Abstract
Excessive ethanol consumption alters the neuroimmune system and particularly impacts the cytokine milieu of the CNS. Cytokine dysregulation has been shown to underlie addictive-like behaviors including alcohol abuse; however, many studies focus primarily on the proinflammatory cytokine profile during alcohol dependence. The current study furthers this research by determining the impact of excessive ethanol consumption on interleukin-10 (IL-10) and interleukin-4 (IL-4) activity in a model of non-dependent binge consumption called the “drinking in the dark” (DID) paradigm. Furthermore, the ability of IL-10 to modulate ethanol consumption was tested using site-directed pharmacology. Immunohistochemistry analyses determined that ethanol decreased IL-10 by 50 % in the basolateral amygdala (BLA) but had no effect on IL-4. Neither IL-10 nor IL-4, however, were altered in the central amygdala (CEA). Enzyme linked immunosorbent assays confirmed that IL-10 was decreased in the amygdala but not in the serum, suggesting changes of this cytokine with the DID paradigm are restricted to the central nervous system. Finally, bilateral infusions of IL-10 into the BLA, but not CeA, reduced binge-like drinking and corresponding blood ethanol concentrations without impacting either locomotor activity or anxiety-like behavioral correlates. Together, these data support the idea that alcohol abuse dysregulates specific anti-inflammatory cytokines; however, ameliorating alcohol-induced effects on cytokines, like IL-10, may prove to be an effective therapy in curbing excessive consumption.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Achur RN, Freeman WM, Vrana KE (2010) Circulating cytokines as biomarkers of alcohol abuse and alcoholism. J NeuroImmune Pharmacol 5:83–91. doi:10.1007/s11481-009-9185-z
Bachis A, Colangelo AM, Vicini S, Doe PP, De Bernardi MA, Brooker G, Mocchetti I (2001) Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci 21:3104–3112
Bajo M et al. (2015a) Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun 45:189–197. doi:10.1016/j.bbi.2014.11.011
Bajo M et al. (2015b) IL-1 interacts with ethanol effects on GABAergic transmission in the mouse central amygdala. Front Pharmacol 6:49. doi:10.3389/fphar.2015.00049
Barak O, Goshen I, Ben-Hur T, Weidenfeld J, Taylor AN, Yirmiya R (2002) Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein120. Brain Res 933:98–108
Bell RL, Lopez MF, Cui C, Egli M, Johnson KW, Franklin KM, Becker HC (2013) Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence Addict Biol doi:10.1111/adb.12106
Blednov YA, Benavidez JM, Geil C, Perra S, Morikawa H, Harris RA (2011) Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice Brain Behav Immun 25 Suppl 1:S92-S105
Blednov YA, Ponomarev I, Geil C, Bergeson S, Koob GF, Harris RA (2012) Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addict Biol 17:108–120. doi:10.1111/j.1369-1600.2010.00284.x
Blednov, YA, Benavidez, JM, Black, M, Harris, RA (2014) Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6 J mice. Front Neurosci 8:129 doi:10.3389/fnins.2014.00129
Bluthe RM et al. (1999) Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats. Psychoneuroendocrinology 24:301–311
Cavaillon JM (2001) Pro- versus anti-inflammatory cytokines: myth or reality. Cell Mol Biol (Noisy-le-grand) 47:695–702
Cox BR et al. (2013) Repeated cycles of binge-like ethanol (EtOH)-drinking in male C57BL/6 J mice augments subsequent voluntary EtOH intake but not other dependence-like phenotypes. Alcohol Clin Exp Res 37:1688–1695. doi:10.1111/acer.12145
Crews FT, Vetreno RP (2014) Neuroimmune basis of alcoholic brain damage. Int Rev Neurobiol 118:315–357. doi:10.1016/B978-0-12-801284-0.00010-5
Der-Avakian A, Markou A (2012) The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci 35:68–77. doi:10.1016/j.tins.2011.11.005
Fee JR, Sparta DR, Knapp DJ, Breese GR, Picker MJ, Thiele TE (2004) Predictors of high ethanol consumption in RIIbeta knock-out mice: assessment of anxiety and ethanol-induced sedation. Alcohol Clin Exp Res 28:1459–1468
Goldstein RB, Dawson DA, Chou SP, Grant BF (2012) Sex differences in prevalence and comorbidity of alcohol and drug use disorders: results from wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. J. Stud. Alcohol Drugs 73:938–950
Gonzalez-Quintela A, Vidal C, Lojo S, Perez LF, Otero-Anton E, Gude F, Barrio E (1999) Serum cytokines and increased total serum IgE in alcoholics. Ann Allergy Asthma Immunol 83:61–67
Hart PH, Ahern MJ, Smith MD, Finlay-Jones JJ (1995) Comparison of the suppressive effects of interleukin-10 and interleukin-4 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis. Immunology 84:536–542
He J, Crews FT (2008) Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 210:349–358
Hernandez RV et al. (2016) Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function. Neuropharmacology 103:27–43. doi:10.1016/j.neuropharm.2015.12.015
Kalk NJ, Lingford-Hughes AR (2014) The clinical pharmacology of acamprosate. Br J Clin Pharmacol 77:315–323. doi:10.1111/bcp.12070
Kelley KW, McCusker RH (2014) Getting nervous about immunity. Semin Immunol 26:389–393. doi:10.1016/j.smim.2014.01.011
Kwilasz AJ, Grace PM, Serbedzija P, Maier SF, Watkins LR (2015) The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology 96:55–69. doi:10.1016/j.neuropharm.2014.10.020
Liesz A et al. (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15:192–199. doi:10.1038/nm.1927
Lim SH, Park E, You B, Jung Y, Park AR, Park SG, Lee JR (2013) Neuronal synapse formation induced by microglia and interleukin 10. PLoS One 8:e81218. doi:10.1371/journal.pone.0081218
Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724
Marshall SA, McClain JA, Kelso ML, Hopkins DM, Pauly JR, Nixon K (2013) Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: the importance of microglia phenotype. Neurobiol Dis 54:239–251
Marshall SA, Rinker JA, Harrison LK, Fletcher CA, Herfel TM, Thiele TE (2015) Assessment of the Effects of 6 Standard Rodent Diets on Binge-Like and Voluntary Ethanol Consumption in Male C57BL/6J Mice. Alcohol Clin Exp Res. doi:10.1111/acer.12773
Marshall SA, Casachahua JD, Rinker JA, Blose AK, Lysle DT, Thiele TE (2016a) IL-1 receptor signaling in the basolateral amygdala modulates binge-like ethanol consumption in male C57BL/6 J mice. Brain Behav Immun 51:258–267. doi:10.1016/j.bbi.2015.09.006
Marshall SA, Geil CR, Nixon K (2016b) Prior binge ethanol exposure potentiates the microglial response in a model of alcohol-induced neurodegeneration. Brain Sci 6. doi:10.3390/brainsci6020016
McClain CJ, Cohen DA (1989) Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology 9:349–351
McClain JA, Morris SA, Deeny MA, Marshall SA, Hayes DM, Kiser ZM, Nixon K (2011) Adolescent binge alcohol exposure induces long-lasting partial activation of microglia Brain Behav Immun 25 Suppl 1:S120–S128
Morita Y et al. (2001) Differential in vitro effects of IL-4, IL-10, and IL-13 on proinflammatory cytokine production and fibroblast proliferation in rheumatoid synovium. Rheumatol Int 20:49–54
NIAAA (2004) NIAAA Council Approves Definition of Binge Drinking, Winter edn. National Institute of Health, Bethesda
Nikou T et al. (2016) Alteration in the concentrations of Interleukin-7 (IL-7), Interleukin-10 (IL-10) and Granulocyte Colony Stimulating Factor (G-CSF) in alcohol-dependent individuals without liver disease, during detoxification therapy. Drug Alcohol Depend. doi:10.1016/j.drugalcdep.2016.03.022
NRC (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, Washington, D.C.
O’Halloran EB, Curtis BJ, Afshar M, Chen MM, Kovacs EJ, Burnham EL (2016) Alveolar macrophage inflammatory mediator expression is elevated in the setting of alcohol use disorders. Alcohol (Fayetteville, NY 50:43–50. doi:10.1016/j.alcohol.2015.11.003
Patterson SL (2015) Immune dysregulation and cognitive vulnerability in the aging brain: interactions of microglia, IL-1beta, BDNF and synaptic plasticity. Neuropharmacology 96:11–18. doi:10.1016/j.neuropharm.2014.12.020
Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates. Compact 2nd edn. Elsevier Academic Press, Amsterdam
Perkeybile AM, Schiml-Webb PA, O’Brien E, Deak T, Hennessy MB (2009) Anti-inflammatory influences on behavioral, but not cortisol, responses during maternal separation. Psychoneuroendocrinology 34:1101–1108. doi:10.1016/j.psyneuen.2009.02.014
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33
Qin L, Crews FT (2012) Chronic ethanol increases systemic TLR3 agonist-induced neuroinflammation and neurodegeneration. J Neuroinflammation 9:130
Qin L, He J, Hanes RN, Pluzarev O, Hong JS, Crews FT (2008) Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflammation 5:10
Rhodes JS, Best K, Belknap JK, Finn DA, Crabbe JC (2005) Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6 J mice. Physiol Behav 84:53–63. doi:10.1016/j.physbeh.2004.10.007
Sacks JJ, Gonzales KR, Bouchery EE, Tomedi LE, Brewer RD (2015) 2010 National and State Costs of Excessive Alcohol Consumption. Am. J. Prev. Med. 49:e73–e79. doi:10.1016/j.amepre.2015.05.031
Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuro-Psychopharmacol Biol Psychiatry 29:201–217. doi:10.1016/j.pnpbp.2004.11.003
Schunck RV et al. (2015) Protracted alcohol abstinence induces analgesia in rats: Possible relationships with BDNF and interleukin-10. Pharmacol Biochem Behav 135:64–69. doi:10.1016/j.pbb.2015.05.011
Sharma S, Yang B, Xi X, Grotta JC, Aronowski J, Savitz SI (2011) IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res 1373:189–194. doi:10.1016/j.brainres.2010.11.096
Sprow GM, Thiele TE (2012) The neurobiology of binge-like ethanol drinking: evidence from rodent models. Physiol Behav 106:325–331. doi:10.1016/j.physbeh.2011.12.026
Steinman L (2008) Nuanced roles of cytokines in three major human brain disorders. J Clin Invest 118:3557–3563. doi:10.1172/JCI36532
Suryanarayanan A, Carter JM, Landin JD, Morrow AL, Werner DF, Spigelman I (2016) Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol. Neuropharmacology 107:181–188. doi:10.1016/j.neuropharm.2016.03.027
Thiele TE, Navarro M (2014) "Drinking in the dark" (DID) procedures: A model of binge-like ethanol drinking in non-dependent mice. Alcohol 48:235–241. doi:10.1016/j.alcohol.2013.08.005
Thompson CD, Zurko JC, Hanna BF, Hellenbrand DJ, Hanna A (2013) The therapeutic role of interleukin-10 after spinal cord injury. J Neurotrauma 30:1311–1324. doi:10.1089/neu.2012.2651
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2:322–328. doi:10.1038/nprot.2007.44
Zou J, Crews FT (2012) Inflammasome-IL-1beta Signaling Mediates Ethanol Inhibition of Hippocampal Neurogenesis. Front Neurosci 6:77. doi:10.3389/fnins.2012.00077
Acknowledgments
The authors thank Rhiannon D. Thomas, Sonia Sabater, Timothy P. Gilliam, and Suzahn Ebert for their technical assistance.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare no conflict of interest.
Funding
This work was supported by National Institutes of Health grants AA022048, AA013573, AA015148, AA021611, AA011605, & GM000678.
Rights and permissions
About this article
Cite this article
Marshall, S.A., McKnight, K.H., Blose, A.K. et al. Modulation of Binge-like Ethanol Consumption by IL-10 Signaling in the Basolateral Amygdala. J Neuroimmune Pharmacol 12, 249–259 (2017). https://doi.org/10.1007/s11481-016-9709-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-016-9709-2