ADVERTISEMENT

Nicotine’s Varying (Positive and Negative) Effects on the Brain

Nicotine has a vast array of neurophysiological effects, not all of which are negative despite popular opinion of nicotine as a simplistically harmful substance. Nicotine has various pro-cognitive effects and has even been used in transdermal therapy to improve attention, memory and psychomotor speed in mild cognitive impairment1. Furthermore, nicotinic receptor agonists are being investigated for treatment in schizophrenia and Alzheimer’s disease2 showing that the molecule’s effects are complex, not black and white as it is described in the media.

Nicotine is a central nervous system stimulant3 with positive and negative effects on the brain (the judgement of positive and negative defined by effects on behaviour which are considered socially as productive to the wellbeing of individuals, with subjective positive effects representing increased wellbeing of individuals in society). Nicotine affects signalling of various neurotransmitters in the brain4, primarily acting through nicotinic receptors of the neurotransmitter acetylcholine5 and its addictive characteristics arise from its stimulation of dopamine release in the nucleus accumbens6 in the part of the brain known as the basal forebrain which creates the subjective experience of pleasure (reward) allowing the creation of addictive behaviour7 such as chain-smoking.

Nicotine is an agonist of nicotinic acetylcholine (nACh) receptors which are ionotropic (agonism induces opening of certain ion channels)8. This article will exclude receptors found at neuromuscular junctions. Acetylcholine agonises both types of acetylcholine receptors: nicotinic and muscarinic receptors which are metabotropic (agonism induces a series metabolic steps)9. Strength and efficacy of pharmacological agents on receptors is multifactorial, including binding affinity, ability to cause agonistic effect (such as inducing gene transcription), effect on receptor (some agonists may cause receptor downregulation), dissociation from receptor etcetera10. In the case of nicotine, it is generally considered at least a moderately strong nACh receptor agonist11, because despite massive chemical structure differences in nicotine and acetylcholine, both molecules contain a region with a nitrogen cation (positively charged nitrogen), and another hydrogen bond acceptor region12.

The nACh receptor is made of 5 polypeptide subunits and mutations in the polypeptide chain subunits causing limited agonism of nACh receptors can cause varying neurological pathologies such as epilepsy, mental retardation and cognitive deficits13. In Alzheimer’s disease, nACh receptors are downregulated14, current smokers are associated with 60% reduced risk of Parkinson’s disease15, drugs increasing nACh agonism in the brain are used to treat Alzheimer’s disease16 (nACh agonists are currently being developed to treat Alzheimer’s17) and the fact that nicotine is a cognitive function enhancer at low-to-moderate doses18 emphasises the importance of nACh receptor agonism for optimal cognitive function.

The primary health concerns over smoking are cancer and heart disease19. However, the risks of smoking need not be the same as the risks of ingesting nicotine without tobacco, such as through vaporising of nicotine fluid or chewing of nicotine gum. Cardiovascular toxicity of nicotine consumption is significantly lower than that of cigarette smoking20. Short and longer term nicotine use tends not to accelerate arterial plaque deposition20 but may still be a risk due to nicotine’s vasoconstrictive effects20. Furthermore, the genotoxicity (therefore carcinogenicity) of nicotine has been tested. Certain assays evaluating genotoxicity of nicotine show potential carcinogenicity through chromosomal aberrations and sister chromatid exchange at concentrations of nicotine only 2 to 3 times higher than smoker serum nicotine concentrations21. However, a study of nicotine’s effects on human lymphocytes did not show any effect21 but this may be anomalous considering the decrease in DNA damage caused by nicotine when co-incubated with a nACh receptor antagonist21 suggesting that causation of oxidative stress by nicotine may be dependant on activation of the nACh receptor itself21.

Prolonged nicotine use can cause desensitisation of nACh receptors22 as endogenous acetylcholine can be metabolised by the acetylcholinesterase enzyme whilst nicotine cannot, therefore leading to prolonged receptor binding22. In mice exposed to nicotine-containing vapour for 6 months, dopamine content in the frontal cortex (FC) was significantly increased whilst dopamine content in the striatum (STR) was significantly decreased23. There was no significant effect on serotonin concentrations23. Glutamate (an excitatory neurotransmitter) was moderately increased in both the FC and the STR and GABA (an inhibitory neurotransmitter was moderately decreased in both23. As GABA inhibits dopamine release whilst glutamate enhances it23, the significant dopaminergic activation of the mesolimbic pathway24 (associated with reward and behaviour25) and releasing effect of nicotine on endogenous opioids26 may explain the high addictiveness of nicotine and development of addictive behaviours. Lastly, the increase in dopamine and nACh receptor activation may explain the improvements from nicotine in motor response in tests of focused and sustained attention, and recognition memory27.

***

References:

  1. Newhouse P., Kellar, K., et al 2012. Nicotine treatment of mild cognitive impairment. A 6-month double-blind pilot clinical trial. Neurology. 2012 Jan 10; 78(2): 91–101. DOI: https://doi.org/10.1212/WNL.0b013e31823efcbb   
  1. Woodruff-Pak DS. and Gould TJ., 2002. Neuronal Nicotinic Acetylcholine Receptors: Involvement in Alzheimer’s Disease and Schizophrenia. Behavioral and Cognitive Neuroscience Reviews. Volume: 1 issue: 1, page(s): 5-20 Issue published: March 1, 2002. DOI: https://doi.org/10.1177/1534582302001001002   
  1. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 89594, Nicotine; [cited 2021 May 8]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Nicotine 
  1. Quattrocki E, Baird A, Yurgelun-Todd D. Biological aspects of the link between smoking and depression. Harv Rev Psychiatry. 2000 Sep;8(3):99-110. PMID: 10973935. Available online at https://pubmed.ncbi.nlm.nih.gov/10973935/  
  1. Benowitz N. L. (2009). Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annual review of pharmacology and toxicology49, 57–71. https://doi.org/10.1146/annurev.pharmtox.48.113006.094742  
  1. Fu Y, Matta SG, Gao W, Brower VG, Sharp BM. Systemic nicotine stimulates dopamine release in nucleus accumbens: re-evaluation of the role of N-methyl-D-aspartate receptors in the ventral tegmental area. J Pharmacol Exp Ther. 2000 Aug;294(2):458-65. PMID: 10900219. https://pubmed.ncbi.nlm.nih.gov/10900219/  
  1. Di Chiara, G., Bassareo, V., Fenu, S., De Luca, M. A., Spina, L., Cadoni, C., Acquas, E., Carboni, E., Valentini, V., & Lecca, D. (2004). Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology47 Suppl 1, 227–241. https://doi.org/10.1016/j.neuropharm.2004.06.032  
  1. Albuquerque, E. X., Pereira, E. F., Alkondon, M., & Rogers, S. W. (2009). Mammalian nicotinic acetylcholine receptors: from structure to function. Physiological reviews89(1), 73–120. https://doi.org/10.1152/physrev.00015.2008  
  1. Chang and Neumann, 1980. Acetylcholine Receptor. Molecular Aspects of Bioelectricity, 1980. Available online at https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/acetylcholine-receptor Accessed on 07 May 2021.   
  1. Kelly A Berg, William P Clarke, Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity, International Journal of Neuropsychopharmacology, Volume 21, Issue 10, October 2018, Pages 962–977, https://doi.org/10.1093/ijnp/pyy071 
  1. Rang & Dale’s Pharmacology, International Edition Rang, Humphrey P.; Dale, Maureen M.; Ritter, James M.; Flower, Rod J.; Henderson, Graeme 11: 
    https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Rod+Flower%3B+Humphrey+P.+Rang%3B+Maureen+M.+Dale%3B+Ritter%2C+James+M.+%282007%29%2C+Rang+%26+Dale%27s+pharmacology%2C+Edinburgh%3A+Churchill+Livingstone%2C&btnG=  
  1. Dani J. A. (2015). Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine. International review of neurobiology124, 3–19. https://doi.org/10.1016/bs.irn.2015.07.001  
  1. Steinlein OK, Kaneko S, Hirose S. Nicotinic acetylcholine receptor mutations. In: Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper’s Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK98138/ 
  1. Narahashi, T., Marszalec, W., Moriguchi, S., Yeh, J. Z., & Zhao, X. (2003). Unique mechanism of action of Alzheimer’s drugs on brain nicotinic acetylcholine receptors and NMDA receptors. Life sciences74(2-3), 281–291. https://doi.org/10.1016/j.lfs.2003.09.015 
  1. Mappin-Kasirer B., Pan H., et al 2020. Tobacco smoking and the risk of Parkinson disease. A 65-year follow-up of 30,000 male British doctors. Neurology. Vol. 94 no. 20 e2132e2138. PubMed: 32371450. DOI: https://doi.org/10.1212/WNL.0000000000009437 
  1. Ferreira-Vieira, T. H., Guimaraes, I. M., Silva, F. R., & Ribeiro, F. M. (2016). Alzheimer’s disease: Targeting the Cholinergic System. Current neuropharmacology14(1), 101–115. https://doi.org/10.2174/1570159×13666150716165726 
  1. Lippiello P.M., Caldwell W.S., Marks M.J., Collins A.C. (1994) Development of Nicotinic Agonists for the Treatment of Alzheimer’s Disease. In: Giacobini E., Becker R.E. (eds) Alzheimer Disease. Advances in Alzheimer Disease Therapy. Birkhäuser Boston. https://doi.org/10.1007/978-1-4615-8149-9_31 
  1. Valentine, G., & Sofuoglu, M. (2018). Cognitive Effects of Nicotine: Recent Progress. Current neuropharmacology16(4), 403–414. https://doi.org/10.2174/1570159X15666171103152136 
  1. CDC 2021. Health Effects of Cigarette Smoking. Available online at https://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/index.htm Accessed on 07 May 2021.  
  1. Benowitz, N. L., & Burbank, A. D. (2016). Cardiovascular toxicity of nicotine: Implications for electronic cigarette use. Trends in cardiovascular medicine26(6), 515–523. https://doi.org/10.1016/j.tcm.2016.03.001 
  1. Sanner, T., & Grimsrud, T. K. (2015). Nicotine: Carcinogenicity and Effects on Response to Cancer Treatment – A Review. Frontiers in oncology5, 196. https://doi.org/10.3389/fonc.2015.00196 
  1. Dani J. A. (2015). Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine. International review of neurobiology124, 3–19. https://doi.org/10.1016/bs.irn.2015.07.001 
  1. Alasmari F., Alexander LEC., et al 2019. Effects of Chronic Inhalation of Electronic Cigarette Vapor Containing Nicotine on Neurotransmitters in the Frontal Cortex and Striatum of C57BL/6 Mice. Front. Pharmacol., 12 August 2019. DOI: https://doi.org/10.3389/fphar.2019.00885 
  1. Clarke P. B. (1990). Mesolimbic dopamine activation–the key to nicotine reinforcement?. Ciba Foundation symposium152, 153–168. https://doi.org/10.1002/9780470513965.ch9 
  1. Science Direct 2021. Mesolimbic Pathway. Available online at https://www.sciencedirect.com/topics/neuroscience/mesolimbic-pathway Accessed on 07 May 2021.  
  1. Hadjiconstantinou M.  and Neff N., 2011. Nicotine and endogenous opioids: Neurochemical and pharmacological evidence. Neuropharmacology. Volume 60, Issues 7–8, June 2011, Pages 1209-1220. DOI: https://doi.org/10.1016/j.neuropharm.2010.11.010  
  1. Ernst M., Matochik J., et al 2001. Effect of nicotine on brain activation during performance of a working memory task. Proceedings of the National Academy of Sciences Apr 2001, 98 (8) 4728-4733; DOI: https://doi.org/10.1073/pnas.061369098  
     

***



Subscribe to our newsletter

To be updated with all the latest news, offers and special announcements.

Most Popular Articles

Bionic Eye: Promise of Vision for Patients With Retinal and Optic Nerve Damage

Studies has shown that the “bionic eye” promises to...

Rejuvenation of Old Cells: Making ageing Easier

A groundbreaking study has discovered a novel way to...

Monkeypox virus (MPXV) variants given new names 

On 08 August 2022, the expert group of WHO...
- Advertisement -
94,669FansLike
47,715FollowersFollow
1,772FollowersFollow
30SubscribersSubscribe