Effects of Nicotine Administration in an Enriched Environment on the Behavior of Male MK-801-Exposed Rats

Document Type : Original Article


1 Department of Psychology, Zarand Branch, Islamic Azad University, Kerman, Iran

2 Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

3 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran



Background: Smoking is more common in patients with schizophrenia than in healthy populations. Some controversial hypotheses 
connect the disease with the high prevalence of smoking. Moreover, environmental factors affect the severity of the positive and 
negative symptoms of schizophrenia. The current study aimed to assess the effect of enriched environment (EE) and nicotine on the 
MK-801 animal model of schizophrenia.
Methods: Male Wistar rat pups randomly received saline or MK-801 (dose:1 mg/kg) for five days from the sixth postnatal day (P) 
until the tenth. The pups were placed in EE or standard cages (SCs) after weaning (P21). Morris water maze (MWM) was used to 
assess spatial learning and memory. The rats received 0.6 mg/kg nicotine twice for three days at the end of the second month and 
were examined in an open-field box and three-chamber social interaction test.
Findings: MK-801 rats’ behaviors were the same as those of the saline rats when they were exposed to nicotine. No positive effects 
of EE were observed when the animals were exposed to nicotine. 
Conclusion: The results suggested that nicotine decreased schizophrenia-like symptoms and covered the positive effects of EE.


Neda Salmani: (Google Scholar) (PubMed)

Fatemeh Darvishzadeh Mahani: (Google Scholar) (PubMed)

Mahdieh Parvan: (Google Scholar) (PubMed)

Masoumeh Nozari: (Google Scholar) (PubMed)


1. Szatkowski L, McNeill A. Diverging trends in smoking 
behaviors according to mental health status. Nicotine Tob 
Res. 2015;17(3):356-60. doi: 10.1093/ntr/ntu173.
2. Dickerson F, Stallings CR, Origoni AE, Vaughan C, Khushalani 
S, Schroeder J, et al. Cigarette smoking among persons with 
schizophrenia or bipolar disorder in routine clinical settings, 
1999-2011. Psychiatr Serv. 2013;64(1):44-50. doi: 10.1176/
3. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: 
overview and treatment options. P T. 2014;39(9):638-45.
4. Dani JA, De Biasi M. Cellular mechanisms of nicotine 
addiction. Pharmacol Biochem Behav. 2001;70(4):439-46. 
doi: 10.1016/s0091-3057(01)00652-9.
5. Benowitz NL. Pharmacology of nicotine: addiction, 
smoking-induced disease, and therapeutics. Annu Rev 
Pharmacol Toxicol. 2009;49:57-71. doi: 10.1146/annurev.
6. Fergusson DM, Goodwin RD, Horwood LJ. Major depression 
and cigarette smoking: results of a 21-year longitudinal 
study. Psychol Med. 2003;33(8):1357-67. doi: 10.1017/
7. Mendelsohn C. Smoking and depression--a review. Aust Fam 
Physician. 2012;41(5):304-7.
8. Novak G, Seeman P, Le Foll B. Exposure to nicotine produces 
an increase in dopamine D2high receptors: a possible 
mechanism for dopamine hypersensitivity. Int J Neurosci. 
2010;120(11):691-7. doi: 10.3109/00207454.2010.513462.
9. Salmani N, Nozari M, Parvan M, Amini-Sardouei S, Shabani 
M, Khaksari M, et al. Nicotine-conditioned place preference, 
reversal learning and social interaction in MK-801-induced 
schizophrenia model: effects of post-weaning enriched 
environment. Clin Exp Pharmacol Physiol. 2022;49(8):871-
80. doi: 10.1111/1440-1681.13674.
10. Gubert C, Hannan AJ. Environmental enrichment as an 
experience-dependent modulator of social plasticity and 
cognition. Brain Res. 2019;1717:1-14. doi: 10.1016/j.
11. Rico-Barrio I, Peñasco S, Puente N, Ramos A, Fontaine CJ, 
Reguero L, et al. Cognitive and neurobehavioral benefits of 
an enriched environment on young adult mice after chronic 
ethanol consumption during adolescence. Addict Biol. 
2019;24(5):969-80. doi: 10.1111/adb.12667.
12. Lim AL, Taylor DA, Malone DT. Consequences of early 
life MK-801 administration: long-term behavioural effects 
and relevance to schizophrenia research. Behav Brain Res. 
2012;227(1):276-86. doi: 10.1016/j.bbr.2011.10.052.
13. Faatehi M, Basiri M, Nezhadi A, Shabani M, Masoumi-Ardakani 
Y, Soltani Z, et al. Early enriched environment prevents 
cognitive impairment in an animal model of schizophrenia 
induced by MK-801: role of hippocampal BDNF. Brain Res. 
2019;1711:115-9. doi: 10.1016/j.brainres.2019.01.023.
14. Nozari M, Suzuki T, Rosa MG, Yamakawa K, Atapour N. The 
impact of early environmental interventions on structural 
plasticity of the axon initial segment in neocortex. Dev 
Psychobiol. 2017;59(1):39-47. doi: 10.1002/dev.21453.
15. Haratizadeh S, Parvan M, Mohammadi S, Shabani M, Nozari 
M. An overview of modeling and behavioral assessment of 
autism in the rodent. Int J Dev Neurosci. 2021;81(3):221-8. 
doi: 10.1002/jdn.10096.
16. Nazeri-Rezaabad M, Jamalpoor Z, Alemrajabi MS, Nozari M, 
Razavinasab M, Nezhadi A. Chronic exposure to morphine 
leads to a reduced affective pain response in the presence of 
hyperalgesia in an animal model of empathy. Addict Health. 
2020;12(4):251-8. doi: 10.22122/ahj.v12i4.280.
17. Haratizadeh S, Ranjbar M, Darvishzadeh-Mahani F, Basiri M, 
Nozari M. The effects of postnatal erythropoietin and nanoerythropoietin on behavioral alterations by mediating K-Cl 
co-transporter 2 in the valproic acid-induced rat model of 
autism. Dev Psychobiol. 2023;65(1):e22353. doi: 10.1002/
18. Eslami SM, Khorshidi L, Ghasemi M, Rashidian A, Mirghazanfari 
M, Nezhadi A, et al. Protective effects of atorvastatin and 
rosuvastatin on 3,4-methylenedioxymethamphetamine 
(MDMA)-induced spatial learning and memory impairment. 
Inflammopharmacology. 2021;29(6):1807-18. doi: 10.1007/
19. Saeedi Goraghani M, Ahmadi-Zeidabadi M, Bakhshaei S, 
Shabani M, Ghotbi Ravandi S, Rezaei Zarchi S, et al. Behavioral 
consequences of simultaneous postnatal exposure to MK-801 
and static magnetic field in male Wistar rats. Neurosci Lett. 
2019;701:77-83. doi: 10.1016/j.neulet.2019.02.026.
20. Huang Y, Jiang H, Zheng Q, Fok AHK, Li X, Lau CG, et 
al. Environmental enrichment or selective activation of 
parvalbumin-expressing interneurons ameliorates synaptic 
and behavioral deficits in animal models with schizophrenialike behaviors during adolescence. Mol Psychiatry. 
2021;26(6):2533-52. doi: 10.1038/s41380-020-01005-w.
21. Xu J, Li Y, Tian B, Liu H, Wu S, Wang W. The effects and 
mechanism of environmental enrichment on MK-801 
induced cognitive impairment in rodents with schizophrenia. 
Front Cell Neurosci. 2022;16:1024649. doi: 10.3389/
fncel.2022.1024649.22. Wang Q, Wang MW, Sun YY, Hu XY, Geng PP, Shu H, et al. 
Nicotine pretreatment alleviates MK-801-induced behavioral 
and cognitive deficits in mice by regulating Pdlim5/CRTC1 
in the PFC. Acta Pharmacol Sin. 2023;44(4):780-90. doi: 
23. Shu H, Wang M, Song M, Sun Y, Shen X, Zhang J, et al. Acute 
nicotine treatment alleviates LPS-induced impairment of fear 
memory reconsolidation through AMPK activation and CRTC1 
upregulation in hippocampus. Int J Neuropsychopharmacol. 
2020;23(10):687-99. doi: 10.1093/ijnp/pyaa043.
24. Hambsch B, Keyworth H, Lind J, Otte DM, Racz I, Kitchen I, et 
al. Chronic nicotine improves short-term memory selectively 
in a G72 mouse model of schizophrenia. Br J Pharmacol. 
2014;171(7):1758-71. doi: 10.1111/bph.12578.
25. Martin LM, Sayette MA. A review of the effects of nicotine 
on social functioning. Exp Clin Psychopharmacol. 
2018;26(5):425-39. doi: 10.1037/pha0000208.