How does nicotine affect the human brain?

Disclaimer

This essay is not encouraging consumption of nicotine as a substance, but rather it is trying to give an objective point of view of the biological processes which occur in the brain of an individual consuming nicotine. Moreover, this essay describes the effects of nicotine on the DEVELOPED human brain, not the DEVELOPING human brain. This essay is also in no way medical advice. Furthermore, the subject who was interviewed was not and shall not be named as per the subject’s request to maintain anonymity. Lastly, this essay uses information obtained from studies performed on mice, if you find animal studies troubling, please do not read this essay. I thank you for your understanding.

Nicotine

Nicotine is a chemical produced by tobacco plants (nicotiana tabacum). In today’s society, nicotine is a widely socially accepted drug with anxiolytic and stimulant properties. However, nicotine was an adaptation of the tobacco plant which evolved to defend the tobacco plant from animals. Nicotine defends tobacco plants from predators in the following way. If the plant tissue is damaged, the already present concentration of nicotine rises. Nicotine ‘targets proteins which tell muscles to fire when they receive signals from the nervous system’ (National Geographic, 2013). At high enough doses of nicotine, these proteins cause the muscles of an organism to contract uncontrollably, leading to paralysis and death. This has negligible implications for humans, however, as overdosing on nicotine by smoking or vaping (most common ways of consuming nicotine) is extremely unlikely.

The main way humans consume nicotine is through smoking or vaping. Smoking relies on the incomplete combustion of tobacco leaves which produces smoke containing nicotine. This smoke is then inhaled by an individual. Once the smoke enters the lungs, nicotine diffuses into the bloodstream of the organism via the alveoli. Vaping relies on a similar mechanism, however, instead of combustion, it utilises heating and evaporation of a solution containing nicotine. After evaporation, the solution, now in a gaseous state, is inhaled by an individual. The vapour then enters the lungs and nicotine diffuses into the bloodstream of the organism through the alveoli. Once nicotine enters the bloodstream, it is taken to the brain, which it reaches within seven seconds of entering the lungs. Nicotine then diffuses through brain tissue reaching the prefrontal cortex.

The prefrontal cortex is the area of the brain which occupies the front part of the frontal lobe. This brain region has been implicated in performing many highly important functions. These include: planning complex cognitive behaviour, personality expression, moderating social behaviour and decision making. The prefrontal cortex is strongly linked with executive function. Executive function is the term given to encompass decision making, social control, prediction of future outcomes of current activities, expectations based on actions and working towards defined goals (this can include essential tasks such as eating when hungry or drinking when thirsty). When nicotine reaches the prefrontal cortex, nicotine stimulates the ‘pleasure centres’ of the brain. These ‘pleasure centres’ are involved in stimulating actions involved in routine and essential tasks, ranging from eating and drinking to work or school. With a consistent consumption of nicotine, the number of receptors involved in the pleasure response diminishes to compensate for regular stimulation. This is one of the reasons, which causes individuals to develop nicotine dependency.

Nicotine, acetylcholine and nAChRs

Nicotine is very similar in structure to a very important neurotransmitter: acetylcholine. This allows nicotine to bind to acetylcholine receptors in the brain. There are two types of acetylcholine receptor: nicotinic and muscarinic. These receptor types are named after the substances (other than acetylcholine) which bind to and stimulate the receptor. Nicotine for nicotinic acetylcholine receptors and muscarine for muscarinic receptors. Nicotinic acetylcholine receptors are pentameric ligand-gated ion channels, whereas muscarinic acetylcholine receptors are seven-helix G-protein coupled membrane proteins. In this essay, I will focus on nicotinic acetylcholine receptors as they are the type of receptor which is stimulated by nicotine. As I mentioned previously, nicotine is an agonist of acetylcholine (a molecule which can bind to a receptor and produce the effect of the neurotransmitter), its similarity in structure to acetylcholine allows it to bind to nicotinic acetylcholine receptors and mimic the effect of acetylcholine. The binding of nicotine to nicotinic acetylcholine receptors causes a change in the structure of the receptor, which opens the ionic channel for a few milliseconds. This channel is selective for cations (especially sodium and calcium), the opening of the channel lets the ions flow through and cause a brief depolarisation, producing the effect of the neurotransmitter and allowing the neuron to fire. The ionic channel then closes and the receptor becomes transitionally refractory to agonists, causing a state of desensitization. After a brief period of time, the receptor goes back to a state of rest, becoming sensitive to neurotransmitters and agonists once again. In the case of prolonged exposure to the agonist (nicotine) (even in small doses), the state of desensitization will last longer (long-term inactivation). This long-term inactivation of the receptors leads to reduced nicotine sensitivity in individuals who frequently consume nicotine.

Nicotine activates dopamine systems in the brain. Dopamine is a, widely known, neurotransmitter, which is directly responsible for mediating the pleasure response. The firing of dopaminergic neurons (stimulated by the binding of nicotine to nicotinic acetylcholine receptors) leads to the production of dopamine in the nucleus accumbens. The nucleus accumbens is found in a midbrain area called the basal forebrain. The nucleus accumbens has largely been associated with the reward and reinforcement circuit of the brain. The nucleus accumbens is a vital component of a major dopaminergic pathway in the brain called the mesolimbic pathway. The mesolimbic pathway has been found to be stimulated during rewarding experiences such as completing tasks, achieving goals, eating food, drinking water, taking drugs and having sex. After consuming nicotine, the levels of dopamine in the nucleus accumbens rise causing a ‘pleasure’ response.

However, the excessive and chronic activation of nicotinic acetylcholine receptors is compensated by the down-regulation of the number of active nicotinic acetylcholine receptors. In addition to nicotinic acetylcholine receptors, the excessive and chronic consumption of nicotine is also compensated by the down-regulation of the number of active dopamine receptors. This is because with excessive consumption of nicotine, there is an increase in the production of dopamine in the nucleus accumbens. This has to be compensated by decreased dopamine efficiency, which is achieved by decreasing the number of active dopamine receptors in the brain. Due to this reduction in the number of nicotinic acetylcholine receptors and dopamine receptors, an individual who frequently consumes nicotine needs to consume more nicotine every time to achieve the same ‘pleasurable’ effect. The decrease in the number of receptors also causes a less rewarding response to the completion of tasks which normally trigger the reward and reinforcement circuit. In other words, achieving goals, eating food, drinking water or having sex become less rewarding or pleasurable and the individual craves nicotine to compensate for the lack of pleasure. This causes individuals who regularly consume nicotine to struggle with focussing or completing daily or routine tasks without nicotine consumption for stimulation.

Nevertheless, after a brief period of abstinence from nicotine consumption (overnight for example), the concentration of nicotine and dopamine in the brain decreases and allows some of the receptors to regain their sensitivity. Unfortunately, the return of the receptors to an active state alter the level of neurotransmission in the brain and the frequent nicotine consumer feels uncomfortable. Sadly, this discomfort is often removed by the individual quenching their desire of ‘pleasure’ through nicotine consumption, creating a cycle. It is due to the recovery of the receptors’ activity that the first dose of nicotine is the most pleasurable of the day, as nicotine and dopamine sensitivity is increased overnight.

Further analysis of nicotinic acetylcholine receptors and their subtypes

The nAChR (nicotinic acetylcholine receptor) complex is composed of five subunits. In the mammalian brain there are as many as 9 α subunits (α2 to α10) and 3 β subunits (β2 to β4). The most common nicotinic acetylcholine receptor subtypes in humans are α4β2, α3β4 and α7 (homomeric {composed of only one type of molecule}).

The α4β2* (asterisk indicates possible presence of other subunits in the receptor) receptor subtype is the most common in the human brain and is believed to be the main receptor subtype mediating nicotine dependence.

A study has shown that knocking out the gene coding for the β2 subunit, in mice, eliminates all behavioural effects of nicotine, such that nicotine consumption no longer releases dopamine in the brain or maintains self-administration. Reinserting the β2 subunit gene into the ventral tegmental area of a β2 knockout mouse’s brain restored behavioural responses to nicotine.

The α4 subunit appears to be an important determining factor in an individual’s sensitivity to nicotine. In mice, a single point nucleotide mutation in the pore-forming region resulted in a receptor, which was hypersensitive to the effects of nicotine. This mutation made mice much more sensitive to nicotine induced reward and reinforcement behaviours and to the effects of sensitization and tolerance. In other words, these mice experienced more severe effects of nicotine, even at lower doses/concentrations, releasing high levels of dopamine even after consuming nicotine in low volumes/concentrations and quickly building up nicotine tolerance (lower nicotine sensitivity) even after consuming small volumes/concentrations of nicotine.

Lastly, the α3β4 nAChR receptor subtype is believed to mediate the cardiovascular effects of nicotine, which include the constriction of blood vessels, the increase in heartrate and the increase in blood pressure.

Practical example of the effects of nicotine (interview with a regular nicotine-consuming subject)

Summary of the information obtained from the interview with the subject:

· The subject has consumed nicotine regularly, for approximately 6 months.

· The initial effects felt by the subject after the first dose of nicotine he consumed, were felt for approximately 4 weeks after the subject started consuming nicotine regularly, after which the subject stopped feeling those effects after consuming a dose of nicotine.

· The subject consumes nicotine in different doses approximately every hour.

· The subject requires nicotine daily to properly concentrate and perform daily tasks.

· The subject stated he knows people who perform approximately 800 inhales, from a vape device, daily.

· The subject doesn’t experience the same effects from nicotine consumption as he did in the first 4 weeks of regular nicotine consumption. He can only experience those effects in the morning as some receptors recover and regain their nicotine sensitivity overnight.

From this interview, once can clearly see the subject has built up nicotine tolerance and is addicted to nicotine to the point where he craves it for performing routine daily tasks, as the repeated releases of dopamine in his brain, after the consumption of nicotine, have interfered with his reward and reinforcement pathway. One can also see how people desire increasingly large amounts of nicotine to feel the same effects they felt originally, at the start of their nicotine consumption, after they develop nicotine tolerance.

Most of these effects are linked to biological causes described in this essay.

References

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