Skip to main content
SpringerLink
Log in

Behavioral and Biochemical Effects of N-Acetylcysteine in Zebrafish Acutely Exposed to Ethanol

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Alcohol hangover refers to unpleasant symptoms experienced as a direct consequence of a binge drinking episode. The effects observed in this condition are related to the increase in alcohol metabolites and imbalance in oxidative status. N-acetylcysteine (NAC) is a mucolytic agent and an antidote for paracetamol overdose. Preclinical and clinical studies have shown that NAC is a multi-target drug acting through neuroprotective, antioxidant and neurotrophic mechanisms as well as a glutamate modulator. The aim of this study was to investigate the effects of NAC in zebrafish acutely exposed to ethanol (EtOH). Animals pretreated or not with NAC (1 mg/L, 10 min) were exposed for 60 min to standard tank water (EtOH−) or to 1% EtOH (EtOH+) to evaluate anxiety-like behavior and locomotion in the novel tank test and oxidative damage in the brain. Zebrafish (Danio rerio) exposed to EtOH displayed a decrease in the distance traveled, crossings, entries and time spent in the top area in the novel tank test. Exposure to EtOH also caused oxidative damage, shown by increased lipid peroxidation, decreased non-protein thiols and increased production of reactive oxygen species (DCF assay). NAC prevented both the behavioral alterations and the oxidative stress observed in EtOH+ animals. Given the effects of NAC in preventing the acute behavioral and biochemical effects of EtOH, additional studies are warranted to further investigate the basis of its anecdotal use to prevent hangover.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Penning R, McKinney A, Verster JC (2012) Alcohol hangover symptoms and their contribution to the overall hangover severity. Alcohol Alcohol Oxf Oxfs 47:248–252. https://doi.org/10.1093/alcalc/ags029

    Article  Google Scholar 

  2. Kim D-J, Yoon S-J, Lee H-P et al (2003) The effects of alcohol hangover on cognitive functions in healthy subjects. Int J Neurosci 113:581–594

    Article  PubMed  Google Scholar 

  3. Prat G, Adan A, Pérez-Pàmies M, Sànchez-Turet M (2008) Neurocognitive effects of alcohol hangover. Addict Behav 33:15–23. https://doi.org/10.1016/j.addbeh.2007.05.002

    Article  PubMed  Google Scholar 

  4. van Schrojenstein Lantman M, Mackus M, van de Loo AJAE., Verster JC (2017) The impact of alcohol hangover symptoms on cognitive and physical functioning, and mood. Hum Psychopharmacol. https://doi.org/10.1002/hup.2623

    PubMed  PubMed Central  Google Scholar 

  5. Verster JC, van Duin D, Volkerts ER et al (2003) Alcohol hangover effects on memory functioning and vigilance performance after an evening of binge drinking. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 28:740–746. https://doi.org/10.1038/sj.npp.1300090

    Article  CAS  Google Scholar 

  6. Louvet A, Mathurin P (2015) Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol 12:231–242. https://doi.org/10.1038/nrgastro.2015.35

    Article  PubMed  Google Scholar 

  7. Cobb CA, Cole MP (2015) Oxidative and nitrative stress in neurodegeneration. Neurobiol Dis 84:4–21. https://doi.org/10.1016/j.nbd.2015.04.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ortiz GG, Pacheco Moisés FP, Mireles-Ramírez M et al (2017) Oxidative stress: love and hate history in central nervous system. Adv Protein Chem Struct Biol 108:1–31. https://doi.org/10.1016/bs.apcsb.2017.01.003

    Article  PubMed  Google Scholar 

  9. Karadayian AG, Malanga G, Czerniczyniec A et al (2017) Free radical production and antioxidant status in brain cortex non-synaptic mitochondria and synaptosomes at alcohol hangover onset. Free Radic Biol Med 108:692–703. https://doi.org/10.1016/j.freeradbiomed.2017.04.344

    Article  CAS  PubMed  Google Scholar 

  10. Swift R, Davidson D (1998) Alcohol hangover: mechanisms and mediators. Alcohol Health Res World 22:54–60

    CAS  PubMed  Google Scholar 

  11. Deepmala N, Slattery J, Kumar N et al (2015) Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev 55:294–321. https://doi.org/10.1016/j.neubiorev.2015.04.015

    Article  CAS  PubMed  Google Scholar 

  12. Minarini A, Ferrari S, Galletti M et al (2017) N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects. Expert Opin Drug Metab Toxicol 13:279–292. https://doi.org/10.1080/17425255.2017.1251580

    Article  CAS  PubMed  Google Scholar 

  13. Berk M, Dean OM, Cotton SM et al (2014) The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 75:628–636. https://doi.org/10.4088/JCP.13m08454

    Article  CAS  PubMed  Google Scholar 

  14. Dean O, Giorlando F, Berk M (2011) N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 36:78–86. https://doi.org/10.1503/jpn.100057

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mocelin R, Herrmann AP, Marcon M et al (2015) N-acetylcysteine prevents stress-induced anxiety behavior in zebrafish. Pharmacol Biochem Behav. https://doi.org/10.1016/j.pbb.2015.08.006

    PubMed  Google Scholar 

  16. Santos P, Herrmann AP, Benvenutti R et al (2017) Anxiolytic properties of N-acetylcysteine in mice. Behav Brain Res 317:461–469. https://doi.org/10.1016/j.bbr.2016.10.010

    Article  CAS  PubMed  Google Scholar 

  17. Schneider R, Santos CF, Clarimundo V et al (2015) N-acetylcysteine prevents behavioral and biochemical changes induced by alcohol cessation in rats. Alcohol 49:259–263. https://doi.org/10.1016/j.alcohol.2015.01.009

    Article  CAS  PubMed  Google Scholar 

  18. Schneider R, Bandiera S, Souza DG et al (2017) N-acetylcysteine prevents alcohol related neuroinflammation in rats. Neurochem Res. https://doi.org/10.1007/s11064-017-2218-8

    Google Scholar 

  19. Morais-Silva G, Alves GC, Marin MT (2016) N-acetylcysteine treatment blocks the development of ethanol-induced behavioural sensitization and related ∆FosB alterations. Neuropharmacology 110:135–142. https://doi.org/10.1016/j.neuropharm.2016.07.009

    Article  CAS  PubMed  Google Scholar 

  20. Ozkol H, Bulut G, Balahoroglu R et al (2017) Protective effects of selenium, N-acetylcysteine and vitamin E against acute ethanol intoxication in rats. Biol Trace Elem Res 175:177–185. https://doi.org/10.1007/s12011-016-0762-8

    Article  CAS  PubMed  Google Scholar 

  21. Litovitz TL (1984) The anecdotal antidotes. Emerg Med Clin N Am 2:145–158

    CAS  Google Scholar 

  22. Rosemberg DB, Braga MM, Rico EP et al (2012) Behavioral effects of taurine pretreatment in zebrafish acutely exposed to ethanol. Neuropharmacology 63:613–623. https://doi.org/10.1016/j.neuropharm.2012.05.009

    Article  CAS  PubMed  Google Scholar 

  23. Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431

    Article  CAS  PubMed  Google Scholar 

  24. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  CAS  PubMed  Google Scholar 

  25. Ali SF, LeBel CP, Bondy SC (1992) Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity. Neurotoxicology 13:637–648

    CAS  PubMed  Google Scholar 

  26. LeBel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231

    Article  CAS  PubMed  Google Scholar 

  27. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  28. Gerlai R (2003) Zebra fish: an uncharted behavior genetic model. Behav Genet 33:461–468

    Article  PubMed  Google Scholar 

  29. Gerlai R, Lahav M, Guo S, Rosenthal A (2000) Drinks like a fish: zebra fish (Danio rerio) as a behavior genetic model to study alcohol effects. Pharmacol Biochem Behav 67:773–782

    Article  CAS  PubMed  Google Scholar 

  30. Reimers MJ, Flockton AR, Tanguay RL (2004) Ethanol- and acetaldehyde-mediated developmental toxicity in zebrafish. Neurotoxicol Teratol 26:769–781. https://doi.org/10.1016/j.ntt.2004.06.012

    Article  CAS  PubMed  Google Scholar 

  31. Hernández JA, López-Sánchez RC, Rendón-Ramírez A (2016) Lipids and oxidative stress associated with ethanol-induced neurological damage. Oxid Med Cell Longev 2016:1543809. https://doi.org/10.1155/2016/1543809

    Article  PubMed  PubMed Central  Google Scholar 

  32. Giacomini ACVV., Abreu MS, Zanandrea R et al (2016) Environmental and pharmacological manipulations blunt the stress response of zebrafish in a similar manner. Sci Rep 6:28986. https://doi.org/10.1038/srep28986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tran S, Nowicki M, Fulcher N et al (2016) Interaction between handling induced stress and anxiolytic effects of ethanol in zebrafish: a behavioral and neurochemical analysis. Behav Brain Res 298:278–285. https://doi.org/10.1016/j.bbr.2015.10.061

    Article  CAS  PubMed  Google Scholar 

  34. Pizzimenti S, Ciamporcero E, Daga M et al (2013) Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol. https://doi.org/10.3389/fphys.2013.00242

    PubMed  PubMed Central  Google Scholar 

  35. Reed DJ (1990) Glutathione: toxicological implications. Annu Rev Pharmacol Toxicol 30:603–631. https://doi.org/10.1146/annurev.pa.30.040190.003131

    Article  CAS  PubMed  Google Scholar 

  36. Kowalczyk-Pachel D, Iciek M, Wydra K et al (2016) Cysteine metabolism and oxidative processes in the rat liver and kidney after acute and repeated cocaine treatment. PLoS ONE 11:e0147238. https://doi.org/10.1371/journal.pone.0147238

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu W, Kato M, Akhand AA et al (2000) 4-hydroxynonenal induces a cellular redox status-related activation of the caspase cascade for apoptotic cell death. J Cell Sci 113(Pt 4):635–641

    CAS  PubMed  Google Scholar 

  38. Raza H, John A (2006) 4-Hydroxynonenal induces mitochondrial oxidative stress, apoptosis and expression of glutathione S-transferase A4–4 and cytochrome P450 2E1 in PC12 cells. Toxicol Appl Pharmacol 216:309–318. https://doi.org/10.1016/j.taap.2006.06.001

    Article  CAS  PubMed  Google Scholar 

  39. Ponsoda X, Jover R, Gómez-Lechón MJ et al (1991) Intracellular glutathione in human hepatocytes incubated with S-adenosyl-L-methionine and GSH-depleting drugs. Toxicology 70:293–302

    Article  CAS  PubMed  Google Scholar 

  40. Vogt BL, Richie JP (2007) Glutathione depletion and recovery after acute ethanol administration in the aging mouse. Biochem Pharmacol 73:1613–1621. https://doi.org/10.1016/j.bcp.2007.01.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sprince H, Parker CM, Smith GG, Gonzales LJ (1974) Protection against acetaldehyde toxicity in the rat by L-cysteine, thiamin and L-2-methylthiazolidine-4-carboxylic acid. Agents Actions 4:125–130

    Article  CAS  PubMed  Google Scholar 

  42. Viña J, Estrela JM, Guerri C, Romero FJ (1980) Effect of ethanol on glutathione concentration in isolated hepatocytes. Biochem J 188:549–552

    Article  PubMed  PubMed Central  Google Scholar 

  43. Rosemberg DB, da Rocha RF, Rico EP et al (2010) Taurine prevents enhancement of acetylcholinesterase activity induced by acute ethanol exposure and decreases the level of markers of oxidative stress in zebrafish brain. Neuroscience 171:683–692. https://doi.org/10.1016/j.neuroscience.2010.09.030

    Article  CAS  PubMed  Google Scholar 

  44. Gass JT, Olive MF (2008) Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 75:218–265. https://doi.org/10.1016/j.bcp.2007.06.039

    Article  CAS  PubMed  Google Scholar 

  45. Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561–572. https://doi.org/10.1038/nrn2515

    Article  CAS  PubMed  Google Scholar 

  46. Stewart AM, Braubach O, Spitsbergen J et al (2014) Zebrafish models for translational neuroscience research: from tank to bedside. Trends Neurosci 37:264–278. https://doi.org/10.1016/j.tins.2014.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tsai GY, Cui JZ, Syed H et al (2009) Effect of N-acetylcysteine on the early expression of inflammatory markers in the retina and plasma of diabetic rats. Clin Exp Ophthalmol 37:223–231. https://doi.org/10.1111/j.1442-9071.2009.02000.x

    Article  PubMed  PubMed Central  Google Scholar 

  48. Faingold CL, N’Gouemo P, Riaz A (1998) Ethanol and neurotransmitter interactions—from molecular to integrative effects. Prog Neurobiol 55:509–535

    Article  CAS  PubMed  Google Scholar 

  49. Valenzuela CF (1997) Alcohol and neurotransmitter interactions. Alcohol Health Res World 21:144–148

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico - Brazil (CNPq, Proc. 401162/2016-8).

Author information

Authors and Affiliations

  1. Laboratório de Psicofarmacologia e Comportamento (LAPCOM), Programa de Pós-graduação em Neurociências, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Sarmento Leite, 500/305, Porto Alegre, RS, 90050-170, Brazil

    Ricieri Mocelin, Matheus Marcon, Simone D’ambros & Angelo Piato

  2. Grupo de Estudos Biológicos e Clínicos em Patologias Humanas, Universidade Federal da Fronteira Sul (UFFS), SC 484 km 02, Chapecó, SC, 89815-899, Brazil

    Ana P. Herrmann

  3. Laboratório de Fisiologia Cardiovascular, Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Sarmento Leite 500/344, Porto Alegre, RS, 90050-170, Brazil

    Alex Sander da Rosa Araujo

  4. Zebrafish Neuroscience Research Consortium (ZNRC), 309 Palmer Court, Slidell, LA, 70458, USA

    Angelo Piato

Authors
  1. Ricieri Mocelin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matheus Marcon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simone D’ambros
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ana P. Herrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alex Sander da Rosa Araujo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Angelo Piato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angelo Piato.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical Approval

All protocols performed in this study were in accordance with the Ethics Committee of Federal University of Rio Grande do Sul (process number #30914) and followed national and international guidelines for the care and use of laboratory animals.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mocelin, R., Marcon, M., D’ambros, S. et al. Behavioral and Biochemical Effects of N-Acetylcysteine in Zebrafish Acutely Exposed to Ethanol. Neurochem Res 43, 458–464 (2018). https://doi.org/10.1007/s11064-017-2442-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-017-2442-2

Keywords

Search

Navigation