Comparative Clinical Pathology

, Volume 28, Issue 5, pp 1229–1236 | Cite as

Co-administration of nicotine ameliorates cannabis-induced behavioral deficits in normal rats: role of oxidative stress and inflammation

  • Mayada A. El-HinyEmail author
  • Dalaal M. Abdallah
  • Omar M. E. Abdel-Salam
  • Neveen A. Salem
  • Zakaria A. El-Khyat
  • Sanaa A. Kenawy
Original Article


Nicotine (Nic) and cannabis are considered to be the most abused drugs worldwide that are progressively taken concomitantly. The present study aimed to investigate the modulatory effect of Nic on cannabis extract–induced neuro-inflammation, oxidative status, and the associated behavioral/biochemical alterations. Nic (0.25 mg/kg) and/or cannabis extract expressed as ∆9-tetrahydrocannabinol (THC10/20; 10 and 20 mg/kg) were given intraperitoneally for 30 days to Wistar rats. Nic shortened the floating time in forced swimming test, increased locomotion in the open field test, and decreased escape latency in the Morris water maze when co-administered with THC. These effects were associated with the inhibition of THC-mediated elevations in brain interleukin-1 beta, lipid peroxidation, superoxide dismutase, and ascorbic acid. Additionally, Nic increased serum butyrylcholinesterase (BChE) when combined with THC without affecting the serum acetylcholinesterase enzyme. The combinations spiked the brain glucose content above normal. In conclusion, the co-administration of Nic reduced THC-induced depressive-like behavior and memory impairment as well as hypo-locomotion associated with THC20. Such effects could be linked to Nic-mediated inhibition of brain oxidative stress, inflammation, and decreased serum BChE deactivity.


Cannabis resin extract 9-tetrahydrocannabinol Nicotine Rats Oxidative stress Inflammation Memory Locomotion, depression 


Compliance with ethical standards

The experiments were conducted in accordance with the ethical guidelines for care and use in handling laboratory animals and were approved by the Ethics Committee of the NRC (Permit Number 10069).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abdel-Salam OME, Salem NA, El-Shamarka MES, Ahmed NAS, Hussein JS, El-Khyat ZA (2013) Cannabis-induced impairment of learning and memory: effect of different nootropic drugs. EXCLI J 12:193–214PubMedPubMedCentralGoogle Scholar
  2. Abdel-Salam OME, Youness ER, Khadrawy YA, Sleem AA (2016) Acetylcholinesterase, butyrylcholinesterase and paraoxonase 1 activities in rats treated with cannabis, tramadol or both. Asian Pac J Trop Med 9(11):1089–1094PubMedGoogle Scholar
  3. Bevan-Jones WR, Surendranathan A, Passamonti L, Rodriguez PV, Arnold R, Mak E, Su L, Coles JP, Fryer TD, Hong YT, Williams G, Aigbirhio F, Rowe JB, O’Brien JT (2017) Neuroimaging of inflammation in memory and related other disorders (NIMROD) study protocol: a deep phenotyping cohort study of the role of brain inflammation in dementia, depression and other neurological illnesses. BMJ 7(1):e013187Google Scholar
  4. Bonsall DR, Kim H, Tocci C, Ndiaye A, Petronzio A, McKay-Corkum G, Molyneux PC, Scammell TE, Harrington ME (2015) Suppression of locomotor activity in female C57Bl/6J mice treated with interleukin-1β: investigating a method for the study of fatigue in laboratory animals. PLoS One 10(10):e0140678. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cabral GA (2001) Marijuana and cannabinoids: effects on infections, immunity, and AIDS. J Cannabis Ther 1(3/4):61–85Google Scholar
  6. Chen X, Fang L, Liu J, Zhan CG (2011) Reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of acetylcholine. J Phys Chem B 115(5):1315–1322PubMedGoogle Scholar
  7. Chen W, Li Z, Guo Y, Zhou Y, Zhang Z, Zhang Y, Luo G, Yang X, Liao W, Li C, Chen L, Sheng P (2015) Wear particles promote reactive oxygen species-mediated inflammation via the nicotinamide adenine dinucleotide phosphate oxidase pathway in macrophages surrounding loosened implants. Cell Physiol Biochem 35:1857–1867PubMedGoogle Scholar
  8. Degenhardt L, Hall W, Lynskey M (2002) Exploring the association between cannabis use and depression. Addiction 98:1493–1504Google Scholar
  9. Ellman GL, Courtney KD, Valentino Andres JR, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–90 IN1, 91–95PubMedGoogle Scholar
  10. Filbey FM, McQueeny T, Kadamangudi S, Bice C, Ketcherside A (2015) Combined effects of marijuana and nicotine on memory performance and hippocampal volume. Behav Brain Res 293:46–53PubMedPubMedCentralGoogle Scholar
  11. File SE, Kenny PJ, Ouagazzal AM (1998) Bimodal modulation by nicotine of anxiety in the social interaction test: role of the dorsal hippocampus. Behav Neurosci 112:1423–1429PubMedGoogle Scholar
  12. Fischedick JT, Glas R, Hazekamp A, Verpoorte R (2009) A qualitative and quantitative HPTLC densitometry method for the analysis of cannabinoids in cannabis sativa. L. Phytochem Anal 20(5):421–426PubMedGoogle Scholar
  13. Freedland CS, Whitlow CT, Miller MD, Porrino LJ (2002) Dose-dependent effects of ∆9-THC on rates of local cerebral glucose utilization in rat. Synapse 45(2):134–142PubMedGoogle Scholar
  14. Gorun V, Proinov I, Baltescu V (1978) Modified Ellman procedure for assay of cholinesterases in crude enzymatic preparations. Anal Biochem 86:324–326PubMedGoogle Scholar
  15. Gotti C, Clementi F (2004) Neuronal nicotinic receptors: from structure to pathology. ProgNeurobiol 74(6):363–396Google Scholar
  16. Graziano A, Petrosini L, Bartoletti A (2003) Automatic recognition of explorative strategies in the Morris water maze. J Neurosci Methods 130(1):33–44PubMedGoogle Scholar
  17. Guan ZZ, Yu WF, Nordberg A (2003) Dual effects of nicotine on oxidative stress and neuroprotection in PC12 cells. Neurochem Int 43:243–249PubMedGoogle Scholar
  18. Harris LJ, Ray SN (1935) Diagnosis of vitamin-C subnutrition by urine analysis. Lancet 1(71):462Google Scholar
  19. Hu SS, Mackie K (2015) Distribution of the endocannabinoid system in the central nervous system. In: Pertwee RG (ed) Handbook of experimental pharmacology, vol 231. Springer, New York, pp 59–93Google Scholar
  20. Iversen L (2003) Cannabis and the brain. Brain 126:1252–1270PubMedGoogle Scholar
  21. Iversen L (2012) How cannabis works in the human brain. In: Castle D, Murray R, D’Souza DC (eds) Marijuana and madness. Cambridge University Press, Cambridge, pp 1–11Google Scholar
  22. Jean-Gilles L, Braitch M, Latif ML, Aram J, Fahey AJ, Edwards LJ, Robins RA, Tanasescu R, Tighe PJ, Gran B, Showe LC, Alexander SP, Chapman V, Kendall DA, Constantinescu CS (2015) Effects of pro-inflammatory cytokines on cannabinoid CB1 and CB2 receptors in immune cells. Acta Physiol (Oxf) 214(1):63–74Google Scholar
  23. Kacham R (2013) Role of nicotine in oxidative stress. Thesis submitted to the faculty of Missouri University of science and technology in partial fulfillment of the requirements for the degree master of science in chemistry. Masters Theses 5447Google Scholar
  24. Kaushal N, Bansal M (2014) Cell signaling and gene regulation by oxidative stress. In: Oxidative stress mechanisms and their modulation. Springer India, pp 105–121Google Scholar
  25. Knedel M, Bottger R (1967) Einekinetsche Methodezur Bestimmung der Aktivitat der Pseudocholinesterase. Klin Wochenschr 45:325PubMedGoogle Scholar
  26. Kruk-Slomka M, Boguszewska-Czubara A, Slomka T, Budzynska B, Biala G (2016) Correlations between the memory-related behavior and the level of oxidative stress biomarkers in the mice brain, provoked by an acute administration of CB receptor ligands. Neural Plast 016, Article ID 9815092, 15 pagesGoogle Scholar
  27. López-Malo D, Sanchez-Martinez JJ, Romero FJ, Barcia JM, Villar VM (2016) Oxidative stress and the combined use of tetrahydrocannabinol and alcohol: is there a need for further research? React Oxyg Species 2(6):388–395Google Scholar
  28. Madras BK (2015) Update of cannabis and its medical use. Report to the WHO Expert Committee on Drug Dependence.
  29. Manzanares J, Julian MD, Carrascosa A (2006) Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol 4(3):239–257PubMedPubMedCentralGoogle Scholar
  30. Miederer I, Uebbing K, Röhrich J, Maus S, Bausbacher N, Krauter K, Weyer-Elberich V, Lutz B, Schreckenberger M, Urban R (2017) Effects of tetrahydrocannabinol on glucose uptake in the rat brain. Neuropharmacology 1(117):273–281Google Scholar
  31. Nishikimi M, Roa NA, Yogi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 46:849–854PubMedGoogle Scholar
  32. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (2006) The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27(1):73–100Google Scholar
  33. Patel SS, Mehta V, Changotra H, Udayabanu M (2016) Depression mediates impaired glucose tolerance and cognitive dysfunction: a neuromodulatory role of rosiglitazone. HormBehav 78:200–210. CrossRefGoogle Scholar
  34. Rose JE, Behm FM, Westman EC, Mathew RJ, London ED, Hawk TC, Turkington TG, Coleman RE (2003) PET studies of the influences of nicotine on neural systems in cigarette smokers. Am J Psychiatry 160:323–333PubMedGoogle Scholar
  35. Ruiz-Larrea MB, Leal AM, Liza M, Lacort M, de Groot H (1994) Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids 59:383–388PubMedGoogle Scholar
  36. Schoeler T, Bhattacharyya S (2013) The effect of cannabis use on memory function: an update. Subst Abus Rehabil 4:11–27Google Scholar
  37. Sedeek M, Nasrallah R, Touyz RM, Hébert RL (2013) NADPH oxidases, reactive oxygen species, and the kidney: friend and foe. J Am Soc Nephrol 24(10):1512–1518PubMedPubMedCentralGoogle Scholar
  38. Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A, Le Meur M, Roques BP, Maldonado R, Kieffer BL (1998) Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonistU-50,488H and attenuates morphine withdrawal. EMBO J 17:886–897PubMedPubMedCentralGoogle Scholar
  39. Slattery DA, Cryan JF (2012) Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat Protoc 7(6):1009–1014PubMedGoogle Scholar
  40. Tai S, Fantegrossi WE (2014) Synthetic cannabinoids: pharmacology, behavioral effects, and abuse potential. Curr Addict Rep 1(2):129–136PubMedPubMedCentralGoogle Scholar
  41. Tanasawet S, Boonruamkaew P, Sukketsiri W, Chonpathompikunlert P (2017) Anxiolytic and free radical scavenging potential of Chinese celery (Apium graveolens) extract in mice. Asian Pac J Trop Biomed 7(1):20–26Google Scholar
  42. The National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda (2017) The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research.
  43. Trinder P (1969) Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 6(1):24–27Google Scholar
  44. Tullis LM, Dupont R, Frost-Pineda K, Gold MS (2003) Marijuana and tobacco: a major connection? J Addict Dis 22:51–62PubMedGoogle Scholar
  45. Tunez I, Drucker-Colin R, Montilla P, Peña J, Jimena I, Medina FJ, Tasset I (2010) Protective effect of nicotine on oxidative and cell damage in rats with depression induced by olfactory bulbectomy. Eur J Pharmacol 627(1–3):115–118PubMedGoogle Scholar
  46. Turner J, Mahlberg P (1984) Separation of acids and neutral cannabinoids in Cannabis sativa L. using HPLC. In: Agurell DW (ed) Chemical pharmacological therapeutic agents. Academic press, New York, pp 79–88Google Scholar
  47. United Nations (2018) Global overview of drug demand and supply latest trends, cross-cutting issues. World Drug Report 2018 (United Nations publication, Sales No. E.18.XI.9)Google Scholar
  48. Valjent E, Mitchell JM, Besson MJ, Caboche J, Maldonado R (2002) Behavioural and biochemical evidence for interactions between D9-tetrahydrocannabinol and nicotine. Br J Pharmacol 135:564–578PubMedPubMedCentralGoogle Scholar
  49. Viveros MP, Marco EM, File SE (2006) Nicotine and cannabinoids: parallels, contrasts and interactions. Neurosci Biobehav Rev 30(8):1161–1181PubMedGoogle Scholar
  50. Volkow ND, Baler RD, Compton WM, Weiss SRB (2014) Adverse health effects of marijuana use. N Engl J Med 370(23):2219–2227PubMedPubMedCentralGoogle Scholar
  51. WHO (2018) Leading cause of death, illness and impoverishment (WHO global report on trends in tobacco smoking 2000–2025)Google Scholar
  52. Wolff V, Schlagowski A-I, Rouyer O, Charles A-L, Singh F, Auger C, Schini-Kerth V, Marescaux C, Raul J-S, Zoll J, Geny B (2015) Tetrahydrocannabinol induces brain mitochondrial respiratory chain dysfunction and increases oxidative stress: a potential mechanism involved in cannabis-related stroke. Biomed Res Int 2015:1–7. CrossRefGoogle Scholar
  53. Yoshikawa H, Kurokawa M, Ozaki N, Nara K, Atou K, Takada E, Kamochi H, Suzuki N (2006) Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-κB phosphorylation and nuclear factor-κB transcriptional activity through nicotinic acetylcholine receptor α7. Clin Exp Immunol 146(1):116–123PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag London Ltd., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Toxicology and NarcoticsNational Research Centre (NRC)CairoEgypt
  2. 2.Pharmacology and Toxicology Department, Faculty of PharmacyCairo UniversityCairoEgypt
  3. 3.Medical Biochemistry DepartmentNRCCairoEgypt

Personalised recommendations