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Targeting neuroinflammation with minocycline in heavy drinkers

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Abstract

Rationale

Alcohol has both acute and chronic effects on neuroimmune signaling, including triggering pro-inflammatory cytokine release by microglia. Minocycline, a second-generation tetracycline antibiotic, inhibits microglial activation and reduces neuroinflammation in preclinical studies. In mice, minocycline also reduces ethanol intake, attenuates ethanol-induced conditioned place preference, and inhibits ethanol-induced microglial activation and pro-inflammatory cytokine release.

Objective

Here, for the first time, we tested the effects of minocycline on subjective response to ethanol and acute ethanol-induced inflammation in humans.

Methods

Forty-eight heavy drinkers participated in a double-blind, placebo-controlled trial in which they were randomized to receive placebo, 100 mg, or 200 mg of minocycline for 10 days. Each subject then underwent two experimental sessions in which they were given a fixed dose of intravenous ethanol using a “clamp” procedure (100 mg%) or placebo (normal saline) on days 8 and 10 of treatment.

Results

Minocycline was well tolerated, but there was no effect of either dose of minocycline on subjective response to ethanol or ethanol-induced craving; minocycline effects on cognitive function seem to interact with age. Minocycline treatment did not alter serum cytokine levels at baseline or during ethanol-exposure, although certain baseline cytokine levels predict sedative response to ethanol.

Conclusion

These findings indicate that a short-term treatment with minocycline may not alter ethanol-related inflammation or subjective response to ethanol in humans. Further research is needed to identify pharmacological agents with robust effects on ethanol-induced inflammation to determine whether neuroimmune modulation represents a viable treatment strategy for alcohol use disorder.

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References

  • Agrawal RG, Hewetson A, George CM, Syapin PJ, Bergeson SE (2011) Minocycline reduces ethanol drinking. Brain Behav Immun 25(Suppl 1):S165–S169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arout CA, Waters AJ, MacLean RR, Compton P, Sofuoglu M (2018) Minocycline does not affect experimental pain or addiction-related outcomes in opioid maintained patients. Psychopharmacology 1–10

  • Arout CA, Waters AJ, MacLean RR, Compton P, Sofuoglu M (in review) Minocycline does not affect experimental pain or addiction-related outcomes in opioid maintained patients

  • Bates ME, Buckman JF, Nguyen TT (2013) A role for cognitive rehabilitation in increasing the effectiveness of treatment for alcohol use disorders. Neuropsychol Rev 23:27–47

    Article  PubMed  PubMed Central  Google Scholar 

  • Bouchery EE, Harwood HJ, Sacks JJ, Simon CJ, Brewer RD (2011) Economic costs of excessive alcohol consumption in the U.S., 2006. Am J Prev Med 41:516–524

    Article  PubMed  Google Scholar 

  • Brandt J (1991) The Hopkins verbal learning test: development of a new memory test with six equivalent forms. Clin Neuropsychol 5:125–142

    Article  Google Scholar 

  • Coleman LG Jr, Crews FT (2018) Innate immune signaling and alcohol use disorders. Handb Exp Pharmacol

  • Coleman LG Jr, Zou J, Crews FT (2017) Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J Neuroinflammation 14:22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Coller JK, Hutchinson MR (2012) Implications of central immune signaling caused by drugs of abuse: mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence. Pharmacol Ther 134:219–245

    Article  CAS  PubMed  Google Scholar 

  • Crews FT, Zou J, Qin L (2011) Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun 25(Suppl 1):S4–S12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crews FT, Lawrimore CJ, Walter TJ, Coleman LG Jr (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dean OM, Data-Franco J, Giorlando F, Berk M (2012) Minocycline: therapeutic potential in psychiatry. CNS Drugs 26:391–401

    Article  CAS  PubMed  Google Scholar 

  • DellaGioia N, Devine L, Pittman B, Hannestad J (2013) Bupropion pre-treatment of endotoxin-induced depressive symptoms. Brain Behav Immun 31:197–204

    Article  CAS  PubMed  Google Scholar 

  • Dickerson D, Pittman B, Ralevski E, Perrino A, Limoncelli D, Edgecombe J, Acampora G, Krystal JH, Petrakis I (2010) Ethanol-like effects of thiopental and ketamine in healthy humans. J Psychopharmacol 24:203–211

    Article  CAS  PubMed  Google Scholar 

  • First MB, Williams JBW, Karg RS, Spitzer RL (2015) StructuredClinical interview for DSM-5: clinician version. AmericanPsychiatric Association, Arlington

    Google Scholar 

  • Galandra C, Basso G, Cappa S, Canessa N (2018) The alcoholic brain: neural bases of impaired reward-based decision-making in alcohol use disorders. Neurol Sci 39:423–435

    Article  PubMed  Google Scholar 

  • Gowin JL, Sloan ME, Stangl BL, Vatsalya V, Ramchandani VA (2017) Vulnerability for alcohol use disorder and rate of alcohol consumption. Am J Psychiatry

  • Grant BF, Chou SP, Saha TD, Pickering RP, Kerridge BT, Ruan WJ, Huang B, Jung J, Zhang H, Fan A, Hasin DS (2017) Prevalence of 12-month alcohol use, high-risk drinking, and DSM-IV alcohol use disorder in the United States, 2001–2002 to 2012–2013: results from the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry

  • Hillmer AT, Sandiego CM, Hannestad J, Angarita GA, Kumar A, McGovern EM, Huang Y, O'Connor KC, Carson RE, O'Malley SS, Cosgrove KP (2017) In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence. Mol Psychiatry 22:1759–1766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalk NJ, Guo Q, Owen D, Cherian R, Erritzoe D, Gilmour A, Ribeiro AS, McGonigle J, Waldman A, Matthews P, Cavanagh J, McInnes I, Dar K, Gunn R, Rabiner EA, Lingford-Hughes AR (2017) Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [(11)C]PBR28 PET study. Transl Psychiatry 7:e996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato TA, Watabe M, Tsuboi S, Ishikawa K, Hashiya K, Monji A, Utsumi H, Kanba S (2012) Minocycline modulates human social decision-making: possible impact of microglia on personality-oriented social behaviors. PLoS One 7:e40461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelley KW, Dantzer R (2011) Alcoholism and inflammation: neuroimmunology of behavioral and mood disorders. Brain Behav Immun 25(Suppl 1):S13–S20

    Article  CAS  PubMed  Google Scholar 

  • Kerfoot K, Pittman B, Ralevski E, Limoncelli D, Koretski J, Newcomb J, Arias AJ, Petrakis IL (2013) Effects of family history of alcohol dependence on the subjective response to alcohol using the intravenous alcohol clamp. Alcohol Clin Exp Res 37:2011–2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SW, Wiers CE, Tyler R, Shokri-Kojori E, Jang YJ, Zehra A, Freeman C, Ramirez V, Lindgren E, Miller G, Cabrera EA, Stodden T, Guo M, Demiral SB, Diazgranados N, Park L, Liow JS, Pike V, Morse C, Vendruscolo LF, Innis RB, Koob GF, Tomasi D, Wang GJ, Volkow ND (2018) Influence of alcoholism and cholesterol on TSPO binding in brain: PET [(11)C]PBR28 studies in humans and rodents. Neuropsychopharmacology 43:1832–1839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lippai D, Bala S, Petrasek J, Csak T, Levin I, Kurt-Jones EA, Szabo G (2013) Alcohol-induced IL-1beta in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation. J Leukoc Biol 94:171–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McIver SR, Muccigrosso MM, Haydon PG (2012) The effect of doxycycline on alcohol consumption and sensitivity: consideration for inducible transgenic mouse models. Exp Biol Med (Maywood) 237:1129–1133

    Article  CAS  Google Scholar 

  • McKee SA, Weinberger AH, Shi J, Tetrault J, Coppola S (2012) Developing and validating a human laboratory model to screen medications for smoking cessation. Nicotine Tob Res 14:1362–1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morean ME, Corbin WR (2010) Subjective response to alcohol: a critical review of the literature. Alcohol Clin Exp Res 34:385–395

    Article  PubMed  Google Scholar 

  • NIAAA NACoAAaA (2004) NIAAA council approves definition of binge drinking. NIAAA Newsletter, Bethesda

    Google Scholar 

  • O'Connor S, Morzorati S, Christian J, Li TK (1998) Clamping breath alcohol concentration reduces experimental variance: application to the study of acute tolerance to alcohol and alcohol elimination rate. Alcoholism Clin Exp Res 22:202–210

    Article  CAS  Google Scholar 

  • O'Malley S, Krishnan-Sarin S, Farren C, Sinha R, Kreek M (2002) Naltrexone decreases craving and alcohol self administration in alcohol dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology 160:19–29

    Article  CAS  PubMed  Google Scholar 

  • Petrakis IL, Limoncelli D, Gueorguieva R, Jatlow P, Boutros NN, Trevisan L, Gelernter J, Krystal JH (2004) Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry 161:1776–1782

    Article  PubMed  Google Scholar 

  • Petrakis I, Pittman B, Limoncelli D, Koretski J, Newcomb J, Ralevski E, Trevisan L, Krystal J (2010) Subjective response to iv ethanol using the clamp in young healthy adults both with and without family history of alcoholism. Alcoholism 34:137a

    Google Scholar 

  • Ralevski E, Horvath TL, Shanabrough M, Hayden R, Newcomb J, Petrakis I (2017) Ghrelin is suppressed by intravenous alcohol and is related to stimulant and sedative effects of alcohol. Alcohol Alcohol 52:431–438

    Article  CAS  PubMed  Google Scholar 

  • Ray LA, Hutchison KE (2004) A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol Clin Exp Res 28:1789–1795

    Article  CAS  PubMed  Google Scholar 

  • Ray LA, Chin PF, Heydari A, Miotto K (2011) A human laboratory study of the effects of quetiapine on subjective intoxication and alcohol craving. Psychopharmacology 217:341–351

    Article  CAS  PubMed  Google Scholar 

  • Ray JM, Pyne JM, Gevirtz RN (2017) Alcohol use disorder moderates the effect of age on heart rate variability in veterans with posttraumatic stress disorder. J Nerv Ment Dis 205:793–800

    Article  PubMed  Google Scholar 

  • Rojewski AM, Morean ME, Toll BA, McKee SA, Krishnan-Sarin S, Green BG, Bartoshuk LM, O'Malley SS (2015) The Yale craving scale: development and psychometric properties. Drug Alcohol Depend 154:158–166

    Article  PubMed  PubMed Central  Google Scholar 

  • Rubio-Araiz A, Porcu F, Perez-Hernandez M, Garcia-Gutierrez MS, Aracil-Fernandez MA, Gutierrez-Lopez MD, Guerri C, Manzanares J, O'Shea E, Colado MI (2017) Disruption of blood-brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model. Addict Biol 22:1103–1116

    Article  CAS  PubMed  Google Scholar 

  • Ruff RM, Parker SB (1993) Gender- and age-specific changes in motor speed and eye-hand coordination in adults: normative values for the finger tapping and grooved pegboard tests. Percept Mot Skills 76:1219–1230

    Article  CAS  Google Scholar 

  • Sobell LC, Sobell MB, Leo GI, Cancilla A (1988) Reliability of a timeline method: assessing normal drinkers' reports of recent drinking and a comparative evaluation across several populations. Br J Addict 83:393–402

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, Waters AJ, Mooney M, Kosten T (2008) Riluzole and D-amphetamine interactions in humans. Prog Neuro-Psychopharmacol Biol Psychiatry 32:16–22

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, Mooney M, Kosten T, Waters A, Hashimoto K (2011) Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans. Psychopharmacology 213:61–68

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, DeVito EE, Waters AJ, Carroll KM (2013) Cognitive enhancement as a treatment for drug addictions. Neuropharmacology 64:452–463

    Article  CAS  PubMed  Google Scholar 

  • Subramanian M, Heil S, Kruger M, Collins K, Buck P, Zawacki T, Abbey A, Sokol R, Diamond M (2002) A three-stage alcohol clamp procedure in human subjects. Alcohol Clin Exp Res 26:1479–1483

    Article  CAS  PubMed  Google Scholar 

  • Watabe M, Kato TA, Monji A, Horikawa H, Kanba S (2012) Does minocycline, an antibiotic with inhibitory effects on microglial activation, sharpen a sense of trust in social interaction? Psychopharmacology 220:551–557

    Article  CAS  PubMed  Google Scholar 

  • Wesnes K, Warburton DM, Matz B (1983) Effects of nicotine on stimulus sensitivity and response bias in a visual vigilance task. Neuropsychobiology 9:41–44

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, Lousberg EL, Moldenhauer LM, Hayball JD, Robertson SA, Coller JK, Watkins LR, Somogyi AA, Hutchinson MR (2011) Attenuation of microglial and IL-1 signaling protects mice from acute alcohol-induced sedation and/or motor impairment. Brain Behav Immun 25(Suppl 1):S155–S164

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Zheng H, Wu R, Zhu F, Kosten TR, Zhang XY, Zhao J (2018) Minocycline adjunctive treatment to risperidone for negative symptoms in schizophrenia: association with pro-inflammatory cytokine levels. Prog Neuro-Psychopharmacol Biol Psychiatry 85:69–76

    Article  CAS  Google Scholar 

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Acknowledgments

Support was provided by NIAAA R21 AA023150 (PI Petrakis) and the VISN I Mental Illness Research Education and Clinical Center (MIRECC). We wished to thank the contributions of the Biostudies staff (Jane Weiner RN; Elizabeth O’Donnell RN; Angelina Genovese RNC, BSN, MBA; Margaret Dion-Marovitz MS, RN; Karen E. Prema RN, BSN).

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Authors and Affiliations

  1. Department of Psychiatry, VA Connecticut Healthcare System, 950 Campbell Avenue, Mail code 116-A, West Haven, CT, 06516, USA

    Ismene L. Petrakis, Elizabeth Ralevski, Matthew E. Sloan, Gihyun Yoon & Mehmet Sofuoglu

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Ismene L. Petrakis, Elizabeth Ralevski, Matthew E. Sloan, Gihyun Yoon & Mehmet Sofuoglu

  3. Department of Biostatistics, School of Public Health, Yale University School of Medicine, New Haven, CT, USA

    Ralitza Gueorguieva & Lesley Devine

  4. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA

    Ralitza Gueorguieva & Lesley Devine

  5. Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Albert J. Arias

Authors
  1. Ismene L. Petrakis
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  2. Elizabeth Ralevski
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  4. Matthew E. Sloan
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  5. Lesley Devine
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  6. Gihyun Yoon
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  7. Albert J. Arias
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  8. Mehmet Sofuoglu
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Corresponding author

Correspondence to Ismene L. Petrakis.

Ethics declarations

Institutional review boards of the VA Connecticut Healthcare System and Yale University School of Medicine approved this study. The trial was also registered (ClinicalTrials.gov Identifier: NCT02187211).

Conflict of interest

Dr. Ismene L. Petrakis has served as a consultant for Alkermes over the past 3 years. Drs Elizabeth Ralevski, Ralitza Gueorguieva, Matthew E. Sloan, Lesley Devine, PhD, Gihyun Yoon, Albert J. Arias, and Mehmet Sofuoglu have no conflict of interest.

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This article belongs to a Special Issue on Neuroimmune Signaling in Psychiatric Disease.

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Petrakis, I.L., Ralevski, E., Gueorguieva, R. et al. Targeting neuroinflammation with minocycline in heavy drinkers. Psychopharmacology 236, 3013–3021 (2019). https://doi.org/10.1007/s00213-019-05205-3

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  • DOI: https://doi.org/10.1007/s00213-019-05205-3

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