Correction of psychological and neurological signs of alcohol hangover in rats with acetylcysteine

The development of medications to treat alcohol hangover is important for a large number of people, especially those, who perform responsible and dangerous types of work. The severity of the hangover syndrome is determined by the toxic effect of acetaldehyde and its metabolic rate, which decreases with the depletion of glutathione, worsening and prolonging the hangover.

The aim of the article is to provide an experimental basis for use of acetylcysteine as a precursor of glutathione in treatment of psychological, neurological and cognitive symptoms of ethanol hangover.

Materials and methods. The study was performed in male Wistar rats. The ethanol hangover was modeled via an acute ethanol injection (i.p., 3 g/kg). After awakening, the animals were divided into 2 groups, receiving acetylcysteine (p.o., 1 mg/ kg) or saline. The intact group of the animals received saline only. Before and after acetylcysteine or saline administration, the animals were assessed according to Combs and D'Alecy scale. The adhesive test, the open field test, the passive avoidance test and Morris water maze test were also performed twice. The liver glutathione level was assessed in sacrificed animals.

Results. The control group animals showed signs of neurological deficits and cognitive impairment, including a decreased locomotion, motor deficits and a memory decline. The rats administered with acetylcysteine after the ethanol intoxication, had a less severe impairment associated with an improved performance in the adhesive test, Morris water maze test and the passive avoidance test, and demonstrated an increased locomotion in the open field test. The liver glutathione content in the animals treated with acetylcysteine, was comparable to the glutathione content in the liver of the animals not exposed to the ethanol intoxication.

Conclusion. Against the background of an acute ethanol intoxication, an oral administration of acetylcysteine in the rats, promoted an increase in liver glutathione levels and led to a decrease in severity of neurological and cognitive deficits in the animals.

1. Mackus M, Adams S, Barzilay A, Benson S, Blau L, Iversen J, Johnson SJ, Keshavarzian A, Scholey A, Smith GS, Trela C, Vatsalya V, Verster JC. Proceeding of the 8th Alcohol Hangover Research Group Meeting. Curr Drug Abuse Rev. 2016;9(2):106-112. doi: 10.2174/1874473709666161229121527.

2. Penning R, McKinney A, Verster JC. Alcohol hangover symptoms and their contribution to the overall hangover severity. Alcohol Alcohol. 2012;47(3):248-252. doi: 10.1093/alcalc/ags029.

3. Devenney LE, Coyle KB, Verster JC. Memory and attention during an alcohol hangover. Hum Psychopharmacol. 2019;34(4):e2701. doi: 10.1002/hup.2701.

4. Grange JA, Stephens R, Jones K, Owen L. The effect of alcohol hangover on choice response time. J Psychopharmacol. 2016;30(7):654-661. doi: 10.1177/0269881116645299.

5. Verster JC, Bervoets AC, de Klerk S, Vreman RA, Olivier B, Roth T, Brookhuis KA. Effects of alcohol hangover on simulated highway driving performance. Psychopharmacology Том 7, Выпуск 5,2019 (Berl). 2014;231(15):2999-3008. doi: 10.1007/s00213-014-3474-3479.

6. Sarkola T, Eriksson CJ. Testosterone increases in men after a low dose of alcohol. Alcohol Clin Exp Res. 2003;27(4):682-685. doi: 10.1097/01.alc.0000060526.43976.68

7. Alomary AA, Vallee M, O'Dell LE, Koob GF, Purdy RH, Fitzgerald RL. Acutely administered ethanol participates in testosterone synthesis and increases testosterone in rat brain. Alcohol Clin Exp Res. 2003;27(1):38-43. doi: 10.1097/01.alc.0000047304.28550.4f

8. Penning R, McKinney A, Bus LD, Olivier B, Slot K, Verster JC. Measurement of alcohol hangover severity: development of the Alcohol Hangover Severity Scale (AHSS). Psychopharmacology (Berl). 2013;225(4):803-810. doi: 10.1007/s00213-012-2866-y.

9. Thprrisen MM, Bonsaksen T, Hashemi N, Kjeken I, van Mechelen W, Aas RW. Association between alcohol consumption and impaired work performance (presenteeism): a systematic review. BMJ Open. 2019;9(7):e029184. doi: 10.1136/bmjopen-2019-029184.

10. Swift R, Davidson D. Alcohol hangover: mechanisms and mediators. Alcohol Health Res World. 1998;22(1): 54-60.

11. Labhart F, Livingston M, Engels R, Kuntsche E. After how many drinks does someone experience acute consequences-determining thresholds for binge drinking based on two event-level studies. Addiction. 2018;113(12):2235-2244. doi: 10.1111/add.14370.

12. Lam T, Liang W, Chikritzhs T, Allsop S. Alcohol and other drug use at school leavers' celebrations. J Public Health (Oxf). 2014;36(3):408-416. doi: 10.1093/pubmed/fdt087.

13. Verster JC, Penning R. Treatment and prevention of alcohol hangover. Curr Drug Abuse Rev. 2010;3(2):103-109. doi: 10.2174/1874473711003020103

14. Green JL, Heard KJ, Reynolds KM, Albert D. Oral and intravenous acetylcysteine for treatment of acetaminophen toxicity: a systematic review and meta-analysis. West J Emerg Med. 2013;14(3):218-226. doi: 10.5811/west-jem.2012.4.6885.

15. Morkovin EI, Kurkin DV, Tyurenkov IN. The assessment of the psychoneurological impairments in rodents: Basic methods. Zhurnal Vysshei Nervnoi Deyatelnosti Imeni I.P. Pavlova. 2018;68(1):3-15. doi: 10.7868/s004446771801001x

16. Combs DJ, D'Alecy LG. Motor performance in rats exposed to severe forebrain ischemia: effect of fasting and 1,3-butanediol. Stroke. 1987;18(2):503-511.

17. Bouet V, Boulouard M, Toutain J, Divoux D, Bernaudin M, Schumann-Bard P, Freret T. The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice. Nat Protoc. 2009;4(10):1560-1564. doi: 10.1038/nprot.2009.125

18. Guidance on preclinical studies of medicines: ed. A.N. Mironov. V.1. Moscow, Grif i K, 2012: 944 pp.

19. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006;1(2):848-858. doi: 10.1038/nprot.2006.116.

20. Shaik IH, Mehvar R. Rapid determination of reduced and oxidized glutathione levels using a new thiol-masking re-agent and the enzymatic recycling method: Application to the rat liver and bile samples. Anal Bioanal Chem. 2006;385(1):105-113. doi: 10.1007/s00216-006-0375-8.

21. Cederbaum AI. Alcohol metabolism. Clin Liver Dis. 2012;16(4):667-685. doi: 10.1016/j.cld.2012.08.002.

22. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. PharmacolTher. 2014;141(2):150-159. doi: 10.1016/j.pharmthera.2013.09.006.

23. Green JL, Heard KJ, Reynolds KM, Albert D. Oral and intravenous acetylcysteine for treatment of acetaminophen toxicity: a systematic review and metaanalysis. West J Emerg Med. 2013;14(3):218-226. doi: 10.5811/west-jem.2012.4.6885.

24. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, Sergio F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018;52(7):751-762. doi: 10.1080/10715762.2018.1468564.

25. Oja SS, Janaky R, Varga V, Saransaari P. Modulation of glutamate receptor functions by glutathione. Neurochem Int. 2000;37(2-3):299-306. doi: 10.1016/s0197-0186(00)00031-0

26. Chen HH, Stoker A, Markou A. The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice. Psychopharmacology (Berl). 2010;209(4):343-350. doi: 10.1007/s00213-010-1802-2.

27. Paterson RL, Galley HF, Webster NR. The effect of N-acetylcysteine on nuclear factor-kappa B activation, in-terleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis. Crit Care Med. 2003;31(11):2574-2578. doi: 10.1097/01.ccm.0000089945.69588.18

28. Kupchik YM, Moussawi K, Tang XC, Wang X, Kalivas BC, Kolokithas R, Ogburn KB, Kalivas PW. The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine. Biol Psychiatry. 2012;71(11):978-986. doi: 10.1016/j.biopsych.2011.10.024.