Abstract
Clinical and preclinical studies have identified immunosuppressive effects of nicotine, with potential implications for treating nicotine addiction. Here we review how nicotine can regulate microglia, the resident macrophages in the brain, and corresponding effects of nicotine on neuroimmune signaling. There is significant evidence that activation of α7 nicotinic acetylcholine receptors (nAChRs) on microglia can trigger an anti-inflammatory cascade that alters microglial polarization and activity, cytokine release, and intracellular calcium concentrations, leading to neuroprotection. These anti-inflammatory effects of nicotine-dependent α7 nAChR signaling are lost during withdrawal, suggesting that neuroimmune signaling is potentiated during abstinence, and thus, heightened microglial activity may drive circuit disruption that contributes to withdrawal symptoms and hyperkatifeia. In sum, the clinical literature has highlighted immunomodulatory effects of nicotine and the potential for anti-inflammatory compounds to treat addiction. The preclinical literature investigating the underlying mechanisms points to a role of microglial engagement in the circuit dysregulation and behavioral changes that occur during nicotine addiction and withdrawal, driven, at least in part, by activation of α7 nAChRs on microglia. Specifically targeting microglial signaling may help alleviate withdrawal symptoms in people with nicotine dependence and help to promote abstinence.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adeluyi A, Guerin L, Fisher ML et al (2019) Microglia morphology and proinflammatory signaling in the nucleus accumbens during nicotine withdrawal. Sci Adv 5:eaax7031. https://doi.org/10.1126/sciadv.aax7031
Agrawal RG, Hewetson A, George CM et al (2011) Minocycline reduces ethanol drinking. Brain Behav Immun 25:S165–S169. https://doi.org/10.1016/j.bbi.2011.03.002
Ali I, Aertgeerts S, Le Blon D et al (2017) Intracerebral delivery of the M2 polarizing cytokine interleukin 13 using mesenchymal stem cell implants in a model of temporal lobe epilepsy in mice. Epilepsia 58:1063–1072. https://doi.org/10.1111/epi.13743
Aryal SP, Fu X, Sandin JN et al (2021) Nicotine induces morphological and functional changes in astrocytes via nicotinic receptor activity. Glia 69:2037–2053. https://doi.org/10.1002/glia.24011
Ayata P, Badimon A, Strasburger HJ et al (2018) Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci 21:1049–1060. https://doi.org/10.1038/s41593-018-0192-3
Babb S (2017) Quitting Smoking Among Adults—United States, 2000–2015. Morb Mortal Wkly Rep. https://doi.org/10.1585/mmwr.mm6552a1
Bai X, Stitzel JA, Bai A et al (2017) Nicotine impairs macrophage control of Mycobacterium tuberculosis. Am J Respir Cell Mol Biol 57:324–333. https://doi.org/10.1165/rcmb.2016-0270OC
Beardsley PM, Shelton KL, Hendrick E, Johnson KW (2010) The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse. Eur J Pharmacol 637:102–108. https://doi.org/10.1016/j.ejphar.2010.04.010
Behnke M, Smith VC (2013) Prenatal substance abuse: short- and long-term effects on the exposed fetus. Pediatrics 131:e1009–e1024. https://doi.org/10.1542/peds.2012-3931
Beynon SB, Walker FR (2012) Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. Neuroscience 225:162–171. https://doi.org/10.1016/j.neuroscience.2012.07.029
Bolton JL, Short AK, Othy S et al (2022) Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses. Cell Rep. https://doi.org/10.1016/j.celrep.2022.110600
Brooks AC, Henderson BJ (2021) Systematic review of nicotine exposure’s effects on neural stem and progenitor cells. Brain Sci 11:172. https://doi.org/10.3390/brainsci11020172
Burmeister AR, Marriott I (2018) The interleukin-10 family of cytokines and their role in the CNS. Front Cell Neurosci 12:458. https://doi.org/10.3389/fncel.2018.00458
Bye LJ, Finol-Urdaneta RK, Tae H-S, Adams DJ (2023) Nicotinic acetylcholine receptors: key targets for attenuating neurodegenerative diseases. Int J Biochem Cell Biol 157:106387. https://doi.org/10.1016/j.biocel.2023.106387
Chaiton M, Diemert L, Cohen JE et al (2016) Estimating the number of quit attempts it takes to quit smoking successfully in a longitudinal cohort of smokers. BMJ Open 6:e011045. https://doi.org/10.1136/bmjopen-2016-011045
Chan YL, Saad S, Pollock C et al (2016) Impact of maternal cigarette smoke exposure on brain inflammation and oxidative stress in male mice offspring. Sci Rep 6:25881. https://doi.org/10.1038/srep25881
Chen D, Li J, Huang Y et al (2022) Interleukin 13 promotes long-term recovery after ischemic stroke by inhibiting the activation of STAT3. J Neuroinflammation 19:112. https://doi.org/10.1186/s12974-022-02471-5
Cohen A, Soleiman MT, Talia R et al (2015) Extended access nicotine self-administration with periodic deprivation increases immature neurons in the hippocampus. Psychopharmacology 232:453–463. https://doi.org/10.1007/s00213-014-3685-0
Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4:399–418. https://doi.org/10.1007/s11481-009-9164-4
Comer DM, Elborn JS, Ennis M (2014) Inflammatory and cytotoxic effects of acrolein, nicotine, acetylaldehyde and cigarette smoke extract on human nasal epithelial cells. BMC Pulm Med 14:32. https://doi.org/10.1186/1471-2466-14-32
Cooper J, Borland R, McKee SA et al (2016) Depression motivates quit attempts but predicts relapse: differential findings for gender from the international tobacco control study. Addict Abingdon Engl 111:1438–1447. https://doi.org/10.1111/add.13290
Cotto B, Li H, Tuma RF et al (2018) Cocaine-mediated activation of microglia and microglial MeCP2 and BDNF production. Neurobiol Dis 117:28–41. https://doi.org/10.1016/j.nbd.2018.05.017
Crews FT, Lawrimore CJ, Walter TJ, Coleman LG (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56–73. https://doi.org/10.1016/j.neuropharm.2017.01.031
Davalos D, Grutzendler J, Yang G et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758. https://doi.org/10.1038/nn1472
Dinardo P, Rome ES (2019) Vaping: The new wave of nicotine addiction. Cleve Clin J Med 86:789–798. https://doi.org/10.3949/ccjm.86a.19118
Drope J, Cahn Z, Kennedy R et al (2017) Key issues surrounding the health impacts of electronic nicotine delivery systems (ENDS) and other sources of nicotine. CA Cancer J Clin 67:449–471. https://doi.org/10.3322/caac.21413
Egea J, Buendia I, Parada E et al (2015) Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol 97:463–472. https://doi.org/10.1016/j.bcp.2015.07.032
Egleton RD, Abbruscato T (2014) Chapter fifteen—drug abuse and the neurovascular unit. In: Davis TP (ed) Advances in pharmacology. Academic Press, Cambridge, pp 451–480
Favuzzi E, Huang S, Saldi GA et al (2021) GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell 184:4048-4063.e32. https://doi.org/10.1016/j.cell.2021.06.018
Franco R, Fernández-Suárez D (2015) Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol 131:65–86. https://doi.org/10.1016/j.pneurobio.2015.05.003
Frøisland DH (2017) Nicotine withdrawal syndrome in a newborn baby after maternal use of oral applied moist tobacco (snus), should result in greater awareness to the use of snus among pregnant women. Acta Paediatr 106:1531–1531. https://doi.org/10.1111/apa.13913
Furube E, Kawai S, Inagaki H et al (2018) Brain region-dependent heterogeneity and dose-dependent difference in transient microglia population increase during lipopolysaccharide-induced inflammation. Sci Rep. https://doi.org/10.1038/s41598-018-20643-3
Gildawie KR, Honeycutt JA, Brenhouse HC (2020) Region-specific effects of maternal separation on perineuronal net and parvalbumin-expressing interneuron formation in male and female rats. Neuroscience 428:23–37. https://doi.org/10.1016/j.neuroscience.2019.12.010
Gipson CD, Rawls S, Scofield MD et al (2021) Interactions of neuroimmune signaling and glutamate plasticity in addiction. J Neuroinflammation 18:56. https://doi.org/10.1186/s12974-021-02072-8
Godding V, Bonnier C, Fiasse L et al (2004) Does in utero exposure to heavy maternal smoking induce nicotine withdrawal symptoms in neonates? Pediatr Res 55:645–651. https://doi.org/10.1203/01.PDR.0000112099.88740.4E
Gou J, Liang S, Cheng W et al (2021) Neuroprotective effect of combined use of nicotine and celecoxib by inhibiting neuroinflammation in ischemic rats. Brain Res Bull 175:234–243. https://doi.org/10.1016/j.brainresbull.2021.07.022
Gould TJ (2023) Epigenetic and long-term effects of nicotine on biology, behavior, and health. Pharmacol Res 192:106741. https://doi.org/10.1016/j.phrs.2023.106741
Guan Y-Z, Jin X-D, Guan L-X et al (2015) Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats. Mol Neurobiol 51:1480–1488. https://doi.org/10.1007/s12035-014-8825-3
Han Z, Li L, Wang L et al (2014) Alpha-7 nicotinic acetylcholine receptor agonist treatment reduces neuroinflammation, oxidative stress and brain injury in mice with ischemic stroke and bone fracture. J Neurochem 131:498–508. https://doi.org/10.1111/jnc.12817
He Y, Gao Y, Zhang Q et al (2020) IL-4 switches microglia/macrophage M1/M2 polarization and alleviates neurological damage by modulating the JAK1/STAT6 pathway following ICH. Neuroscience 437:161–171. https://doi.org/10.1016/j.neuroscience.2020.03.008
Hedström A, Hillert J, Olsson T, Alfredsson L (2013) Nicotine might have a protective effect in the etiology of multiple sclerosis. Mult Scler J 19:1009–1013. https://doi.org/10.1177/1352458512471879
Hellwig S, Brioschi S, Dieni S et al (2016) Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient mice. Brain Behav Immun 55:126–137. https://doi.org/10.1016/j.bbi.2015.11.008
Hijioka M, Matsushita H, Hisatsune A et al (2011) Therapeutic effect of nicotine in a mouse model of intracerebral hemorrhage. J Pharmacol Exp Ther 338:741–749. https://doi.org/10.1124/jpet.111.182519
Hillmer AT, Holden D, Fowles K et al (2017) Microglial depletion and activation: A [11C]PBR28 PET study in nonhuman primates. EJNMMI Res. https://doi.org/10.1186/s13550-017-0305-0
Hillmer AT, Matuskey D, Huang H et al (2020) Tobacco smoking in people is not associated with altered 18 kDa-translocator protein levels: a positron emission tomography study. J Nucl Med. https://doi.org/10.2967/jnumed.119.237735
Hughes AN, Appel B (2020) Microglia phagocytose myelin sheaths to modify developmental myelination. Nat Neurosci. https://doi.org/10.1038/s41593-020-0654-2
Jia J, Peng J, Li Z et al (2016) Cannabinoid CB2 receptor mediates nicotine-induced anti-inflammation in N9 microglial cells exposed to β amyloid via protein kinase C. Mediators Inflamm 2016:4854378. https://doi.org/10.1155/2016/4854378
Kabbani N, Nichols RA (2018) Beyond the channel: metabotropic signaling by nicotinic receptors. Trends Pharmacol Sci 39:354–366. https://doi.org/10.1016/j.tips.2018.01.002
Kigerl KA, de Rivero Vaccari JP, Dietrich WD et al (2014) Pattern recognition receptors and central nervous system repair. Exp Neurol 258:5–16. https://doi.org/10.1016/j.expneurol.2014.01.001
King JR, Gillevet TC, Kabbani N (2017) A G protein-coupled α7 nicotinic receptor regulates signaling and TNF-α release in microglia. FEBS Open Bio 7:1350–1361. https://doi.org/10.1002/2211-5463.12270
Kirkley KS, Popichak KA, Afzali MF et al (2017) Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity. J Neuroinflammation 14:99. https://doi.org/10.1186/s12974-017-0871-0
Kobayashi K, Imagama S, Ohgomori T et al (2013) Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4:e525–e525. https://doi.org/10.1038/cddis.2013.54
Kohno M, Link J, Dennis LE et al (2019) Neuroinflammation in addiction: a review of neuroimaging studies and potential immunotherapies. Pharmacol Biochem Behav 179:34–42. https://doi.org/10.1016/j.pbb.2019.01.007
Koob GF (2021) Drug addiction: hyperkatifeia/negative reinforcement as a framework for medications development. Pharmacol Rev 73:163–201. https://doi.org/10.1124/pharmrev.120.000083
Kumar M, Adeluyi A, Anderson EL, Turner JR (2020) Glial cells as therapeutic targets for smoking cessation. Neuropharmacology 175:108157. https://doi.org/10.1016/j.neuropharm.2020.108157
Lakhan SE, Kirchgessner A (2011) Anti-inflammatory effects of nicotine in obesity and ulcerative colitis. J Transl Med 9:129. https://doi.org/10.1186/1479-5876-9-129
Law KL, Stroud LR, LaGasse LL et al (2003) Smoking during pregnancy and newborn neurobehavior. Pediatrics 111:1318–1323. https://doi.org/10.1542/peds.111.6.1318
Le Foll B, Piper ME, Fowler CD et al (2022) Tobacco and nicotine use. Nat Rev Dis Primer 8:1–16. https://doi.org/10.1038/s41572-022-00346-w
Lee D, Jo H, Go C et al (2022) The roles of IL-22 and its receptor in the regulation of inflammatory responses in the brain. Int J Mol Sci 23:757. https://doi.org/10.3390/ijms23020757
Li C, Sun H, Arrick DM, Mayhan WG (2016) Chronic nicotine exposure exacerbates transient focal cerebral ischemia-induced brain injury. J Appl Physiol 120:328–333. https://doi.org/10.1152/japplphysiol.00663.2015
Li X, Han X, Bao J et al (2016) Nicotine increases eclampsia-like seizure threshold and attenuates microglial activity in rat hippocampus through the α7 nicotinic acetylcholine receptor. Brain Res 1642:487–496. https://doi.org/10.1016/j.brainres.2016.04.043
Li S, Fang Y, Zhang Y et al (2022) Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice. Cell Rep 41:111532. https://doi.org/10.1016/j.celrep.2022.111532
Lim TK, Ruthazer ES (2021) Microglial trogocytosis and the complement system regulate axonal pruning in vivo. eLife 10:e62167. https://doi.org/10.7554/eLife.62167
Liska SR (2013) In utero exposure to black bull chewing tobacco and neonatal nicotine withdrawal: a review of the literature. Neonatal Netw 33:5–10. https://doi.org/10.1891/0730-0832.33.1.5
Liu F, Tao X, Pang G et al (2020) Maternal nicotine exposure during gestation and lactation period affects behavior and hippocampal neurogenesis in mouse offspring. Front Pharmacol 10:1569. https://doi.org/10.3389/fphar.2019.01569
Liu Y, Dai Y, Li Q et al (2020) Beta-amyloid activates NLRP3 inflammasome via TLR4 in mouse microglia. Neurosci Lett 736:135279. https://doi.org/10.1016/j.neulet.2020.135279
Livingston JA, Chen C-H, Kwon M, Park E (2022) Physical and mental health outcomes associated with adolescent E-cigarette use. J Pediatr Nurs 64:1–17. https://doi.org/10.1016/j.pedn.2022.01.006
Martin EM, Clapp PW, Rebuli ME et al (2016) E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke. Am J Physiol Lung Cell Mol Physiol 311:L135–L144. https://doi.org/10.1152/ajplung.00170.2016
Mineur YS, Garcia-Rivas V, Thomas MA et al (2022) Sex differences in stress-induced alcohol intake: a review of preclinical studies focused on amygdala and inflammatory pathways. Psychopharmacology 239:2041–2061. https://doi.org/10.1007/s00213-022-06120-w
Moon JH, Kim SY, Lee HG et al (2008) Activation of nicotinic acetylcholine receptor prevents the production of reactive oxygen species in fibrillar β amyloid peptide (1–42)-stimulated microglia. Exp Mol Med 40:11–18. https://doi.org/10.3858/emm.2008.40.1.11
Morioka N, Tokuhara M, Nakamura Y et al (2014) Primary cultures of rat cortical microglia treated with nicotine increases in the expression of excitatory amino acid transporter 1 (GLAST) via the activation of the α7 nicotinic acetylcholine receptor. Neuroscience 258:374–384. https://doi.org/10.1016/j.neuroscience.2013.11.044
Münzel T, Hahad O, Kuntic M et al (2020) Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes. Eur Heart J 41:4057–4070. https://doi.org/10.1093/eurheartj/ehaa460
Namujju PB, Pajunen E, Simen-Kapeu A et al (2014) Impact of smoking on the quantity and quality of antibodies induced by human papillomavirus type 16 and 18 AS04-adjuvanted virus-like-particle vaccine—a pilot study. BMC Res Notes 7:445. https://doi.org/10.1186/1756-0500-7-445
Nguyen HM-H, Torres JA, Agrawal S, Agrawal A (2020) Nicotine impairs the response of lung epithelial cells to IL-22. Mediators Inflamm 2020:6705428. https://doi.org/10.1155/2020/6705428
Nguyen PT, Dorman LC, Pan S et al (2020) Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell. https://doi.org/10.1016/j.cell.2020.05.050
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. https://doi.org/10.1126/science.1110647
Noda M, Kobayashi A (2017) Nicotine inhibits activation of microglial proton currents via interactions with α7 acetylcholine receptors. J Physiol Sci 67:235–245. https://doi.org/10.1007/s12576-016-0460-5
Notter T, Coughlin JM, Sawa A, Meyer U (2018) Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry. Mol Psychiatry 23:36–47. https://doi.org/10.1038/mp.2017.232
Ohnishi M, Machida A, Deguchi M et al (2023) Long-term stimulation of α7 nicotinic acetylcholine receptor rescues hemorrhagic neuron loss via apoptosis of M1 microglia. J Neuroimmune Pharmacol. https://doi.org/10.1007/s11481-023-10065-y
Okutani H, Yamanaka H, Kobayashi K et al (2018) Recombinant interleukin-4 alleviates mechanical allodynia via injury-induced interleukin-4 receptor alpha in spinal microglia in a rat model of neuropathic pain. Glia 66:1775–1787. https://doi.org/10.1002/glia.23340
Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665. https://doi.org/10.1111/bph.13139
Panlilio LV, Justinova Z, Mascia P et al (2012) Novel use of a lipid-lowering fibrate medication to prevent nicotine reward and relapse: preclinical findings. Neuropsychopharmacology 37:1838–1847. https://doi.org/10.1038/npp.2012.31
Paolicelli RC, Sierra A, Stevens B et al (2022) Microglia states and nomenclature: a field at its crossroads. Neuron 110:3458–3483. https://doi.org/10.1016/j.neuron.2022.10.020
Peixoto TC, Moura EG, Oliveira E et al (2019) Hypothalamic neuropeptides expression and hypothalamic inflammation in adult rats that were exposed to tobacco smoke during breastfeeding: sex-related differences. Neuroscience 418:69–81. https://doi.org/10.1016/j.neuroscience.2019.08.006
Picciotto MR, Caldarone BJ, King SL, Zachariou V (2000) Nicotinic receptors in the brain: links between molecular biology and behavior. Neuropsychopharmacology 22:451–465. https://doi.org/10.1016/S0893-133X(99)00146-3
Pichini S, Garcia-Algar O (2006) In utero exposure to smoking and newborn neurobehavior: how to assess neonatal withdrawal syndrome? Ther Drug Monit 28:288. https://doi.org/10.1097/01.ftd.0000211809.81816.1b
Piovesana R, Salazar Intriago MS, Dini L, Tata AM (2021) Cholinergic modulation of neuroinflammation: focus on α7 nicotinic receptor. Int J Mol Sci 22:4912. https://doi.org/10.3390/ijms22094912
Quero L, Tiaden AN, Hanser E et al (2020) miR-221-3p drives the shift of M2-macrophages to a pro-inflammatory function by suppressing JAK3/STAT3 activation. Front Immunol 10:3087. https://doi.org/10.3389/fimmu.2019.03087
Rakhecha B, Agnihotri P, Dakal TC et al (2022) Anti-inflammatory activity of nicotine isolated from Brassica oleracea in rheumatoid arthritis. Biosci Rep 42:BSR20211392. https://doi.org/10.1042/BSR20211392
Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19:987–991. https://doi.org/10.1038/nn.4338
Ray LA, Roche DJO, Heinzerling K, Shoptaw S (2014) Chapter twelve—opportunities for the development of neuroimmune therapies in addiction. In: Cui C, Shurtleff D, Harris RA (eds) International review of neurobiology. Academic Press, Cambridge, pp 381–401
Reale M, Di Bari M, Di Nicola M et al (2015) Nicotinic receptor activation negatively modulates pro-inflammatory cytokine production in multiple sclerosis patients. Int Immunopharmacol 29:152–157. https://doi.org/10.1016/j.intimp.2015.06.034
Reitsma MB, Kendrick PJ, Ababneh E et al (2021) Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990–2019: a systematic analysis from the global burden of disease study 2019. Lancet 397:2337–2360. https://doi.org/10.1016/S0140-6736(21)01169-7
Rigotti NA, Kruse GR, Livingstone-Banks J, Hartmann-Boyce J (2022) Treatment of tobacco smoking: a review. JAMA 327:566–577. https://doi.org/10.1001/jama.2022.0395
Rock RB, Gekker G, Aravalli RN et al (2008) Potentiation of HIV-1 expression in microglial cells by nicotine: involvement of transforming growth factor-β1. J Neuroimmune Pharmacol 3:143–149. https://doi.org/10.1007/s11481-007-9098-7
Ruan S, Xie J, Wang L et al (2023) Nicotine alleviates MPTP-induced nigrostriatal damage through modulation of JNK and ERK signaling pathways in the mice model of Parkinson’s disease. Front Pharmacol 14:1088957. https://doi.org/10.3389/fphar.2023.1088957
Saravia R, Ten-Blanco M, Grande MT et al (2019) Anti-inflammatory agents for smoking cessation? focus on cognitive deficits associated with nicotine withdrawal in male mice. Brain Behav Immun 75:228–239. https://doi.org/10.1016/j.bbi.2018.11.003
Shytle RD, Mori T, Townsend K et al (2004) Cholinergic modulation of microglial activation by α7 nicotinic receptors. J Neurochem 89:337–343. https://doi.org/10.1046/j.1471-4159.2004.02347.x
Singh K, Singh S, Singhal NK et al (2010) Nicotine- and caffeine-mediated changes in gene expression patterns of MPTP-lesioned mouse striatum: Implications in neuroprotection mechanism. Chem Biol Interact 185:81–93. https://doi.org/10.1016/j.cbi.2010.03.015
Sinkus ML, Graw S, Freedman R et al (2015) The human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation, and function. Neuropharmacology 96:274–288. https://doi.org/10.1016/j.neuropharm.2015.02.006
Sofuoglu M, Waters AJ, Mooney M, O’Malley SS (2009) Minocycline reduced craving for cigarettes but did not affect smoking or intravenous nicotine responses in humans. Pharmacol Biochem Behav 92:135–140. https://doi.org/10.1016/j.pbb.2008.11.004
Sofuoglu M, Mooney M, Kosten T et al (2011) Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans. Psychopharmacology 213:61–68. https://doi.org/10.1007/s00213-010-2014-5
Sood AK, Kesic MJ, Hernandez ML (2018) Electronic cigarettes: one size does not fit all. J Allergy Clin Immunol 141:1973–1982. https://doi.org/10.1016/j.jaci.2018.02.029
Sørensen LT, Toft B, Rygaard J et al (2010) Smoking attenuates wound inflammation and proliferation while smoking cessation restores inflammation but not proliferation. Wound Repair Regen 18:186–192. https://doi.org/10.1111/j.1524-475X.2010.00569.x
Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33:256–266
Stopponi S, Somaini L, Cippitelli A et al (2011) Activation of nuclear PPARγ receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. Biol Psychiatry 69:642–649. https://doi.org/10.1016/j.biopsych.2010.12.010
Suzuki T, Hide I, Matsubara A et al (2006) Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J Neurosci Res 83:1461–1470. https://doi.org/10.1002/jnr.20850
Takata K, Kimura H, Yanagisawa D et al (2022) Nicotinic acetylcholine receptors and microglia as therapeutic and imaging targets in Alzheimer’s disease. Molecules 27:2780. https://doi.org/10.3390/molecules27092780
Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53:1181–1194. https://doi.org/10.1007/s12035-014-9070-5
Tsai S-J (2021) Role of interleukin 8 in depression and other psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 106:110173. https://doi.org/10.1016/j.pnpbp.2020.110173
Vagnarelli F, Amarri S, Scaravelli G et al (2006) TDM grand rounds: neonatal nicotine withdrawal syndrome in an infant prenatally and postnatally exposed to heavy cigarette smoke. Ther Drug Monit 28:585. https://doi.org/10.1097/01.ftd.0000245391.56176.ad
Valdez-Miramontes CE, Trejo Martínez LA, Torres-Juárez F et al (2020) Nicotine modulates molecules of the innate immune response in epithelial cells and macrophages during infection with M. tuberculosis. Clin Exp Immunol 199:230–243. https://doi.org/10.1111/cei.13388
van Zyl-Smit RN, Binder A, Meldau R et al (2014) Cigarette smoke impairs cytokine responses and BCG containment in alveolar macrophages. Thorax 69:363–370. https://doi.org/10.1136/thoraxjnl-2013-204229
Wang H, Yu M, Ochani M et al (2003) Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421:384–388. https://doi.org/10.1038/nature01339
Wang H, Chen Y, Liu X et al (2022) TNF-α derived from arsenite-induced microglia activation mediated neuronal necroptosis. Ecotoxicol Environ Saf 236:113468. https://doi.org/10.1016/j.ecoenv.2022.113468
Wang Q, Gou J, Guo S et al (2022) Nicotine activating α4β2 nicotinic acetylcholine receptors to suppress neuroinflammation via JAK2-STAT3 signaling pathway in ischemic rats and inflammatory cells. Mol Neurobiol 59:3280–3293. https://doi.org/10.1007/s12035-022-02797-4
Wongtrakool C, Grooms K, Ping X-D et al (2012) In utero nicotine exposure promotes M2 activation in neonatal mice alveolar macrophages. Pediatr Res 72:147–153. https://doi.org/10.1038/pr.2012.55
Woodburn SC, Bollinger JL, Wohleb ES (2021) The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation 18:258. https://doi.org/10.1186/s12974-021-02309-6
Woodburn SC, Bollinger JL, Wohleb ES (2021) Synaptic and behavioral effects of chronic stress are linked to dynamic and sex-specific changes in microglia function and astrocyte dystrophy. Neurobiol Stress 14:100312. https://doi.org/10.1016/j.ynstr.2021.100312
Wu S-Y, Xing F, Sharma S et al (2020) Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function. J Exp Med 217:e20191131. https://doi.org/10.1084/jem.20191131
Xu E, Liu J, Liu H et al (2018) Inflammasome activation by methamphetamine potentiates lipopolysaccharide stimulation of IL-1β production in microglia. J Neuroimmune Pharmacol off J Soc NeuroImmune Pharmacol 13:237–253. https://doi.org/10.1007/s11481-018-9780-y
Yang S, Tian G, Cui Y et al (2016) Factors influencing immunologic response to hepatitis B vaccine in adults. Sci Rep 6:27251. https://doi.org/10.1038/srep27251
Yao G, Bai Z, Niu J et al (2022) Astragalin attenuates depression-like behaviors and memory deficits and promotes M2 microglia polarization by regulating IL-4R/JAK1/STAT6 signaling pathway in a murine model of perimenopausal depression. Psychopharmacology 239:2421–2443. https://doi.org/10.1007/s00213-022-06133-5
Younes-Rapozo V, Moura EG, Manhães AC et al (2015) Neonatal nicotine exposure leads to hypothalamic gliosis in adult overweight Rats. J Neuroendocrinol 27:887–898. https://doi.org/10.1111/jne.12328
Zhang Q, Lu Y, Bian H et al (2017) Activation of the α7 nicotinic receptor promotes lipopolysaccharide-induced conversion of M1 microglia to M2. Am J Transl Res 9:971–985
Zhang C-J, Jiang M, Zhou H et al (2018) TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation. J Clin Invest 128:5399–5412. https://doi.org/10.1172/JCI121901
Zhang J, Jiang H, Wu F et al (2021) Neuroprotective effects of hesperetin in regulating microglia polarization after ischemic stroke by inhibiting TLR4/NF-κB pathway. J Healthc Eng 2021:9938874. https://doi.org/10.1155/2021/9938874
Zhao J, Bi W, Xiao S et al (2019) Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep 9:5790. https://doi.org/10.1038/s41598-019-42286-8
Zhou Y, Zuo X, Li Y et al (2012) Nicotine inhibits tumor necrosis factor-α induced IL-6 and IL-8 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Rheumatol Int 32:97–104. https://doi.org/10.1007/s00296-010-1549-4
Zhou D, Ji L, Chen Y (2020) TSPO Modulates IL-4-Induced Microglia/Macrophage M2 Polarization via PPAR-γ Pathway. J Mol Neurosci 70:542–549. https://doi.org/10.1007/s12031-019-01454-1
Zhou L, Tao X, Pang G et al (2021) Maternal nicotine exposure alters hippocampal microglia polarization and promotes anti-inflammatory signaling in juvenile offspring in mice. Front Pharmacol 12:661304. https://doi.org/10.3389/fphar.2021.661304
Acknowledgements
This work was supported by National Institutes of Health grants AA027989, DA14241 and DA036151. This work was funded in part by the State of Connecticut, Department of Mental Health and Addiction Services, but this publication does not express the views of the Department of Mental Health and Addiction Services or the State of Connecticut. The views and opinions expressed are those of the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Soares, A.R., Picciotto, M.R. Nicotinic regulation of microglia: potential contributions to addiction. J Neural Transm 131, 425–435 (2024). https://doi.org/10.1007/s00702-023-02703-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-023-02703-9