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

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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.

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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.

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