–1682
Sullivan E V, Zahr N M. Neuroinflammation as a neurotoxic mechanism in alcoholism: commentary on “Increased MCP-1 and microglia in various regions of human alcoholic brain”. Exp Neurology, 2008, 213: 10–17
Ciarmiello A. Imaging of neuroinflammation. Eur J Nucl Med Mol Imag, 2011, 38: 2198–2201
Kessler R M, Goble J C, Bird J H, et al. Measurement of blood-brain barrier permeability with positron emission tomography and EDTA. J Cerebral Blood Flow Metabolism, 1984, 4: 323–328
Pozzilli C, Bernardi S, Mansi L, et al. Quantitative assessment of blood-brain barrier permeability in multiple sclerosis using 68-Ga-EDTA and positron emission tomography. J Neurol Neurosurgery Psychiatry, 1988, 51: 1058–1062
Wunder A, Klohs J, Dirnagl U. Non-invasive visualization of CNS inflammation with nuclear and optical imaging. Neuroscience, 2009, 158: 1161–1173
Hafkemeijer A, Altmann-Schneider I, de Craen A J M, et al. Associations between age and gray matter volume in anatomical brain networks in middle-aged to older adults. Aging Cell, 2014, 13: 1068–1074
Paul C A, Au R, Fredman L, et al. Association of alcohol consumption with brain volume in the Framingham Study. Archives Neurol, 2008, 65: 1363–1367
Erickson K I, Raji C A, Lopez O L, et al. Physical activity predicts gray matter volume in late adulthood: the cardiovascular health study. Neurology, 2010, 75: 1415–1422
Good C D, Johnsrude I S, Ashburner J, et al. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage, 2001, 14: 21–36
Guerri C, Pascual M. Role of toll-like receptor 4 in alcohol-induced neuroinflammation and behavioral dysfunctions. In: Neural-Immune Interactions in Brain Function and Alcohol Related Disorders. Boston: Springer, 2013. 279–306
Lehnardt S, Massillon L, Follett P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA, 2003, 100: 8514–8519
Hagerty S L, Bidwell L C, Harlaar N, et al. An exploratory association study of alcohol use disorder and DNA methylation. Alcohol Clin Exp Res, 2016, 40: 1633–1640
Karoly H C, Thayer R E, Hagerty S L, et al. TLR4 methylation moderates the relationship between alcohol use severity and gray matter loss. J Stud Alcohol Drugs, 2017, 78: 696–705
Thayer R E, Hagerty S L, Sabbineni A, et al. Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry. Hum Brain Mapp, 2016, 37: 2276–2292
Fede S J, Grodin E N, Dean S F, et al. Resting state connectivity best predicts alcohol use severity in moderate to heavy alcohol users. Neuroimage Clin, 2019, 22: 101782
Shokri-Kojori E, Tomasi D, Alipanahi B, et al. Correspondence between cerebral glucose metabolism and BOLD reveals relative power and cost in human brain. Nat Commun, 2019, 10: 690
Wang Y, Zhao Y, Nie H, et al. Disrupted brain network efficiency and decreased functional connectivity in multi-sensory modality regions in male patients with alcohol use disorder. Front Hum Neurosci, 2018, 12: 513
Schacht J P, Anton R F, Myrick H. Functional neuroimaging studies of alcohol cue reactivity: a quantitative meta-analysis and systematic review. Addiction Biol, 2013, 18: 121–133
Agrawal R G, Hewetson A, George C M, et al. Minocycline reduces ethanol drinking. Brain Behavior Immunity, 2011, 25: 165–169
George F R. The role of arachidonic acid metabolites in mediating ethanol self-administration and intoxication. Ann New York Acad Sci, 1989, 559: 382–391
Pascual M, Blanco A M, Cauli O, et al. Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci, 2007, 25: 541–550
Bell R L, Lopez M F, Cui C, et al. Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addiction Biol, 2015, 20: 38–42
Franklin K M, Hauser S R, Lasek A W, et al. Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4). Psychopharmacology, 2015, 232: 2251–2262
Wen R T, Zhang M, Qin W J, et al. The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring Fawn-Hooded rats. Alcohol Clin Exp Res, 2012, 36: 2157–2167
Ray L A, Bujarski S, Shoptaw S, et al. Development of the neuroimmune modulator ibudilast for the treatment of alcoholism: a randomized, placebo-controlled, human laboratory trial. Neuropsychopharmacol, 2017, 42: 1776–1788
Montesinos J, Gil A, Guerri C. Nalmefene prevents alcohol-induced neuroinflammation and alcohol drinking preference in adolescent female mice: role of TLR4. Alcohol Clin Exp Res, 2017, 41: 1257–1270
Sinclair J D. Drugs to decrease alcohol drinking. Ann Med, 1990, 22: 357–362
Castera P, Stewart E, Grosskopf J, et al. Nalmefene, given as needed, in the routine treatment of patients with alcohol dependence: an interventional, open-label study in primary care. Eur Addict Res, 2019, 24: 293–303
Hendershot C S, Wardell J D, Samokhvalov A V, et al. Effects of naltrexone on alcohol self-administration and craving: meta-analysis of human laboratory studies. Addiction Biol, 2017, 22: 1515–1527
Ray L A, Chin P F, Miotto K. Naltrexone for the treatment of alcoholism: clinical findings, mechanisms of action, and pharmacogenetics. CNS Neurol Disorders-Drug Targets, 2010, 9: 13–22
Ramanoël S, Hoyau E, Kauffmann L, et al. Gray matter volume and cognitive performance during normal aging: a voxel-based morphometry study. Front Aging Neurosci, 2018, 10: 235
Tisserand D J. A voxel-based morphometric study to determine individual differences in gray matter density associated with age and cognitive change over time. Cerebral Cortex, 2004, 14: 966–973
Magill M, Ray L A. Cognitive-behavioral treatment with adult alcohol and illicit drug users: a meta-analysis of randomized controlled trials. J Stud Alcohol Drugs, 2009, 70: 516–527
Lopresti A L. Cognitive behaviour therapy and inflammation: a systematic review of its relationship and the potential implications for the treatment of depression. Aust New Zealand J Psychiatry, 2017, 51: 565–582
Gryczynski J, Schwartz R P, Fishman M J, et al. Integration of transcendental meditation(r) (TM) into alcohol use disorder (AUD) treatment. J Substance Abuse Treatment, 2018, 87: 23–30
Creswell J D, Irwin M R, Burklund L J, et al. Mindfulness-based stress reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Brain Behav Immun, 2012, 26: 1095–1101
Creswell J D, Taren A A, Lindsay E K, et al. Alterations in resting-state functional connectivity link mindfulness meditation with reduced interleukin-6: a randomized controlled trial. Biol Psychiatry, 2016, 80: 53–61
Malarkey W B, Jarjoura D, Klatt M. Workplace based mindfulness practice and inflammation: a randomized trial. Brain Behav Immun, 2013, 27: 145–154
Seo D Y, Heo J W, Ko J R, et al. Exercise and neuroinflammation in health and disease. Int Neurourol J, 2019, 23: S82–92
Hallgren M, Vancampfort D, Giesen E S, et al. Exercise as treatment for alcohol use disorders: systematic review and meta-analysis. Br J Sports Med, 2017, 51: 1058–1064
Acknowledgements
This work was supported by National Institute on Alcohol Abuse and Alcoholism (Grant No. Y1AA-3009). We thank Yang HU for his valuable support in text formatting and reference management.
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Feldman, D.E., McPherson, K.L., Biesecker, C.L. et al. Neuroimaging of inflammation in alcohol use disorder: a review. Sci. China Inf. Sci. 63, 170102 (2020). https://doi.org/10.1007/s11432-019-2857-5
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DOI: https://doi.org/10.1007/s11432-019-2857-5