Abstract
Background:
Caffeine antagonizes the intoxicating effects of alcohol. Consequently, there has been a dramatic global increase in the consumption of caffeinated drinks together with alcohol, especially among young adults. We assessed the seizure vulnerability and anxiety responses following the chronic co-administration of, and withdrawal from, caffeine and ethanol in male rats.
Methods:
The rats were randomly assigned to six groups consisting of 10 animals each: 10 mg/kg of caffeine, 20 mg/kg of caffeine, 4 g/kg of 20% ethanol, combined caffeine (20 mg/kg) and ethanol (4 g/kg of 20%), 4 mL/kg distilled water, and an untreated control group. The test substances were administered intragastrically twice daily for 29 days. On day 29, the rats were tested on the elevated plus maze to assess anxiety-related responses. On day 30, pentylenetetrazol (PTZ), a chemoconvulsant, was administered intraperitoneally at a dose of 40 mg/kg to the animals. Seizure responses and mortality up to 72 h were recorded.
Results:
Compared with the control group, the rats that received chronic treatment with low-dose caffeine, ethanol alone, and combined caffeine and ethanol exhibited significant anxiogenic-like effects, unlike with high-dose caffeine. Both low- and high-dose caffeine significantly increased PTZ seizure latency. Ethanol alone and combined caffeine and ethanol both lowered PTZ seizure latency. No significant difference occurred between the controls and the untreated group for either anxiety or seizure expression. Combined caffeine and ethanol increased the seizure-induced mortality from withdrawal effects at 72 h.
Conclusions:
These findings suggest that the chronic co-administration of caffeine and ethanol and the acute withdrawal from these drugs lead to anxiogenic effects and increased seizure vulnerability.
Acknowledgments
We thank Genny Dominguez and Patrick Ogwang for their thoughtful critiques of this work. We also acknowledge the excellent technical assistance of Deneth Muhereza and David Nkwangu.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Morelli M, Simola N. Methylxanthines and drug dependence: a focus on interactions with substances of abuse, in Methylxanthines. Handb Exp Pharmacol 2011:483–507.10.1007/978-3-642-13443-2_20Search in Google Scholar PubMed
2. Marczinski CA, Fillmore MT. Energy drinks mixed with alcohol: what are the risks? Nutr Rev 2014;72:98–107.10.1111/nure.12127Search in Google Scholar PubMed PubMed Central
3. Marczinski CA. Can energy drinks increase the desire for more alcohol? Adv Nutr 2015;6:96–101.10.3945/an.114.007393Search in Google Scholar PubMed PubMed Central
4. Swahn MH, Palmier JB, Kasirye R. Alcohol exposures, alcohol marketing, and their associations with problem drinking and drunkenness among youth living in the slums of Kampala, Uganda. ISRN Public Health 2013;2013:9.10.1155/2013/948675Search in Google Scholar
5. World Health Organization. Global status report on alcohol and health. 2015 [cited 2017 April 8]. Available at: http://www.who.int/substance_abuse/publications/global_alcohol_report/en.Search in Google Scholar
6. Nabiruma D. Uganda: energy drinks could be bad for the heart. 2014 [cited 2016 4/9/2016]. Available at: http://allafrica.com/stories/201402190038.html.Search in Google Scholar
7. McKetin R, Coen A. The effect of energy drinks on the urge to drink alcohol in young adults. Alcohol Clini Exp Res 2014;38:2279–85.10.1111/acer.12498Search in Google Scholar PubMed
8. Emond JA, Gilbert-Diamond D, Tanski SE, Sargent JD. Energy drink consumption and the risk of alcohol use disorder among a national sample of adolescents and young adults. J Pediatr 2014;165:1194–200.10.1016/j.jpeds.2014.08.050Search in Google Scholar PubMed PubMed Central
9. White A, Hingson R. The burden of alcohol use: excessive alcohol consumption and related consequences among college students. Alcohol Res Curr Rev 2014;35:201–18.Search in Google Scholar
10. Ferré S, O’Brien MC. Alcohol and caffeine: the perfect storm. J Caffeine Res 2011;1:153–62.10.1089/jcr.2011.0017Search in Google Scholar PubMed PubMed Central
11. Jankiewicz K, Chroscinska-Krawczyk M, Blaszczyk B, Czuczwar SJ. Caffeine and antiepileptic drugs: experimental and clinical data. Przegl Lek 2007;64:965–7.Search in Google Scholar PubMed
12. Retson TA, Reyes BA, Van Bockstaele EJ. Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors. Prog Neuro-Psychopharmacol Biol Psychiatry 2015;56:66–74.10.1016/j.pnpbp.2014.08.005Search in Google Scholar PubMed PubMed Central
13. Devaud LL, Alele P, Chadda R. Sex differences in the central nervous system actions of ethanol. Crit Rev Neurobiol 2003;15:41–59.10.1615/CritRevNeurobiol.v15.i1.20Search in Google Scholar PubMed
14. Abburi C, Wolfman SL, Metz RA, Kamber R, McGehee DS. Tolerance to ethanol or nicotine results in increased ethanol self-administration and long-term depression in the dorsolateral striatum. eNeuro 2016;3:112–5.10.1523/ENEURO.0112-15.2016Search in Google Scholar PubMed PubMed Central
15. Thorsell A, Johnson J, Heilig M. Effect of the adenosine A2a receptor antagonist 3, 7-dimethyl-propargylxanthine on anxiety-like and depression-like behavior and alcohol consumption in Wistar rats. Alcohol Clin Exp Res 2007;31:1302–7.10.1111/j.1530-0277.2007.00425.xSearch in Google Scholar PubMed
16. Butler TR, Prendergast MA. Neuroadaptations in adenosine receptor signaling following long-term ethanol exposure and withdrawal. Alcohol Clin Exp Res 2012;36:4–13.10.1111/j.1530-0277.2011.01586.xSearch in Google Scholar PubMed
17. Butler TR, Smith KJ, Berry JN, Sharrett-Field LJ, Prendergast MA. Sex differences in caffeine neurotoxicity following chronic ethanol exposure and withdrawal. Alcohol Alcohol 2009;44:567–74.10.1093/alcalc/agp050Search in Google Scholar PubMed
18. Alele PE, Rujumba JB. Khat (Catha edulis) and ethanol co-dependence modulate seizure expression in a pentylenetetrazol seizure model. J Ethnopharmacol 2011;137:1431–6.10.1016/j.jep.2011.08.017Search in Google Scholar
19. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999;51:83–133.Search in Google Scholar PubMed
20. Soellner DE, Grandys T, Nuñez JL. Chronic prenatal caffeine exposure impairs novel object recognition and radial arm maze behaviors in adult rats. Behav Brain Res 2009;205:191–9.10.1016/j.bbr.2009.08.012Search in Google Scholar PubMed
21. Miquel M, Correa M, Sanchis-Segura C, Aragon CM. The ethanol-induced open-field activity in rodents treated with isethionic acid, a central metabolite of taurine. Life Sci 1999;64:1613–21.10.1016/S0024-3205(99)00098-3Search in Google Scholar PubMed
22. Alele PE, Ajayi AM, Imanirampa. L. Chronic khat (Catha edulis) and alcohol marginally alter complete blood counts, clinical chemistry, and testosterone in male rats. J Exp Pharmacol 2013;5:33–44.10.2147/JEP.S46635Search in Google Scholar
23. Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2007;2:322–8.10.1038/nprot.2007.44Search in Google Scholar
24. Hogg S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 1996;54:21–30.10.1016/0091-3057(95)02126-4Search in Google Scholar PubMed
25. Alele PE, Devaud LL. Differential adaptations in GABAergic and glutamatergic systems during ethanol withdrawal in male and female rats. Alcohol Clin Exp Res 2005;29:1027–34.10.1097/01.ALC.0000167743.96121.40Search in Google Scholar PubMed
26. Alele PE, Devaud LL. Sex differences in steroid modulation of ethanol withdrawal in male and female rats. J Pharmacol Exp Ther 2007;320:427–36.10.1124/jpet.106.107896Search in Google Scholar PubMed
27. Marsh DJ, Baraban SC, Hollopeter G, Palmiter RD. Role of the Y5 neuropeptide Y receptor in limbic seizures. Proc Nat Acad Sci USA 1999;96:13518–23.10.1073/pnas.96.23.13518Search in Google Scholar
28. National Institutes of Health. Guide for the care and use of laboratory animals, 2011.Search in Google Scholar
29. Lord R. Use of ethanol for euthanasia of mice. Aust Vet J 1989;66:268–8.10.1111/j.1751-0813.1989.tb13590.xSearch in Google Scholar PubMed
30. Leary S, Underwood W, Anthony R, Cartner S, Corey D, Grandin T, et al. AVMA guidelines for the euthanasia of animals. Am Vet Med Assoc 2013.Search in Google Scholar
31. Ardais AP, Borges MF, Rocha AS, Sallaberry C, Cunha RA, Porciúncula LO. Caffeine triggers behavioral and neurochemical alterations in adolescent rats. Neurosci 2014;270:27–39.10.1016/j.neuroscience.2014.04.003Search in Google Scholar
32. Hughes RN, Hancock NJ, Henwood GA, Rapley SA. Evidence for anxiolytic effects of acute caffeine on anxiety-related behavior in male and female rats tested with and without bright light. Behav Brain Res 2014;271:7–15.10.1016/j.bbr.2014.05.038Search in Google Scholar PubMed
33. López-Cruz L, Salamone JD, Correa M. The impact of caffeine on the behavioral effects of ethanol related to abuse and addiction: a review of animal studies. J Caffeine Res 2013;3:9–21.10.1089/jcr.2013.0003Search in Google Scholar PubMed
34. Langen B, Dietze S, Fink H. Acute effect of ethanol on anxiety and 5-HT in the prefrontal cortex of rats. Alcohol 2002;27:135–41.10.1016/S0741-8329(02)00219-7Search in Google Scholar PubMed
35. Van Skike CE, Diaz-Granados JL, Matthews DB, Chronic intermittent ethanol exposure produces persistent anxiety in adolescent and adult rats. Alcohol Clin Exp Res 2015;39:262–71.10.1111/acer.12617Search in Google Scholar PubMed PubMed Central
36. Witt ED. Puberty, hormones, and sex differences in alcohol abuse and dependence. Neurotoxicol Teratol 2007;29:81–95.10.1016/j.ntt.2006.10.013Search in Google Scholar PubMed
37. Corda MG, Giorgi O, Longoni B, Orlandi M, Biggio G. Decrease in the function of the γ-aminobutyric acid-coupled chloride channel produced by the repeated administration of pentylenetetrazol to rats. J Neurochem 1990;55:1216–21.10.1111/j.1471-4159.1990.tb03127.xSearch in Google Scholar PubMed
38. Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM. Convulsant potencies of tetrazoles are highly correlated with actions on GABA/benzodiazepine/picrotoxin receptor complexes in brain. Life Sci 1984;35:1439–44.10.1016/0024-3205(84)90159-0Search in Google Scholar PubMed
39. Psarropoulou C, Matsokis N, Angelatou F, Kostopoulos G. Pentylenetetrazol-induced seizures decrease γ-aminobutyric acid-mediated recurrent inhibition and enhance adenosine-mediated depression. Epilepsia 1994;35:12–9.10.1111/j.1528-1157.1994.tb02906.xSearch in Google Scholar PubMed
40. Ferre S. Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders. PLoS One 2016;233:1963–79.10.1007/s00213-016-4212-2Search in Google Scholar
41. Boison D. Methylxanthines, seizures, and excitotoxicity, in Methylxanthines. Handb Exp Pharmacol 2011:251–66.10.1007/978-3-642-13443-2_9Search in Google Scholar PubMed
42. Souza MA, Mota BC, Gerbatin RR, Rodrigues FS, Castro M, Fighera MR, et al. Antioxidant activity elicited by low dose of caffeine attenuates pentylenetetrazol-induced seizures and oxidative damage in rats. Neurochem Int 2013;62:821–30.10.1016/j.neuint.2013.02.021Search in Google Scholar PubMed
43. Lusardi TA, Lytle NK, Szybala C, Boison D. Caffeine prevents acute mortality after TBI in rats without increased morbidity. Exp Neurol 2012;234:161–8.10.1016/j.expneurol.2011.12.026Search in Google Scholar PubMed
44. Naseer MI, Ullah I, Rasool M, Ansari SA, Sheikh IA, Bibi F, et al. Downregulation of dopamine D1 receptors and increased neuronal apoptosis upon ethanol and PTZ exposure in prenatal rat cortical and hippocampal neurons. Neurol Sci 2014;35:1681–8.10.1007/s10072-014-1812-7Search in Google Scholar PubMed
45. Fredholm BB, Chen JF, Cunha RA, Svenningsson P, Vaugeois JM. Adenosine and brain function. Int Rev Neurobiol 2005;63:191–270.10.1016/S0074-7742(05)63007-3Search in Google Scholar PubMed
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