Nicotine: helping those who help themselves?
By John A. Rosecrans
Copyright 1998 Chemcistry and Industry Magazine
July 6, 1998
One of the most frequently asked questions in tobacco research is 'why do people smoke?' This is a difficult question to answer. Tobacco displays the qualities of an addictive substance, and it is likely that nicotine, the main active chemical in tobacco, plays an important role in people's addiction to smoking. The dependency induced by tobacco is curious because, despite the well-documented health risks of lung and heart disease, people consciously choose to continue smoking. Indeed, many alcoholics and cocaine and heroin addicts claim that stopping smoking was harder than breaking their other drug dependency.
A major characteristic of nicotine dependence is the behaviour associated with tobacco use, especially for cigarette smokers. Smoking is often intertwined with environmental and internal cues (for example smoking after a meal, or when the telephone rings). This behavioural element makes giving up smoking even harder.
As more people have begun to question why people choose to use tobacco, it has become evident that nicotine may have beneficial effects that are 'therapeutic' rather than addictive. These more positive effects are, I believe, essential to why some people use nicotine. In other words, humans may learn that when they smoke they get something good from it, and this may explain why they continue to smoke in spite of the possible health consequences.
Addiction or self-help?
Tobacco use is similar to other drug dependencies, such as cocaine or alcohol addiction. But is nicotine really used just to get high? Research conducted by the US National Institutes of Drug Abuse has shown that nicotine administered intravenously in large doses of 13mg produced effects that were viewed as positive in some human subjects. 1 In addition, nicotine will be self-injected by rats, one of the hallmarks of a chemical that will induce dependence in humans.2
We have investigated smokers' abilities to detect the difference between two cigarettes with different nicotine concentrations (1.3 or 0.3mg nicotine/cigarette).3 The subjects learned to discriminate between the cigarettes, but had difficulty explaining how they knew the differences between the cigarettes. The most distinguishing characteristic was differences in hoarseness at the back of the throat; however, the smokers were not always correct when they used this as a guide for telling one cigarette from another. On the other hand, the two different levels of nicotine caused very clear differences in the subjects' responses to a visual stimulus.4 This indicates that the smokers were being altered neurophysiologically, but couldn't translate this effect into subjective terms.
This study gives a new view of a smoker. The subjects did not appear to be affected behaviourally, nor were they 'high'. Each smoker had difficulty explaining why they could discriminate between doses of nicotine in similar tasting cigarettes, which suggests that the nicotine was inducing a more subtle pharmacological effect.
Research in our laboratory using rats has indicated that nicotine has an unusual quality: it tends to have a 'normalising' effect on behaviour. Highly aroused rats tend to calm down, while under-aroused rats tend to be stimulated.4 The nicotine's effects also appear to be long-lasting - the rats respond differently weeks after receiving a dose of nicotine. But can the effects on rats be translated into human terms?
The average smoker inhales about 20 cigarettes a day, which averages out as about 200220 puffs/day, or about 80,000 puffs/year. Put another way, a smoker has to puff on a cigarette an average of every 4.8 min during their waking hours to maintain this behaviour. It is interesting that, whether a person continues to smoke because of behavioural conditioning or the drug itself, a level of nicotine is present in the brain for most of the smoker's waking hours. Perhaps a person can learn that having a brain nicotine level is beneficial to them and may even serve a therapeutic purpose.
Pain relief
One reason why humans use tobacco may be for pain relief. Work by Mario Aceto and Billy Martin at the Virginia Commonwealth University, who showed that nicotine could act as an analgesic in mice and rats,6 has been verified by Ovide Pomerleau and colleagues at the University of Michigan, who were among the first to suggest that nicotine acts as an analgesic in humans.7 The way in which nicotine achieves this is not clear, although it may have some effects on the opiate system. Nicotine appears to induce analgesia by acting on internal systems that work via opiate receptors, as demonstrated by the ability of naloxone (which selectively blocks opiates) to block nicotine's effects in mice.6 Interestingly, naloxone doesn't block nicotine's effects in rats, while mecamylamine (a compound that specifically blocks the action of nicotine) blocks the effects in both mice and rats.
More recently, the frog neurotoxin epibatidine (a chemical relative of nicotine) proved to be a significantly better pain reliever than nicotine (more than 50 times as potent).8 Epibatidine is also blocked by both mecamylamine and naloxone, providing further evidence that these chemicals are linked to the opiate system. Abbott Laboratories has been studying a variety of nicotine analogues, one of which (ABT-594) is an extremely potent painkiller, and hopes to test these compounds in humans (see Figure 1).9
Anxiety and depression
Several researchers have observed that many smokers claim they smoke to relieve stress or anxiety.10 Naomi Breslau and co-workers at the Henry Ford Hospital, Detroit, on the other hand, suggest that many smokers use tobacco to relieve an underlying depression. They evaluated levels of depression in several thousand members of a health maintenance organisation and concluded that there is a powerful correlation between smoking rate and depression.11 So, do people learn to smoke and continue to use tobacco to relieve an underlying depression or anxiety?
Research has shown that those with depression have a more difficult time stopping smoking, and that some develop depressive symptoms after nicotine tobacco use.12 Antidepressants such as Wellbutrin, or, when used to treat nicotine dependence, Zyban, appear to help certain smokers stop using nicotine. These drugs could be substituting for nicotine's antidepressant effects in a way not dissimilar to a nicotine patch.
Other research has provided support for nicotine's role in depression. In one study, non-smoking depressed patients were given transdermal nicotine patches (17.5mg) and their sleep patterns and mood were evaluated.13 The amount of REM (rapid eye movement), which is usually less in depression, was increased in these depressed patients. They also showed a short term improvement in mood. Interestingly, the sleep of normal volunteers was disrupted, indicating that nicotine had a different, more positive effect in the depressed.
Other workers have suggested that the beneficial effects of nicotine may in part depend on genetic factors controlling the function of the neurotransmitter dopamine. They found a significant statistical interaction between a dopamine receptor gene (DRD4 genotype) and depression in a population of 231 smokers.14 This work also infers that nicotine may be acting at central dopamine nerve cells, a neurotransmitter system associated with behavioural reward systems.15 Researchers such as George Koob and co-workers at the Scripps Research Institute also point out the similarities between depression and drug dependence in general, and the fact that man may self-medicate with a variety of drugs to relieve depression. Furthermore, this research also suggests that these drugs may act on a variety of brain neurotransmitters such as serotonin and dopamine, chemicals involved in many psychiatric syndromes including depression and schizophrenia.16
Clearly, nicotine replacement could be beneficial in smokers who are depressed, as these studies have shown. Furthermore, there may also be a role for using the nicotine patch in depressed non-smokers.13 However, much research needs to be conducted under a variety of conditions before the possible use of nicotine patches in depression can be implemented. Overall, these studies indicate a link between nicotine and the 'positive reward systems' such as dopamine-containing nerve cells in the brain. More importantly, as nicotine itself acts on receptors for another neurotransmitter, acetylcholine, they provide evidence for the role of these receptors in controlling behaviour.
Attention deficit hyperactivity disorders
Adults and adolescents with attention deficit hyperactivity disorders (ADHD) smoke more frequently than normal individuals.17 Ed Levin and co-workers at Duke University suggested that ADHD sufferers may be using nicotine to treat their disorder. To test this hypothesis, smokers and non-smokers with ADHD were given nicotine patches (7 or 21mg/day). The researchers found a significant improvement in concentration, vigour and performance in measures of attention and timing.17
In a second study, these workers conducted a similar investigation on smokers and non-smokers with ADHD. They found a similar effect, which appeared to be independent of whether or not the subject was a smoker.18 Much as with the rats described earlier, nicotine appears to be able to normalise arousal levels, so that the ADHD individual can maintain focus and attention when the brain is receiving too much information (high arousal) or possibly not enough information (low arousal).
Schizophrenia
Most counsellors working in a psychiatric hospital will tell you that schizophrenics smoke an awful lot. This may be because nicotine might be acting at the brain dopamine system, one of the brain neurochemical systems that appears to be the cause of some schizophrenias (most antipsychotic drugs work by calming a hyperactive dopamine system). Another possibility is that nicotine may relieve the side effects of the drugs used to treat the disorder, or even reduce some negative effects of the schizophrenia itself. There is some evidence to support this concept.
In addition, several psychiatrists and doctors have observed major psychotic events associated with tobacco cessation, which has been interpreted as nicotine withdrawal. Some health professionals have suggested, on the other hand, that these individuals may smoke to reduce the symptoms of behavioural disorder.
So, which came first, the behavioural disorder or chronic tobacco use? While this is difficult to answer, recent research by Robert Freedman, Sheri Leonard and co-workers at the University of Colorado has shown that schizophrenics process sensory information differently to 'normal' people.19, 20 Unlike a schizophrenic, if a non-schizophrenic is startled by an auditory or visual stimulus, they quickly become accustomed to it if it is repeated. Research has found that when schizophrenics are given nicotine, via a patch or gum, they can cope with auditory or visual stimuli in much the same way as 'normal' people. This supports the theory that nicotine is acting in a therapeutic manner via receptors associated with the sensory habituation.
In addition, schizophrenics have fewer nicotine receptors in their brains than normal people,21 and the expression of one of the nicotine receptor subunits (the alpha-7 unit) is also reduced in these subjects. These studies may have provided us with some important clues about the central workings of schizophrenia. First, the findings indicate that a nicotinic receptor may be at fault in at least one aspect of this behavioural syndrome - the inability of the schizophrenic to process certain kinds of sensory information. Second, the work also indicates that there may be a genetic link involving the inheritance of the alpha-7 nicotinic receptor gene from one generation to another.19 All of this provides important clues as to why schizophrenics smoke, and may be a rationale for using nicotine (nicotine patch or gum) in non-smokers with these abnormal behavioural symptoms. Again, much careful research is needed before we can make the jump to using nicotine in the clinic.
Tourette's syndrome
Tourette's syndrome is a disorder characterised by uncontrolled speech and limb movement. Sufferers, who tend to be young adolescents, often curse and swear uncontrollably. The cause of Tourette's is still unknown, but it appears to involve problems in dopamine transmission. The syndrome is difficult to control medically, especially in patients who are resistant to drugs containing typical antipsychotic agents such as haldol or chlorpromazine.
Paul Sanberg at the University of South Florida gave a nicotine patch or gum (7mg or 2mg, respectively) to an adolescent Tourette's sufferer. The nicotine reduced the movement and speech syndrome within minutes. Interestingly, the nicotine patch attenuated the movement disorder for several days after a single application. While nicotine appears to be effective in treating Tourette's syndrome, these researchers suggest that the best use of the nicotine patch at this point is as an adjunct to antipsychotic treatment (rather than using nicotine alone), until more research is conducted.
Nicotine's success here may be a result of its unusual mode of action. When it binds to the nicotine receptors in the brain (actually members of the family of receptors sensitive to the neurotransmitter acetylcholine) it first activates them and then desensitises them, effectively turning them off (see Figure 2).22 In addition, the ability of nicotine to activate or desensitise a receptor may also depend on the receptor's activity at the time the nicotine is administered or gets to the receptor. Thus, nicotine may tend to activate the receptor if it is inactive (as it is if there is little acetylcholine present at the receptor). On the other hand, nicotine may deactivate (desensitise) the receptor when it is very active because of a high level of acetylcholine at the receptor. Thus, nicotine may be acting to normalise the receptor in a way analogous to the observations of nicotine's action on 'high' or 'low' aroused rat behaviour.
If we take this hypothesis a little further and assume that Tourette's syndrome results from an overproduction of a neurotransmitter such as dopamine, then nicotine could be acting to stabilise the dopamine nerve cell by its ability to desensitise nicotinic receptors located on it.23 Stabilisation or shutting down an overproduction of dopamine could explain why nicotine is working in this syndrome, assuming dopamine is the culprit.
More recent research by the same group, has shown that mecamylamine (which blocks the action of nicotine) is also effective in reducing Tourette's symptoms.24 At first glance, this drug would not be expected to have this effect, as it would act at the same nicotinic receptor - in other words, the receptor would have to be activated to get the same effect. The reason mecamylamine is working, however, is the fact that it is not inducing nicotine blockade by acting at the receptor, but can block nicotine by acting directly in the channel - clogging it up (see Figure 2). Thus, mecamylamine is having the same effect as nicotine but is working at a different site. This is an important study as it provides additional support for the contention that nicotine (as well as mecamylamine) is stabilising an overactive nerve cell which releases dopamine.
Parkinson's disease
Parkinson's disease (PD) is another condition that involves exaggerated movements, tics and rigidity. It appears to be the result of a declining dopamine nerve cell system. Once, this disease was thought to be caused by viruses, but we now realise that environmental toxicity and/or the ability of our brains to make neurotoxic substances such as 6-hydroxydopamine25 may cause nerve cells to degenerate, reducing the amount of dopamine that can be made and released. The main treatment for this condition is the administration of the dopamine precursor l-dopa, which helps the brain synthesise more dopamine.
The role of nicotine in PD has evolved over the past 20 years. Early reports indicated that smokers were less likely to develop the disease.26 While some work suggested that this relationship was due to differences that might arise from factors such as selective mortality rather than any specific effect of tobacco or nicotine,27 other research evaluated much of the evidence further and concluded that the effect is real - nicotine did reduce the onset of PD.28
Following the initial suggestion that nicotine might be protective in the development of PD, workers such as Karl Fagerstrom at Pharmacia Research Laboratories in Helsingborg, one of the developers of nicotine gum, observed that the symptoms of PD were relieved by the administration of nicotine gum or patch.29 This work has been repeated in other laboratories30 with the suggestion that nicotine may somehow be acting on dopamine nerve cells destroyed by PD.31 In other words, nicotine is most likely either increasing the central availability of dopamine or preventing the loss of neuronal dopamine at brain area sites important for movement.
However, this concept may have been partially compromised by data suggesting that there may be other chemical(s) in tobacco smoke that also produce therapeutic benefits in PD sufferers.32 This has become more evident as the neurotoxic mechanisms underlying PD have been uncovered. Recent work has shown that levels of the enzyme monamine oxidase B (MAO B), which has been implicated in PD, are 40% lower in smokers than in non-smokers, but this32 and other studies33 suggest that chemicals other than nicotine in tobacco smoke may be responsible for the lowered level of MAO B. It is now evident that MAO B may be responsible for the synthesis of the neurotoxins which may lead to PD. The relationship between smoking and PD appears to be quite complex, but work with nicotine patches and the smoking studies indicate that nicotine and/or some other chemical in tobacco smoke may provide some benefits to the PD sufferer.34
Several studies examining the nicotine patch as a treatment for PD have produced some positive outcomes. In addition, quite a few drug companies,35 such as SIBA Neurosciences in LaJolla,36 are developing nicotine analogues as PD therapeutics, and have had some success in monkeys. While nicotine does appear to help protect against PD, further investigation of the other substances in smoke that may be involved needs to be done.
Alzheimer's disease
Nicotine may also have a role to play in the severe dementia of Alzheimer's disease (AD). The number of nicotine receptors in the brain is reduced by 4060% in AD patients37-39 (a similar effect is seen in select PD patients,40 linking these two neurological syndromes together in relation to nicotine). Workers such as Paul Newhouse and colleagues at the University of Vermont have observed that nicotine, when administered as a patch, may have some benefit as a cognitive enhancer in AD as well.41
The relationship between smoking and AD is not that clear. There is some suggestion of a link between smoking and a lowered risk of AD,41 but this relationship has not always held up. Neuroscience is just beginning to evaluate the many causes of AD from genetics to immunological mechanisms. The one thing we do know about AD is that nicotine receptors in the brain are destroyed, and these somehow play a role in cognition. Abbott Laboratories has invested much in the search for cognitive enhancers and has developed one nicotine analogue, ABT-418 (see Figure 1), which may hold some promise in this area.35
The drug of choice?
The reasons behind a smoking habit are clearly more complex than they seem at first sight. For example, a person may smoke in response to social and environmental cues, or in order to avoid the negative effects associated with giving up. On the other hand, the smoker may be using tobacco as self-medication to relieve some underlying behavioural and/or neurological problem.
The nicotine receptors in the brain appear to have a very important role in overall brain function. These receptors are actually made up of a variety of subunits, and the number of combinations is enormous. This variety appears to be related to the genetics of a specific individual who may then choose to use nicotine via tobacco to modulate one of these receptors, which in turn will alter behaviour and sensory input.
It is interesting to note that habitual nicotine use actually increases the number of nicotine receptors in the brain, probably because of the drug's receptor desensitising effects.42 The increase seems to reflect an adaptive capacity (acute and chronic tolerance) in the brain, which may be related to how and why nicotine can exert some benefits in constant tobacco use.23
The wide spectrum of nicotine's therapeutic potential is only now being discovered and there may be other effects not yet found; for example, data are now accumulating that nicotine may have beneficial effects in ulcerative colitis.43
Many people who use tobacco, including smokers, do so because of some potential therapeutic benefit they receive, such as to relieve depression, schizophrenia or pain. While this appears to be one reason why some people use tobacco, we should not forget that many people engage in this behaviour for other reasons, such as boredom or just to do something that is now 'antisocial'. The future for developing nicotine as a therapeutic agent, or an adjunct to other therapies, using a safe delivery system is relatively good. One of the difficulties with a chemical such as nicotine is that it has been thought of as a 'dirty drug', or 'demon drug' like heroin, which makes people addicts. We first need to pull away from this concept of demonism and treat nicotine and its analogues like any other drug. If you were to ask a clinician whether he or she would use nicotine or heroin to help the patient, the answer would be 'give the drug'. Most clinicians are objective about the drugs they use so long as they help the patient.
Another problem with future research on nicotine concerns its potential addictive properties, and how such a compound should be marketed. Pharmaceutical houses are very sensitive to this problem and might stay away from a nicotine research programme because the drugs they would find could be perceived as addictive. Nicotine is also not high on the list of priorities of things to do when research resources are at a low ebb. Problems such as AIDS in the world or cocaine in the US have much higher priorities. Thus, except for a couple of companies mentioned here, we may never establish large research programmes to develop new chemicals that are nicotine-like, or further evaluate the therapeutic potential of nicotine. This is frustrating to many researchers in this area, but somehow many will continue, and we will eventually learn what nicotine's full therapeutic potential is regardless of the environment.
References
1. Henningfield, J.E., & Goldberg, S.R., Pharmacol. Biochem. Behav., 1988, 30, 221-6; Henningfield, J.E., Cohen, C., & Slade, J.D., Br. J. Addict., 1991, 86, 565-9
2. Rose, J.E., & Corrigal, W.A., Psychopharmacology, 1997, 130, 28-40
3. Kallman, N.M., Kaliman, M.J., Harry, G.J., Woodson, P.P., & Rosecrans, J.A., in 'Drug discrimination application in CNS pharmacology', (Eds F.C. Colpaert & J.L. Slangen), Amsterdam: Elsevier Biomedical Press, 1982, 211-18
4. Woodson, P.P., et al, Pharmacol. Biochem. Behav., 1982, 17, 915-20
5. Rosecrans, J.A., Behav. Genet., 1995, 25, 187-96
6. Tripathi, H.L., Martin, B.R., & Aceto, M.D., J. Pharmacol. Exp. Therap., 1982, 221, 91-6
7. Pomerleau, O.F., Turk, D.C., & Fertig, J.B., Addict. Behav., 1984, 9, 265-71
8. Bado, B., & Daly, J.W., Mol. Pharmacol., 1994, 45, 563-70
9. Bannon, A.W., et al, Science, 1998, 279, 77-81
10. Kassel, J.D., & Shiffman, S., Health Psychol., 1997, 16, 359-68
11. Bressau, N., Peeterson, E.L., Schultz, L.R., Chilcoat, H.D., & Andreski, P., Arch. Gen. Psychiat., 1998, 559, 161-6
12. Glassman, A.H., et al, JAMA, 1990, 264, 1546-9
13. Slin-Pascual, R.J., de la Fuente, J.R., Galicia-Polo, L., & Drucker-Colin, R., Psychopharmacology, 1995, 121, 476-9
14. Lerman, C., et al, Health Psychol., 1998, 17, 56-62
15. Rosecrans, J.A., Chem. Ind., 1994, 221-4
16. Markou, A., Kosten, T.T., & Koob, G.F., Neuropsychopharmacol., 1998, 18, 135-74
17. Conners, C.K., et al, Psychopharmacol. Bull., 1996, 32, 67-73
18. Levin, E.D., et al, Psychopharmacology, 1996, 123, 55-63
19. Freedman, R., et al, Proc. Natl Acad. Sci. USA, 1997, 94, 587-92
20. Leonard, S., et al, Schizophr. Bull., 1996, 22, 431-45
21. Freedman, B., Hall, M., Adler, L.E., & Leonard, S., Biol. Psychiat., 1995, 38, 22-33
22. Marks, M.J., Busch, J.B., & Collins, A.C., J. Pharmacol. Exp. Therap., 1983, 226, 554-64
23. Rosecrans, J.A., & Karan, L., J. Subst. Abuse Res., 1992, 10, 161-70
24. Shytle, R.D., Silver, A.A., & Sanberg, P.R., Poster presented at the International Behavioural Neuroscience Society Annual Meeting, 11-14 June 1998, Richmond, VA, US
25. Jellinger, K., Linert, L., Kienzl, E., Herlinger, E., & Youdim, M.B.H., J. Neural. Transm., 1995, 46(Suppl), 297-314
26. Baron, J.A., Neurology, 1986, 36, 1490-6
27. Haack, D.G., Baumann, R.J., McKean, H.E., Jameson, H.D., & Turbek, J.A., Am. J. Epidemiol., 1981, 114, 191-200
28. Morens, D.M., et al, ibid, 1996, 144, 400-4
29. Fagerstrom, K.O., Pomerleau, O., Giordani, B., & Stelson, F., Psychopharmacology, 1994, 116, 117-19
30. Clemens, P., Baron, J.A., Coffey, D., & Reeves, A., ibid, 1995, 117, 253- 6
31. Kirch, D.G., Alho, A.M., & Wyatt, R.J., Cell. Mol. Neurobiol., 1988, 8, 285-91
32. Fowler, J.S., et al, Nature, 1996, 379, 733-6
33. Mendez-Alvarez, E., Soto-Otero, R., Sanchez-Sellero, I., & Lopez-Rivadulla Lomas, M., Life Sci., 1997, 60, 1719-927
34. Shytle, R.D., Borlongan, C.V., Cahill, D.W., & Sanberg, P.R., Med. Chem. Res., 1996, 6, 555-61
35. Brioni, J.D., Decker, M.W., Sullivan, J.P., & Arneric, S.P., Advan. Pharmacol., 1997, 37, 153-214
36. Menzaghi, F., Whelan, K.T., Risbrough, V.B., Rao, T.S., & Lloyd, G.K., J. Pharmacol. Exp. Therap., 1997, 280, 393-401
37. Flynn, D.D., & Mash, D.C., J. Neurochem., 1986, 47, 1984-54
38. Nordberg, A., et al, J. Neural Transm., 1990, 2, 215-24
39. Whitehouse, P.J., et al, Arch. Neurol., 1988, 45, 722-4
40. Perry, E.K., et al, J. Neurol. Neurosurg. Psychiat., 1987, 50, 806-9
41. Newhouse, P.A., Potter, A., & Levin, E.D., Drugs Aging, 1997, 11, 206-28
42. Balfour, D.J., & Fagerstrom, K.O., Pharmacol. Therap., 1996, 72, 51-81
43. Kennedy, L.D., Ann. Pharmacotherap., 1996, 30, 1022-3
By John A. Rosecrans
Copyright 1998 Chemcistry and Industry Magazine
July 6, 1998
One of the most frequently asked questions in tobacco research is 'why do people smoke?' This is a difficult question to answer. Tobacco displays the qualities of an addictive substance, and it is likely that nicotine, the main active chemical in tobacco, plays an important role in people's addiction to smoking. The dependency induced by tobacco is curious because, despite the well-documented health risks of lung and heart disease, people consciously choose to continue smoking. Indeed, many alcoholics and cocaine and heroin addicts claim that stopping smoking was harder than breaking their other drug dependency.
A major characteristic of nicotine dependence is the behaviour associated with tobacco use, especially for cigarette smokers. Smoking is often intertwined with environmental and internal cues (for example smoking after a meal, or when the telephone rings). This behavioural element makes giving up smoking even harder.
As more people have begun to question why people choose to use tobacco, it has become evident that nicotine may have beneficial effects that are 'therapeutic' rather than addictive. These more positive effects are, I believe, essential to why some people use nicotine. In other words, humans may learn that when they smoke they get something good from it, and this may explain why they continue to smoke in spite of the possible health consequences.
Addiction or self-help?
Tobacco use is similar to other drug dependencies, such as cocaine or alcohol addiction. But is nicotine really used just to get high? Research conducted by the US National Institutes of Drug Abuse has shown that nicotine administered intravenously in large doses of 13mg produced effects that were viewed as positive in some human subjects. 1 In addition, nicotine will be self-injected by rats, one of the hallmarks of a chemical that will induce dependence in humans.2
We have investigated smokers' abilities to detect the difference between two cigarettes with different nicotine concentrations (1.3 or 0.3mg nicotine/cigarette).3 The subjects learned to discriminate between the cigarettes, but had difficulty explaining how they knew the differences between the cigarettes. The most distinguishing characteristic was differences in hoarseness at the back of the throat; however, the smokers were not always correct when they used this as a guide for telling one cigarette from another. On the other hand, the two different levels of nicotine caused very clear differences in the subjects' responses to a visual stimulus.4 This indicates that the smokers were being altered neurophysiologically, but couldn't translate this effect into subjective terms.
This study gives a new view of a smoker. The subjects did not appear to be affected behaviourally, nor were they 'high'. Each smoker had difficulty explaining why they could discriminate between doses of nicotine in similar tasting cigarettes, which suggests that the nicotine was inducing a more subtle pharmacological effect.
Research in our laboratory using rats has indicated that nicotine has an unusual quality: it tends to have a 'normalising' effect on behaviour. Highly aroused rats tend to calm down, while under-aroused rats tend to be stimulated.4 The nicotine's effects also appear to be long-lasting - the rats respond differently weeks after receiving a dose of nicotine. But can the effects on rats be translated into human terms?
The average smoker inhales about 20 cigarettes a day, which averages out as about 200220 puffs/day, or about 80,000 puffs/year. Put another way, a smoker has to puff on a cigarette an average of every 4.8 min during their waking hours to maintain this behaviour. It is interesting that, whether a person continues to smoke because of behavioural conditioning or the drug itself, a level of nicotine is present in the brain for most of the smoker's waking hours. Perhaps a person can learn that having a brain nicotine level is beneficial to them and may even serve a therapeutic purpose.
Pain relief
One reason why humans use tobacco may be for pain relief. Work by Mario Aceto and Billy Martin at the Virginia Commonwealth University, who showed that nicotine could act as an analgesic in mice and rats,6 has been verified by Ovide Pomerleau and colleagues at the University of Michigan, who were among the first to suggest that nicotine acts as an analgesic in humans.7 The way in which nicotine achieves this is not clear, although it may have some effects on the opiate system. Nicotine appears to induce analgesia by acting on internal systems that work via opiate receptors, as demonstrated by the ability of naloxone (which selectively blocks opiates) to block nicotine's effects in mice.6 Interestingly, naloxone doesn't block nicotine's effects in rats, while mecamylamine (a compound that specifically blocks the action of nicotine) blocks the effects in both mice and rats.
More recently, the frog neurotoxin epibatidine (a chemical relative of nicotine) proved to be a significantly better pain reliever than nicotine (more than 50 times as potent).8 Epibatidine is also blocked by both mecamylamine and naloxone, providing further evidence that these chemicals are linked to the opiate system. Abbott Laboratories has been studying a variety of nicotine analogues, one of which (ABT-594) is an extremely potent painkiller, and hopes to test these compounds in humans (see Figure 1).9
Anxiety and depression
Several researchers have observed that many smokers claim they smoke to relieve stress or anxiety.10 Naomi Breslau and co-workers at the Henry Ford Hospital, Detroit, on the other hand, suggest that many smokers use tobacco to relieve an underlying depression. They evaluated levels of depression in several thousand members of a health maintenance organisation and concluded that there is a powerful correlation between smoking rate and depression.11 So, do people learn to smoke and continue to use tobacco to relieve an underlying depression or anxiety?
Research has shown that those with depression have a more difficult time stopping smoking, and that some develop depressive symptoms after nicotine tobacco use.12 Antidepressants such as Wellbutrin, or, when used to treat nicotine dependence, Zyban, appear to help certain smokers stop using nicotine. These drugs could be substituting for nicotine's antidepressant effects in a way not dissimilar to a nicotine patch.
Other research has provided support for nicotine's role in depression. In one study, non-smoking depressed patients were given transdermal nicotine patches (17.5mg) and their sleep patterns and mood were evaluated.13 The amount of REM (rapid eye movement), which is usually less in depression, was increased in these depressed patients. They also showed a short term improvement in mood. Interestingly, the sleep of normal volunteers was disrupted, indicating that nicotine had a different, more positive effect in the depressed.
Other workers have suggested that the beneficial effects of nicotine may in part depend on genetic factors controlling the function of the neurotransmitter dopamine. They found a significant statistical interaction between a dopamine receptor gene (DRD4 genotype) and depression in a population of 231 smokers.14 This work also infers that nicotine may be acting at central dopamine nerve cells, a neurotransmitter system associated with behavioural reward systems.15 Researchers such as George Koob and co-workers at the Scripps Research Institute also point out the similarities between depression and drug dependence in general, and the fact that man may self-medicate with a variety of drugs to relieve depression. Furthermore, this research also suggests that these drugs may act on a variety of brain neurotransmitters such as serotonin and dopamine, chemicals involved in many psychiatric syndromes including depression and schizophrenia.16
Clearly, nicotine replacement could be beneficial in smokers who are depressed, as these studies have shown. Furthermore, there may also be a role for using the nicotine patch in depressed non-smokers.13 However, much research needs to be conducted under a variety of conditions before the possible use of nicotine patches in depression can be implemented. Overall, these studies indicate a link between nicotine and the 'positive reward systems' such as dopamine-containing nerve cells in the brain. More importantly, as nicotine itself acts on receptors for another neurotransmitter, acetylcholine, they provide evidence for the role of these receptors in controlling behaviour.
Attention deficit hyperactivity disorders
Adults and adolescents with attention deficit hyperactivity disorders (ADHD) smoke more frequently than normal individuals.17 Ed Levin and co-workers at Duke University suggested that ADHD sufferers may be using nicotine to treat their disorder. To test this hypothesis, smokers and non-smokers with ADHD were given nicotine patches (7 or 21mg/day). The researchers found a significant improvement in concentration, vigour and performance in measures of attention and timing.17
In a second study, these workers conducted a similar investigation on smokers and non-smokers with ADHD. They found a similar effect, which appeared to be independent of whether or not the subject was a smoker.18 Much as with the rats described earlier, nicotine appears to be able to normalise arousal levels, so that the ADHD individual can maintain focus and attention when the brain is receiving too much information (high arousal) or possibly not enough information (low arousal).
Schizophrenia
Most counsellors working in a psychiatric hospital will tell you that schizophrenics smoke an awful lot. This may be because nicotine might be acting at the brain dopamine system, one of the brain neurochemical systems that appears to be the cause of some schizophrenias (most antipsychotic drugs work by calming a hyperactive dopamine system). Another possibility is that nicotine may relieve the side effects of the drugs used to treat the disorder, or even reduce some negative effects of the schizophrenia itself. There is some evidence to support this concept.
In addition, several psychiatrists and doctors have observed major psychotic events associated with tobacco cessation, which has been interpreted as nicotine withdrawal. Some health professionals have suggested, on the other hand, that these individuals may smoke to reduce the symptoms of behavioural disorder.
So, which came first, the behavioural disorder or chronic tobacco use? While this is difficult to answer, recent research by Robert Freedman, Sheri Leonard and co-workers at the University of Colorado has shown that schizophrenics process sensory information differently to 'normal' people.19, 20 Unlike a schizophrenic, if a non-schizophrenic is startled by an auditory or visual stimulus, they quickly become accustomed to it if it is repeated. Research has found that when schizophrenics are given nicotine, via a patch or gum, they can cope with auditory or visual stimuli in much the same way as 'normal' people. This supports the theory that nicotine is acting in a therapeutic manner via receptors associated with the sensory habituation.
In addition, schizophrenics have fewer nicotine receptors in their brains than normal people,21 and the expression of one of the nicotine receptor subunits (the alpha-7 unit) is also reduced in these subjects. These studies may have provided us with some important clues about the central workings of schizophrenia. First, the findings indicate that a nicotinic receptor may be at fault in at least one aspect of this behavioural syndrome - the inability of the schizophrenic to process certain kinds of sensory information. Second, the work also indicates that there may be a genetic link involving the inheritance of the alpha-7 nicotinic receptor gene from one generation to another.19 All of this provides important clues as to why schizophrenics smoke, and may be a rationale for using nicotine (nicotine patch or gum) in non-smokers with these abnormal behavioural symptoms. Again, much careful research is needed before we can make the jump to using nicotine in the clinic.
Tourette's syndrome
Tourette's syndrome is a disorder characterised by uncontrolled speech and limb movement. Sufferers, who tend to be young adolescents, often curse and swear uncontrollably. The cause of Tourette's is still unknown, but it appears to involve problems in dopamine transmission. The syndrome is difficult to control medically, especially in patients who are resistant to drugs containing typical antipsychotic agents such as haldol or chlorpromazine.
Paul Sanberg at the University of South Florida gave a nicotine patch or gum (7mg or 2mg, respectively) to an adolescent Tourette's sufferer. The nicotine reduced the movement and speech syndrome within minutes. Interestingly, the nicotine patch attenuated the movement disorder for several days after a single application. While nicotine appears to be effective in treating Tourette's syndrome, these researchers suggest that the best use of the nicotine patch at this point is as an adjunct to antipsychotic treatment (rather than using nicotine alone), until more research is conducted.
Nicotine's success here may be a result of its unusual mode of action. When it binds to the nicotine receptors in the brain (actually members of the family of receptors sensitive to the neurotransmitter acetylcholine) it first activates them and then desensitises them, effectively turning them off (see Figure 2).22 In addition, the ability of nicotine to activate or desensitise a receptor may also depend on the receptor's activity at the time the nicotine is administered or gets to the receptor. Thus, nicotine may tend to activate the receptor if it is inactive (as it is if there is little acetylcholine present at the receptor). On the other hand, nicotine may deactivate (desensitise) the receptor when it is very active because of a high level of acetylcholine at the receptor. Thus, nicotine may be acting to normalise the receptor in a way analogous to the observations of nicotine's action on 'high' or 'low' aroused rat behaviour.
If we take this hypothesis a little further and assume that Tourette's syndrome results from an overproduction of a neurotransmitter such as dopamine, then nicotine could be acting to stabilise the dopamine nerve cell by its ability to desensitise nicotinic receptors located on it.23 Stabilisation or shutting down an overproduction of dopamine could explain why nicotine is working in this syndrome, assuming dopamine is the culprit.
More recent research by the same group, has shown that mecamylamine (which blocks the action of nicotine) is also effective in reducing Tourette's symptoms.24 At first glance, this drug would not be expected to have this effect, as it would act at the same nicotinic receptor - in other words, the receptor would have to be activated to get the same effect. The reason mecamylamine is working, however, is the fact that it is not inducing nicotine blockade by acting at the receptor, but can block nicotine by acting directly in the channel - clogging it up (see Figure 2). Thus, mecamylamine is having the same effect as nicotine but is working at a different site. This is an important study as it provides additional support for the contention that nicotine (as well as mecamylamine) is stabilising an overactive nerve cell which releases dopamine.
Parkinson's disease
Parkinson's disease (PD) is another condition that involves exaggerated movements, tics and rigidity. It appears to be the result of a declining dopamine nerve cell system. Once, this disease was thought to be caused by viruses, but we now realise that environmental toxicity and/or the ability of our brains to make neurotoxic substances such as 6-hydroxydopamine25 may cause nerve cells to degenerate, reducing the amount of dopamine that can be made and released. The main treatment for this condition is the administration of the dopamine precursor l-dopa, which helps the brain synthesise more dopamine.
The role of nicotine in PD has evolved over the past 20 years. Early reports indicated that smokers were less likely to develop the disease.26 While some work suggested that this relationship was due to differences that might arise from factors such as selective mortality rather than any specific effect of tobacco or nicotine,27 other research evaluated much of the evidence further and concluded that the effect is real - nicotine did reduce the onset of PD.28
Following the initial suggestion that nicotine might be protective in the development of PD, workers such as Karl Fagerstrom at Pharmacia Research Laboratories in Helsingborg, one of the developers of nicotine gum, observed that the symptoms of PD were relieved by the administration of nicotine gum or patch.29 This work has been repeated in other laboratories30 with the suggestion that nicotine may somehow be acting on dopamine nerve cells destroyed by PD.31 In other words, nicotine is most likely either increasing the central availability of dopamine or preventing the loss of neuronal dopamine at brain area sites important for movement.
However, this concept may have been partially compromised by data suggesting that there may be other chemical(s) in tobacco smoke that also produce therapeutic benefits in PD sufferers.32 This has become more evident as the neurotoxic mechanisms underlying PD have been uncovered. Recent work has shown that levels of the enzyme monamine oxidase B (MAO B), which has been implicated in PD, are 40% lower in smokers than in non-smokers, but this32 and other studies33 suggest that chemicals other than nicotine in tobacco smoke may be responsible for the lowered level of MAO B. It is now evident that MAO B may be responsible for the synthesis of the neurotoxins which may lead to PD. The relationship between smoking and PD appears to be quite complex, but work with nicotine patches and the smoking studies indicate that nicotine and/or some other chemical in tobacco smoke may provide some benefits to the PD sufferer.34
Several studies examining the nicotine patch as a treatment for PD have produced some positive outcomes. In addition, quite a few drug companies,35 such as SIBA Neurosciences in LaJolla,36 are developing nicotine analogues as PD therapeutics, and have had some success in monkeys. While nicotine does appear to help protect against PD, further investigation of the other substances in smoke that may be involved needs to be done.
Alzheimer's disease
Nicotine may also have a role to play in the severe dementia of Alzheimer's disease (AD). The number of nicotine receptors in the brain is reduced by 4060% in AD patients37-39 (a similar effect is seen in select PD patients,40 linking these two neurological syndromes together in relation to nicotine). Workers such as Paul Newhouse and colleagues at the University of Vermont have observed that nicotine, when administered as a patch, may have some benefit as a cognitive enhancer in AD as well.41
The relationship between smoking and AD is not that clear. There is some suggestion of a link between smoking and a lowered risk of AD,41 but this relationship has not always held up. Neuroscience is just beginning to evaluate the many causes of AD from genetics to immunological mechanisms. The one thing we do know about AD is that nicotine receptors in the brain are destroyed, and these somehow play a role in cognition. Abbott Laboratories has invested much in the search for cognitive enhancers and has developed one nicotine analogue, ABT-418 (see Figure 1), which may hold some promise in this area.35
The drug of choice?
The reasons behind a smoking habit are clearly more complex than they seem at first sight. For example, a person may smoke in response to social and environmental cues, or in order to avoid the negative effects associated with giving up. On the other hand, the smoker may be using tobacco as self-medication to relieve some underlying behavioural and/or neurological problem.
The nicotine receptors in the brain appear to have a very important role in overall brain function. These receptors are actually made up of a variety of subunits, and the number of combinations is enormous. This variety appears to be related to the genetics of a specific individual who may then choose to use nicotine via tobacco to modulate one of these receptors, which in turn will alter behaviour and sensory input.
It is interesting to note that habitual nicotine use actually increases the number of nicotine receptors in the brain, probably because of the drug's receptor desensitising effects.42 The increase seems to reflect an adaptive capacity (acute and chronic tolerance) in the brain, which may be related to how and why nicotine can exert some benefits in constant tobacco use.23
The wide spectrum of nicotine's therapeutic potential is only now being discovered and there may be other effects not yet found; for example, data are now accumulating that nicotine may have beneficial effects in ulcerative colitis.43
Many people who use tobacco, including smokers, do so because of some potential therapeutic benefit they receive, such as to relieve depression, schizophrenia or pain. While this appears to be one reason why some people use tobacco, we should not forget that many people engage in this behaviour for other reasons, such as boredom or just to do something that is now 'antisocial'. The future for developing nicotine as a therapeutic agent, or an adjunct to other therapies, using a safe delivery system is relatively good. One of the difficulties with a chemical such as nicotine is that it has been thought of as a 'dirty drug', or 'demon drug' like heroin, which makes people addicts. We first need to pull away from this concept of demonism and treat nicotine and its analogues like any other drug. If you were to ask a clinician whether he or she would use nicotine or heroin to help the patient, the answer would be 'give the drug'. Most clinicians are objective about the drugs they use so long as they help the patient.
Another problem with future research on nicotine concerns its potential addictive properties, and how such a compound should be marketed. Pharmaceutical houses are very sensitive to this problem and might stay away from a nicotine research programme because the drugs they would find could be perceived as addictive. Nicotine is also not high on the list of priorities of things to do when research resources are at a low ebb. Problems such as AIDS in the world or cocaine in the US have much higher priorities. Thus, except for a couple of companies mentioned here, we may never establish large research programmes to develop new chemicals that are nicotine-like, or further evaluate the therapeutic potential of nicotine. This is frustrating to many researchers in this area, but somehow many will continue, and we will eventually learn what nicotine's full therapeutic potential is regardless of the environment.
References
1. Henningfield, J.E., & Goldberg, S.R., Pharmacol. Biochem. Behav., 1988, 30, 221-6; Henningfield, J.E., Cohen, C., & Slade, J.D., Br. J. Addict., 1991, 86, 565-9
2. Rose, J.E., & Corrigal, W.A., Psychopharmacology, 1997, 130, 28-40
3. Kallman, N.M., Kaliman, M.J., Harry, G.J., Woodson, P.P., & Rosecrans, J.A., in 'Drug discrimination application in CNS pharmacology', (Eds F.C. Colpaert & J.L. Slangen), Amsterdam: Elsevier Biomedical Press, 1982, 211-18
4. Woodson, P.P., et al, Pharmacol. Biochem. Behav., 1982, 17, 915-20
5. Rosecrans, J.A., Behav. Genet., 1995, 25, 187-96
6. Tripathi, H.L., Martin, B.R., & Aceto, M.D., J. Pharmacol. Exp. Therap., 1982, 221, 91-6
7. Pomerleau, O.F., Turk, D.C., & Fertig, J.B., Addict. Behav., 1984, 9, 265-71
8. Bado, B., & Daly, J.W., Mol. Pharmacol., 1994, 45, 563-70
9. Bannon, A.W., et al, Science, 1998, 279, 77-81
10. Kassel, J.D., & Shiffman, S., Health Psychol., 1997, 16, 359-68
11. Bressau, N., Peeterson, E.L., Schultz, L.R., Chilcoat, H.D., & Andreski, P., Arch. Gen. Psychiat., 1998, 559, 161-6
12. Glassman, A.H., et al, JAMA, 1990, 264, 1546-9
13. Slin-Pascual, R.J., de la Fuente, J.R., Galicia-Polo, L., & Drucker-Colin, R., Psychopharmacology, 1995, 121, 476-9
14. Lerman, C., et al, Health Psychol., 1998, 17, 56-62
15. Rosecrans, J.A., Chem. Ind., 1994, 221-4
16. Markou, A., Kosten, T.T., & Koob, G.F., Neuropsychopharmacol., 1998, 18, 135-74
17. Conners, C.K., et al, Psychopharmacol. Bull., 1996, 32, 67-73
18. Levin, E.D., et al, Psychopharmacology, 1996, 123, 55-63
19. Freedman, R., et al, Proc. Natl Acad. Sci. USA, 1997, 94, 587-92
20. Leonard, S., et al, Schizophr. Bull., 1996, 22, 431-45
21. Freedman, B., Hall, M., Adler, L.E., & Leonard, S., Biol. Psychiat., 1995, 38, 22-33
22. Marks, M.J., Busch, J.B., & Collins, A.C., J. Pharmacol. Exp. Therap., 1983, 226, 554-64
23. Rosecrans, J.A., & Karan, L., J. Subst. Abuse Res., 1992, 10, 161-70
24. Shytle, R.D., Silver, A.A., & Sanberg, P.R., Poster presented at the International Behavioural Neuroscience Society Annual Meeting, 11-14 June 1998, Richmond, VA, US
25. Jellinger, K., Linert, L., Kienzl, E., Herlinger, E., & Youdim, M.B.H., J. Neural. Transm., 1995, 46(Suppl), 297-314
26. Baron, J.A., Neurology, 1986, 36, 1490-6
27. Haack, D.G., Baumann, R.J., McKean, H.E., Jameson, H.D., & Turbek, J.A., Am. J. Epidemiol., 1981, 114, 191-200
28. Morens, D.M., et al, ibid, 1996, 144, 400-4
29. Fagerstrom, K.O., Pomerleau, O., Giordani, B., & Stelson, F., Psychopharmacology, 1994, 116, 117-19
30. Clemens, P., Baron, J.A., Coffey, D., & Reeves, A., ibid, 1995, 117, 253- 6
31. Kirch, D.G., Alho, A.M., & Wyatt, R.J., Cell. Mol. Neurobiol., 1988, 8, 285-91
32. Fowler, J.S., et al, Nature, 1996, 379, 733-6
33. Mendez-Alvarez, E., Soto-Otero, R., Sanchez-Sellero, I., & Lopez-Rivadulla Lomas, M., Life Sci., 1997, 60, 1719-927
34. Shytle, R.D., Borlongan, C.V., Cahill, D.W., & Sanberg, P.R., Med. Chem. Res., 1996, 6, 555-61
35. Brioni, J.D., Decker, M.W., Sullivan, J.P., & Arneric, S.P., Advan. Pharmacol., 1997, 37, 153-214
36. Menzaghi, F., Whelan, K.T., Risbrough, V.B., Rao, T.S., & Lloyd, G.K., J. Pharmacol. Exp. Therap., 1997, 280, 393-401
37. Flynn, D.D., & Mash, D.C., J. Neurochem., 1986, 47, 1984-54
38. Nordberg, A., et al, J. Neural Transm., 1990, 2, 215-24
39. Whitehouse, P.J., et al, Arch. Neurol., 1988, 45, 722-4
40. Perry, E.K., et al, J. Neurol. Neurosurg. Psychiat., 1987, 50, 806-9
41. Newhouse, P.A., Potter, A., & Levin, E.D., Drugs Aging, 1997, 11, 206-28
42. Balfour, D.J., & Fagerstrom, K.O., Pharmacol. Therap., 1996, 72, 51-81
43. Kennedy, L.D., Ann. Pharmacotherap., 1996, 30, 1022-3
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