Nicotinic acetylcholine receptor agonists

Acetylcholine (often abbreviated ACh) is a naturally produced ‘endogenous’ neurotransmitter within our [and many other animals’] bodies.  There are two main classes of acetylcholine receptor (AChR):

• nicotinic acetylcholine receptors (nAChR)
• and muscarinic acetylcholine receptors (mAChR).

They are named for the ligands used to activate the receptors.  Thus by definition Nicotine activates  - is an agonist of - the Nicotinic acetycholine receptors.

The main location of nicotinic AChRs is on muscle end plates, autonomic ganglia (both sympathetic and parasympathetic), and in the central nervous system. Nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression:

• muscle-type nicotinic receptors - found at the neuromuscular junction, receptors are either composed of α1, β1, δ, and γ or α1, β1, δ, and ε subunits
• neuronal-type nicotinic receptors - are various combinations of twelve different nicotinic receptor subunits: α2 through α10 and β2 through β4.  These receptors are combinations of these types thus for example alpha4beta2 or alpha6beta2

At the time of writing the various functions associated with all these receptors was still being investigated, however, it is known that

• The  3β4 receptor subtype is responsible for vasoconstriction of various soft muscle tissue – heart lungs muscles etc
• The α7 subtype is  involved in cognitive processes.
• The α4β2 subtype is involved in pain relief, and dopamine release as a by-product of agonist action.  Although the α4β2 subtype seems to be the primary receptor in pain relief, other receptors 3 , 4, and 7 subunits seem to be also present throughout the pain pathway.

Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle.

Nicotine is a trigger to the release of a number of other neurotransmitters.  When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many other chemical messengers including acetylcholine, norepinephrine, epinephrine, vasopressin, arginine, dopamine, autocrine agents, and beta-endorphins. This release of other neurotransmitters and hormones is responsible for many of nicotine's effects.

Positive Effects

Nicotine is essentially a stimulant and superficially would not appear to contribute to any form of hallucinations or  spiritual experience.  Its main actions in one-off and small doses are as follows and as you will see, its effects in some areas  - as long as it is not over used or ‘abused’  - are potentially beneficial:

• Stimulation - By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases the flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration.   

• Pain reduction -  pain is reduced by the increases of acetylcholine and beta-endorphin

• Increase alertness - The increases of acetylcholine and norepinephrine also appear to enhance alertness.

• Energy increase – nicotine causes  a release of glucose from the liver, theoretically helping energy levels and supposedly combating fatigue. 

• Appetite suppression  - Nicotine reduces the appetite and raises the metabolism, [some smokers lose weight as a result].  In its own way it thus also acts like an anorectic – reducing the need for food because we feel full of energy and not in need of food. The link with the dopamine system also helps in this respect.  

• Pleasure  - Dopamine release is a by-product of the agonist action at the  α4β2 subtype and dopamine is associated with pleasure and bliss.  As a purely flippant addition there is thus every reason to smoke a cigarette after sex as it will prolong the effects of orgasm, as dopamine is a key pleasure/reward neurotransmitter during sex.  We appear to have been engineered to be rewarded for reproducing!

• Cognitive ‘enhancement’ – nicotine theoretically boosts the rate at which we think and learn.  In the short term this can prove useful – the fight or flight situation for example. 

• Anti-depressant -  Nicotine has a form of anti-depressive effect via the dopamine release.  Anxiety is reduced by the increase of beta-endorphin.   Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in the brain reward systems.  Again, on a short term basis this can be useful – a sudden flush of dopamine to give us a sense of peace and bliss.

Its action is not at all dissimilar to the amphetamines and other stimulants.  There is not, however,  the same destruction of cells that take place in the use of other stimulants.  The  α4β2 receptors, for example, account for about 90% of the nAChRs in the human brain.  When chronically exposed to nicotine or other nicotine agonists there is an  increase in density of α4β2 receptors which is the opposite of what usually happens when receptors are chronically exposed to their agonists.  Increase can of itself be highly dangerous in those with an adequate supply, however, it can simply lead to cell proliferation – cancer. 

Thus nicotine is a natural compound which if used infrequently performs some useful functions. 

For the ill, it may well be a potential lifeline.  Patients with Alzheimer’s disease suffer a dramatic reduction in hippocampal and cortical nicotine-receptor density. There is also a link between epilepsy and the nicotinic receptors.  Significant nicotinic-receptor loss also occurs in Parkinson’s disease , and postmortem studies in schizophrenics show a decrease in the number of α7 nicotinic receptors in the brain . Nicotine is an agonist of the α7 nicotinic receptor.  There is thus a possibility that nicotine regularly administered to  those with Alzheimer’s disease, Epilepsy, Parkinson’s disease and Schizophrenia may help.  There may also be a case for helping manic depressives during their depressive phases.

Negative effects

Used regularly and frequently   - what we might think of as ‘abuse’  - by the well, nicotine can be  highly destructive and addictive.  This tends to be borne out by research that has found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent. Research on nicotine as administered through a patch or gum is ongoing, but I can see no reason why the results should be any different – nicotine is nicotine – what you have gained is freedom from the tars of the cigarrettes, that is all.

“For the nonselective nAChR agonist nicotine, analgesic, anxiolytic and cytoprotective properties are seen, as well as beneficial effects in Alzheimer's disease, Parkinson's disease, Tourette's syndrome and certain forms of epilepsy and schizophrenia. However, the therapeutic use of nicotine is hindered by its adverse effects on the cardiovascular and gastrointestinal systems as well as its addictive potential. ……. A prerequisite for the development of selective drugs is the identification and pharmacological characterization of the various receptor subtypes, and the determination of their precise subunit composition and physiological function(s)”.

Thus if we look at the problems of over-use we see that………..

• Stimulation – the constant increase in heart rate, blood pressure and respiration affect the heart and can lead to heart disease.   

• Increase alertness - long term use and over –use can lead to what is termed ‘Akathisia’, or acathisia  -  a syndrome characterised by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless.  Unscientifically we might term this ‘the jitters’.

• Energy increase – Long term use causes  higher blood glucose levels.  This is why many smokers get diabetes

• Increase in metabolism  - Nicotine raises the metabolism.  This is the reason why, when people stop smoking they put on weight – they can taste their food more – true, but their appetite for food returns because their body adapts to needing energy, because the metabolism has slowed.  The increase in metabolic rate has its own consequences in the long term – we age faster - for example the catalysis of retinal molecules, implicates nicotine in age-related macular degeneration. It may also  lead to the premature ageing of the skin

• Pleasure  - Dopamine is associated with pleasure and bliss.  But it is a major factor in the addictive properties of nicotine.  The dopamine receptors adapt to floods of dopamine in time and adjust to balance the over activity – thus we need to smoke more to get the same ‘hit’. 

• Cognitive ‘enhancement’ – nicotine theoretically boosts the rate at which we think and learn.  But like amphetamines, the enhancement is illusory, as we may think faster, but we don’t necessarily reason better and longer term we may become deluded that we are actually clever or more intelligent than others

• Anti-depressant -  long term not only can we not live with bliss all the time, the body adjusts [as we have seen] to reduce the dopamine back to normal and balance, which is why nicotine is addictive and why people need to keep on smoking more to get the same effects.  It is also why they are so agonisingly sad and depressed when they try to quit.

Observations

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• Nicotine patches in Alzheimer's disease: pilot study on learning, memory, and safety
• Nicotine treatment of mild cognitive impairment A 6-month double-blind pilot clinical trial