Chemically Correct: Nicotine
by Andrew Novick
Stemming from the frequent observation that cigarette smokers tend to maintain lower body weights than their non-smoking counterparts, it is an intriguing idea that by using a nicotine product (such as a patch or gum), one could experience beneficial body composition effects while avoiding the carcinogenic dangers of cigarette smoke. In this issue of “Chemically Correct,” we take an in-depth look at the science behind one of the world’s most popular drugs.
Despite having similar stimulant qualities, nicotine has a distinct chemical structure from the phenylethylamines such as amphetamine and ephedrine. As opposed to these substances, nicotine is comprised of a pyridine ring connected to a pyrrolidine ring. There are two stereoisomers, (-)—nicotine being the active isomer and having the most affinity for nicotinic acetylcholine receptors (nAChr). Because nicotine is a weak base, it requires an alkaline environment to cross cell membranes (1). This explains the tobacco companies’ use of the controversial “ammonia chemistry” to boost cigarette impact. What makes the chemical structure of nicotine particularly fascinating (or not particularly so, depending how you look at it) is its resemblance to the acetylcholine (ACh) molecule. Because of ACh’s flexibility as a molecule, it can be configured to resemble nicotine. Both the pyridine nitrogen of nicotine and the keto oxygen of ACh are electron donors, while the positive charge of nicotine’s pyrrolidine nitrogen is similar to that of ACh’s nitrogen. Using computer graphics, the two molecules are even super-imposable (2).
Although the pharmacological effects of nicotine span across multiple receptor systems, the primary mode of action is elicited through nicotinic acetylcholine receptors (nAChr’s) (3). These receptors are divided into subunits: alpha2-alpha7 and beta2-beta4. It is known that nicotine binds with the highest affinity to the alpha4beta2 subunit, with an affinity approximately 13 times greater than ACh itself (4). While the alpha4beta2 subunit appears to be responsible for most of nicotine’s pharmacological effects—as determined by the use of genetically altered knockout mice—other subtypes may contribute as well. Particularly, alpha6 and beta3 impact sensitization and reinforcement of nicotine and alpha7 for nicotine’s anti-anxiety effect (5,6). But the pharmacology does not end there, as it’s not merely the nAChr subtype that does all the magic, but rather the cascade of events that occur once that particular subtype is triggered. This includes nicotine’s effects on other neurotransmitter systems.
Dopamine neurons in the ventral tegmental area and the substantia nigra have nAChr’s (particularly the alpha4beta2 and alpha3beta2 subunits) located on their nerve terminal membranes; when these receptors are stimulated, dopamine is secreted (7,8,9,10). Nicotine-evoked glutamate release can enhance such secretion due to the presence of NMDA receptors on the dopamine terminals (11, 12). However, despite such robust dopamine release, overflow of dopamine in areas of the brain like the nucleus accumbens is tightly controlled by the dopamine re-uptake system (13).
In order to overcome such an effect, a dopamine re-uptake inhibitor might prove very useful in potentiating nicotine’s dopaminergic action. But even without a re-uptake inhibitor, chronic use of nicotine by itself can increase dopamine overflow (14), and it is the NMDA receptors that are at least somewhat responsible for this sensitization mechanism (15). Another sensitization mechanism could be induced via nicotine’s upregulation of D1, D2, and D3 receptor mRNA (16,17).
A third mechanism by which dopamine release is sensitized by chronic nicotine treatment is through increased tyrosine hydoxylase expression. Nicotine increases tyrosine hydroxylase mRNA in the brain, as well as the actual tyrosine hydroxylase protein (18). Since tyrosine hydroxylase is the limiting factor in the conversion of L-tyrosine to dopamine, nicotine should result in increased synthesis of dopamine, assuming that L-tyrosine intake is adequate. And indeed, when L-tyrosine and nicotine are administered together in-vitro to human lymphocytes, synthesis of L-Dopa and norepinephrine commences. (19)
Monoamine Oxidase type B (MAO-B) is one of the enzymes responsible for degrading dopamine. It’s been known for some time that cigarette smoke has the capability of irreversibly inhibiting MAO-B (20). And while nicotine metabolite concentration is inversely proportional to MAO-B levels, nicotine itself does not inhibit MAO-B (21). Inhibition of MAO-B compounded by nicotine’s effects on dopamine release is probably one of the primary reasons why cigarettes are so rewarding and might add to their effect on body composition. In order to potentiate nicotine’s dopaminergic action without smoking, one could take the MAO-B inhibitor l-deprenyl. Also, since l-deprenyl has dopamine re-uptake blocking activity (22), it would provide a double mechanism for making nicotine’s effect on dopamine more pronounced.
As with dopamine, nicotine elicits noradrenaline secretion by binding to nAChr’s on noradrenergic neurons (3). Chronic nicotine administration will cause sensitization to its effects on NA release through increased expression of tyrosine hydroxylase (23,18). An indirect mechanism by which nicotine releases NA is through secretion of GABA (24). But that doesn’t make sense, you might assert, as GABA is an inhibitory neurotransmitter, right? Right; but by some unknown mechanism, activation of the GABA-A receptor stimulates NA release (25). Effects of nicotine on GABA will be discussed later.
Eventually, with chronic nicotine infusion, NA overflow is abolished, alluding to the possibility of receptor desensitization (3). Interestingly enough, this phenomenon might add to the reinforcing effects of nicotine use. Because NA release is a component of the response to stressful stimuli (26), halting NA overflow during a stressful situation would explain once more the calming effects of smoking (3, 27).
Nicotine increases the release of serotonin in various parts of the brain, though to a lesser extent than the catecholamines. Mixed evidence exists to whether serotonergic neurons express nAChr’s (28,29). Instead, nicotine induced 5-HT release has been attributed to stimulation of nicotinic receptors located in the dorsal raphe nucleus, and such stimulation appears to be directly responsible for the anxiolytic effects of nicotine (28,30). Serotonin release is controlled by several serotonergic-nicotinic interactions. One such example is that while stimulation of nicotinic receptors leads to 5-HT release (31), stimulation of 5-HT1A receptors will inhibit ACh release (33). Nicotine also increases serotonin transporter density—another inhibitory response to increased 5-HT release (34).
Since this is the case, one might wonder whether it would make sense to add an SSRI to a nicotine regimen? The answer is probably not; sensitization to nicotine’s stimulatory effects has been shown to be blocked by increasing 5-HT levels with the SSRI citalopram, known more commonly as Celexa (35). Finally, in food-deprived rats, tryptophan hydroxylase and serotonin synthesis is upregulated by nicotine (36). This is probably a very important mechanism by which nicotine’s exerts its appetite and weight-controlling effects.
Those who can remember their elementary school D.A.R.E seminar (“Drugs Are Really Expensive” was our favorite interpretation) might recall that nicotine fell under the category of “stimulants.” Such a designation baffled many of us given that most people report they get a calming effect from smoking. So which is it: a stimulant, or a relaxant? So far we’ve mentioned two mechanisms by which nicotine might exert anxiolysis: desensitizing the noradrenergic response to stress and via the increase of serotonin release. The third mechanism by which this may occur is GABAergic in nature. GABAergic neurons express nAChr’s (37), and when stimulated by nicotine increase GABA release (38). Nicotine also decreases the expression of the GABA-B1 receptor, which serves as an inhibitory mechanism on GABA release and thereby minimizes negative feedback (39).
Leptin and Neuropeptide Y
While evidence of increased dopaminergic and serotonergic activity does much to explain nicotine’s effects on body weight and food intake, such a discussion would not be complete without reference to the food intake regulators leptin and neuropeptide Y (NPY). A detailed discussion of these two peptides is beyond the scope of this article; I refer those interested in a comprehensive review of the physiology and function behind these hormones to Par Deus’ “Leptin: The Next Big Thing” series.
It would be wonderful if we could conclude that nicotine raises leptin levels, lowers neuropeptide Y levels, and in turn decreases appetite and body weight. Unfortunately, as is so often the case, nicotine’s effects on these hormones are unclear, and often conflictual. Several studies have demonstrated that smokers have lower leptin levels than non-smokers (40,41,42), while others have established that nicotine raises leptin concentrations (43). In obese rats, nicotine was able to lower bodyweight independent of its effects on leptin levels (44). Such contradictions are somewhat reconciled when we accept that nicotine doesn’t modulate leptin levels per se, but rather increases leptin receptor expression and sensitivity (44,45).
Similar confusions arise with Nicotine’s effects on NPY, as nicotine has been shown to both increase (45) and decrease (46) NPY expression in the hypothalamus. These contradictions are slightly easier to digest when we take into account the conditions in each study. NPY expression decreased under food deprivation and higher nicotine doses (12mg/kg in rats), while it increased with lower doses of nicotine (2-6mg/kg). Interestingly, despite the scenario in which NPY expression was increased, anorectic effects were still prevalent, which suggests that nicotine’s effects on NPY might be the product of a desensitization phenomenon (47).
From a hormonal perspective, nicotine is attractive to male athletes because it can lower estrogen levels by competitively inhibiting the aromatase enzyme (48-52). Also beneficial might be the observation that in dogs, nicotine inhibits 3 alpha-hydroxysteroid dehydrogenase, preventing metabolism of DHT to a less potent androgen (53). While theoretically, this would allow one to gain increased benefits from DHT, it might also potentiate DHT’s negative effects on the prostate and hairline.
Unfortunately, beyond individual inhibition of enzymes, nicotine and its metabolite cotinine appear to have a largely negative effect on steroidogenesis. Both nicotine and cotinine have been implicated in decreasing testosterone synthesis in rodent leydig cells (54,55). This decrease might be due to nicotine’s effect on increased ACTH release, leading to increased circulating coritcosteroids, which have been known to alter sex hormone synthesis. While the in vivo action of nicotine on sex steroids might be less pronounced (55), those using nicotine with the purpose of aromatase inhibition should be aware of its other effects on steroidogenesis.
nAChr Desensitization or Upregulation?
In most neurotransmitter systems, chronic administration of an agonist results in receptor desensitization; this is not surprising in view of the body’s tendency towards homeostasis. At first glance, nicotinic receptors appear to be no exception in this regard, given that overnight exposure to nicotine does indeed cause desensitization (59). However, with chronic nicotine exposure, it appears that nicotinic receptors, particularly the alpha4beta2 subtype, undergo what is termed “functional upregulation.” It is proposed that with chronic exposure, the number of high affinity versus low affinity receptors for nicotine actually increases, causing enhanced synaptic transmission of neurotransmitters (60). This upregulation could help elucidate nicotine’s sustained effect on body weight, as well as its addictive qualities.