reason for this is because smoking causes a chemical compound called
acetylcholine. it is depleted in people with alzheimer's.

The increase in acetylcholine is certainly one piece of the puzzle of neuro-protective effects of tobacco smoke. But it doesn't explain nearly the entire magnitude of the neuro-protection of tobacco smoke, since pharmaceuticals simulating such individual components (similarly the effects on nicotinic receptors) have not shown nearly as strong protective or therapeutic effect as the real tobacco smoke. For example, the near doubling of glutathione levels in smokers, which is the enzyme vital in mercury & lead detox, is not covered by the acetylcholine aspect. Similarly the increase in levels of CoQ10 (the top CoQ10 brands, containing full synergistic complexes, are manufactured from tobacco leaf) in smokers is also not covered. And so goes for the myriad other aspects, mostly unknown.

The interaction of tobacco leaf smoke with human biochemical networks, including those in brain, has been honed over millenia of cultivation for this precise purpose, resulting in an extremely complex and as yet poorly understood symbiotic relation between the two biochemical networks, the medicinal tobacco plant and human organism. Driving acetylcholine up, applying nicotine patches or any such single or mere few aspects of the interaction, is like trying to substitute a marriage to a widower by making him a toast in the morning -- it is a tiny fragment of the complex relation between the two or more complex networks intertwining into a symbiotic relation, marriage. The relation of tobacco to B vitamin complex is well covered in the earlier post (which has many additional links).

Here is one excerpt from an antismoking article hinting at some of the complexity and unknowns involved:

[color:"blue"]Tobacco Smoke May Contain a Psychoactive Ingredient Other Than Nicotine

Nicotine may not be the only psychoactive component in tobacco smoke, according to a study funded in part by NIDA. Using positron emission tomography, an advanced neuroimaging technology, Dr. Joanna S. Fowler and her colleagues at Brookhaven National Laboratory in Upton, New York, have produced images showing that smoking decreases the brain levels of an important enzyme that breaks down the neurotransmitter dopamine. The amount of the enzyme, called monoamine oxidase (MAO), is reduced by 30 to 40 percent in the brains of smokers, compared to nonsmokers or former smokers, the brain scans show. The reduction in brain MAO levels may result in an increase in levels of dopamine, which scientists associate with the reinforcing effects of drugs of abuse.

Although nicotine causes increases in brain dopamine, it does not affect MAO levels, research has shown. Thus it appears that another component of tobacco smoke is inhibiting MAO. "Whatever is inhibiting MAO could be acting in concert with nicotine to enhance dopamine's activity by preventing its breakdown," says Dr. Fowler.

The concept that the smoking-related reduction of MAO activity may synergize with nicotine's stimulation of dopamine levels to produce the diverse behavioral effects of smoking suggests that MAO inhibitor drugs may be useful as an additional therapy in smoking cessation efforts, she adds. MAO inhibitor drugs are used to treat depression and Parkinson's disease. One such drug, moclobemide, is already being used experimentally to assist persons trying to quit smoking.

Dr. Fowler's research was funded by NIDA, the National Institute of Neurological Diseases and Stroke, and the Department of Energy's Office of Health and Environmental Research.

Sources
Fowler, J.S.; Volkow, N.D.; et al. Inhibition of monoamine oxidase B in the brains of smokers. Nature 379:733-736, 1996.
Fowler, J.S.; Volkow, N.D.; et al. Brain monoamine oxidase inhibition in cigarette smokers. Proceedings of the National Academy of Sciences 93:14065-14069, 1996.[/color]

Another article (from a pharmaceutical industry sponsored organization SRNT, dedicated to reasearch on how to replicate the medicinal effects of tobacco smoke with pharmaceuticals) gives even more nuanced picture (again, with the obligatory antismoking spin, since their sponsors would rather sell their own substitutes):

[color:"blue"]
Potential Therapeutic Applications of Nicotine and Nicotine Analogues[/b]
SRNT Vol 1, No 4, 1995
John Baron (Dartmouth Medical School), Edward Levin (Duke University Medical Center), Alexandra Potter and Paul Newhouse (University of Vermont)

Cigarette smoking has a well-deserved bad reputation; it is among the leading causes of mortality and morbidity throughout the world, largely because of its strong effects on the risk of cancer, cardiovascular disease, and chronic lung disease. Nevertheless, nicotine is one of the most widely used drugs in the world, most commonly by chewing the leaves or inhaling the smoke from the leaves of a plant that synthesizes nicotine, tobacco. In spite of health warnings, hundreds of millions of people continue to use tobacco.

Why is tobacco so widely used? Addiction to nicotine is a common explanation for the persistence of nicotine use, once established. Because nicotine has [b]multiple neural and functional effects, however, the simple addiction model may be too narrow to account for nicotine use.

A multifactorial model including a variety of nicotine effects, such as

* improved attentiveness and
* memory,
* quickened reaction time,
* reduced appetite, and
* lessening of anxiety and
* stress,

may be needed to explain why the drug is so widely sought after. These effects also suggest possible therapeutic uses of nicotine when delivered without hazardous compounds present in tobacco tar, as well as of novel nicotinic ligands.

For example, there is evidence to suggest that these agents may be useful in preventing or treating a wide variety of central nervous system (CNS) disorders, including

* Parkinson’s disease,
* Alzheimer’s disease,
* attention deficit/hyperactivity disorder, and possibly
* Tourette’s syndrome;

other conditions for which nicotinic agents could theoretically be helpful include

*obesity,
* depression, and
* anxiety.

In addition to its effects on CNS disorders and functioning, cigarette smoke seems to exert a protective or beneficial influence on some

* immunological and
* inflammatory disorders and on certain

* hormone-related and
* reproductive problems.

Although the moiety in cigarette smoking that underlies the effect of smoking on immunological or inflammatory disturbances is not clear, there are indications that it may be at least in part related to nicotine. If so, a role for nicotine therapy for those disorders could usefully be investigated. For the hormone-related disorders, the effects of smoking may well not be due to nicotine.

This article will highlight recent work examining the epidemiological and clinical evidence for the inverse association between cigarette smoking and a variety of disorders and review what is known about the mechanisms underlying these relationships. For a number of these diseases, the potential therapeutic value of nicotinic agents represents a particularly promising area of research. Even for conditions for which the smoke components responsible for the beneficial effects are unknown and/or unlikely to be nicotine, a better understanding of the relationship with smoking may help to clarify the etiology and suggest treatments and preventive measures that will likely be far safer than cigarettes.

Central nervous system functioning

Mental functioning in nonimpaired individuals. Smoking may affect CNS performance in non-diseased individuals. Smoking or nicotine clearly ameliorates the impairments associated with nicotine withdrawal; among smokers, cigarettes seem to provide modest improvements in vigilance and information processing, facilitation of some motor responses, and perhaps enhancement of memory. The use of smokers in much of the cognitive research has necessarily involved individuals with chronic nicotine exposure; this may well have played a role in the effects observed through withdrawal, tolerance or changes in receptors. Nonetheless, there are data suggesting that non-smokers may experience nicotine-related benefits in performance and information processing. Consistent with these findings, studies in animals have indicated that nicotine may improve learning and memory, although some investigations have also shown evidence of nicotine-associated impairments.

Parkinson’s disease

An inverse association between smoking and Parkinson’s disease (PD) is well established; ever smokers have about half the risk of never smokers. The association is not explained by defects in study design or analysis, although the possibility that individuals destined to be at high risk for Parkinson’s disease have an aversion to smoking has not been completely excluded.

Nicotine is thought to activate the nigrostriatal dopaminergic pathway and increase the release of dopamine in the striatum. Smoking or nicotine can reduce drug-induced parkinsonism, ameliorate Tourette’s syndrome, and neuroleptic tardive dyskinesia, effects that all point to a substantial impact of nicotine on the dopaminergic motor systems. Chronic nicotine dosing has also been shown to protect against degeneration of central dopamine neurons induced by mechanical lesions. Thus, the positive effects of nicotine on the movement disorders of PD are not surprising.

Other human and animal evidence also support a protective effect: Cigarette smoke or nicotine can ameliorate experimental parkinsonism in rodents.9,10 Two case studies by Fagerstrom and colleagues using nicotine gum and nicotine patch demonstrated diminished bradykinesia and increased energy in one patient, and diminished tremor and disorganized thinking in the other.11 Case studies by Ishikawa and Miyatake show reduced tremor, rigidity, bradykinesia, and gait disturbances which lasted 10-30 minutes after cigarette smoking in 6 patients with early onset PD.12

Alzheimer’s disease

The epidemiological data regarding a possible inverse association between cigarette smoking and Alzheimer’s dementia (AD) is certainly suggestive, although less compelling than that for PD.13 Deficits in short- and long-term memory, impaired attention, liberal response bias, and slowing of reaction times are hallmarks of the dementing picture seen in AD.

Nicotine has also been found in various studies to nicotine improve attentiveness, memory or learning in patients with Alzheimer’s disease.14-17 These effects may be related to direct nicotinic stimulation, which may be useful because Alzheimer’s patients have been consistently found to have decreased numbers of nicotinic receptors compared with age-matched controls.18-23

The potential effects of the loss of these receptors was examined by administering the nicotinic antagonist mecamylamine to young and elderly normals, AD and PD patients. Mecamylamine produced a dose-related impairment in acquisition of both verbal and non-verbal information, slowing of reaction times, and liberalizing of response bias.24 PD patients did not show the sensitivity that AD patients did, despite a prior finding that PD patients also show loss of nicotinic receptors. Studies with intravenous nicotine in AD patients have shown that nicotine can improve cognitive function in many of these same cognitive domains with a dose-related decline in errors on verbal learning tasks and increase in long-term recall.25,26 These results suggest that nicotinic modulation may alleviate cognitive impairments in various dementing disorders which show loss of nicotinic receptors.

Attention Deficit Hyperactivity Disorder (ADHD)

Individuals diagnosed as having ADHD also have higher rates of cigarette smoking than the general population.27 Nicotine administration has been shown to improve attentiveness, and nicotine also promotes the release of dopamine as does current pharmacologic treatments of ADHD. A study by Levin and colleagues showed significant reduction in reaction time, reaction time variability, and increased accuracy on several cognitive tasks with nicotine administration in 11 adults diagnosed with ADHD.28 Additionally, these subjects rated themselves as having significantly more vigor than when they were administered placebo. Further studies are continuing with chronic administration. Currently used treatments, methylphenidate, amphetamine and pemoline have this mechanism of action.

Tourette’s syndrome

Tourette’s (TS) is a disorder characterized by multiple motor and vocal tics. Some patients with TS do not fully respond to standard treatments and/or experience significant side effects with high doses of neuroleptics. Animal studies have found that nicotine dramatically potentiated the cataleptic effects of neuroleptics, while not producing these effects when administered alone.29 These studies have lead to open trials in adults and children to examine the possible benefit of augment nicotine treatment. Administration of nicotine gum or patch to patients showing incomplete responses to haloperidol produced dramatic relief of symptoms as soon as 20 minutes after administration. Improvement was seen in both the frequency and severity of motor and vocal tics as well as improved concentration and attention.

Preliminary studies by Sanberg and co-workers have found transdermal nicotine patches to be effective in reducing tic frequency in Tourette’s syndrome.30,31 Nicotine significantly facilitates the effectiveness of haloperidol and other dopamine receptor blockers which are the usual treatment for this disorder. This effect of nicotine is paradoxical since it causes dopamine release. Sanberg and coworkers have hypothesized that nicotine-induced GABA release in the striatum may be important for its effectiveness in Tourette’s syndrome. Unexpectedly, some patients showed sustained improvement in symptoms after a single exposure to nicotine, with suppression of symptoms lasting up to several weeks.32

Schizophrenia

Nearly 90% of schizophrenics smoke [NOTE: yet they have 30-50 percent lower lung & other cancer rates, compared to general population]. One possible explanation for this phenomenon is that schizophrenics may smoke in part because nicotine may improve their ability to filter out and ignore irrelevant sensory information, which may be related to an impairment of inhibitory mechanisms which act to decrease attention to repeated stimuli (sensory gating).34

One of the neuronal mechanisms responsible for such gating involves the activation of nicotinic receptors in the hippocampus, which appear diminished in schizophrenics. Investigations have shown that schizophrenic patients and 50% of their first degree relatives show deficient sensory gating to repeated auditory stimuli (P50) and that nicotine transiently restores normal suppression (gating) of P50.34

Pretreatment with the ganglionic-type (C6) nicotinic antagonist mecamylamine did not block the restoration of gating, suggesting that this effect may be mediated through bungarotoxin-type nicotinic receptors. Drug strategies to improve sensory gating in schizophrenic patients using nicotinic agents may be an attractive therapeutic target Levin and colleagues recently found in a study of schizophrenics in a haloperidol dose effect study that the spatial working memory and spatial information processing speed deficits induced by haloperidol were attenuated by nicotine skin patches.35 In a related study, they found that higher haloperidol doses resulted in higher levels of ad lib smoking.36 Thus, schizophrenics may also smoke to counteract the adverse side effects of antipsychotic dopamine blockers. Interestingly, clozapine an atypical antipsychotic with less dopamine D2 receptor blockade actually caused a dose related decrease in ad libitum smoking.37

Body weight

An inverse association between cigarette smoking and body weight is well known.38 The weight difference between smokers and non-smokers appears to be larger at older ages, and is most marked for moderate smokers. Cessation of smoking is associated with weight gain, a factor which impedes smoking control efforts. The effect of smoking is not completely explained by differences in energy intake or physical activity; cigarette smokers seem to have a higher metabolic rate than non-smokers.39 The weight-reducing effects of smoking may well be due to nicotine, although there are also suggestions of a behavioral component.

Immunological and inflammatory disorders

Cigarette smoking seems to impair [affect] several aspects of immune functioning, including T-cell functioning and antibody response;40 consequently, a benefit for immunologically-mediated disorders is conceivable.

Inflammatory bowel disease

Illustrative of the diversity of sites of nicotine’s action in the body is preliminary evidence of a potential role in inflammatory bowel disease. Silverstein reported several cases which linked cessation of cigarette smoking to the onset of inflammatory bowel disease, and/or symptom improvement with nicotine administration via nicotine gum.41 These studies show that current smokers have a reduced risk and former smokers had a slightly increased risk of being diagnosed with ulcerative colitis (UC) and that the risk of onset of UC appears to be substantially increased shortly after quitting smoking. Initial clinical trials of the addition of nicotine gum to standard treatment in UC have shown improvement in about 50% of patients. A study of 6-week treatment with nicotine patches has also shown significant improvements in global clinical and histological appearance, severity of symptoms, and remissions.41

An inverse association between cigarette smoking and ulcerative colitis has been repeatedly documented. Current smokers have a relative risk of 0.5 or lower in comparison to never smokers, but former smokers have, if anything, an increased risk.42 These findings, and reports of the amelioration of ulcerative colitis symptoms by smoking or nicotine led to formal trials of transdermal nicotine. The pattern of response resembles that of corticosteroid therapy: a benefit for patients in relapse, but no effect in prolonging remission.43 The mechanisms for the effect remain unexplained, although several have been proposed, including changes in bowel mucus or prostaglandins, immune suppression, and other effects in the bowel.44

Aphthous ulcers

A protective effect of cigarette smoking or smokeless tobacco use and the risk of recurrent aphthous ulceration of the mouth has emerged in several studies, though not in all.43 Some investigators have published case reports noting a worsening of the ulcers after smoking cessation, with relief after resumption. These effects may be due to the increased oral keratinization associated with tobacco use; the possible efficacy of nicotine chewing gum suggests that nicotine is an active moiety.43

Extrinsic Allergic Alveolitis

Smoking is clearly inversely related to extrinsic allergic alveolitis (farmers’ lung, pigeon breeders’ lung), a chronic immunologically-mediated lung disorder. In addition to a lower risk of the clinical syndrome itself, smokers have lower levels of the serum antibodies associated with the disorder.45

Sarcoidosis

Several case-control studies have reported an inverse association between smoking and the risk of sarcoidosis.45 It is possible, however, that artifacts in the studies may have distorted the findings, and some negative reports have been published. The association thus remains uncertain, although the effects of smoking on lymphocyte populations make it plausible.

Reproductive and hormone-related disorders

Endometrial cancer

Endometrial cancer is the only malignancy that has repeatedly been found to be inversely related to cigarette smoking. Smokers have about half the endometrial cancer risk of non-smokers, an association that is most marked among post-menopausal women and weaker in former smokers.46 The lower body weight and earlier age at menopause in smokers does not explain the association. The endometrium is probably the only anatomic site where such an effect is conceivable: Here carcinogenesis from direct smoke contact is not an issue, and the "anti-estrogenic effect" of smoking might play a protective role.2

Other apparently beneficial effects have also been ascribed to the hormonal effects of smoking, including a

* reduced risk of uterine fibroids and
* endometriosis.2

Current epidemiological data are far from conclusive, however. Other effects on the female reproductive system, similarly not established, include a lower risks of vomiting of pregnancy and hypertensive disorders of pregnancy. For these, it is not clear what the mechanism of effect might be.43

Nicotine and nicotinic compounds as therapeutic agents

Nicotinic treatment holds considerable promise for preventing or treating a variety of conditions. Experimental studies with humans and animal models will help to identify critical mechanisms for the beneficial and adverse effects of nicotine. Much of the health risk associated with smoking, especially cancer and pulmonary disease, is attributable to some of the 4,000 compounds other than nicotine present in cigarette smoke. Nicotine apart from tobacco can be much safer, although like any drug it is not without adverse effects. When developing nicotine for therapeutic use, it is critical to determine the mechanisms of its actions so that its beneficial effects can be maximized and its adverse effects can be minimized. Alternate routes of nicotine administration may reduce adverse effects. For example, the nicotine skin patch seems to have much lower dependence liability than smoking because it is administered only once per day and produces a slow release of nicotine.47,48 Novel ligands may help determine which subtypes of nicotinic receptors are important for which effects of nicotine. Subtype selective ligands might have some of the beneficial effects of nicotine with fewer adverse side effects.

It is important to consider the mechanisms of action of nicotine to understand both its potential risks and benefits. Nicotine has complex primary actions at nicotinic receptors as well as primary effects at other receptor sites. Nicotine also has a cascade of secondary effects which involve a wide variety of neurotransmitter systems. All of these mechanisms may differentially contribute to the variety of functional effects of nicotine.

Nicotine is the prototypic agonist of the nicotinic subtype of acetylcholine receptor. This straightforward mechanism of action, however, is complicated in several respects. Nicotine potently stimulates the nicotinic receptor, but also can rapidly desensitize it. It is currently unclear precisely which of nicotine’s effects derive from its agonist actions and which from its desensitizing actions. A variety of nicotinic receptor subtypes have been identified. It is not clear which subtypes are important for which nicotine effects. In addition, nicotine has primary effects at other sites, such as N-methyl-D-aspartate (NMDA) receptors.49,50 Likewise NMDA ligands appear to have cross-reactivity with nicotinic receptors.51 This makes it difficult to sort out which receptor is responsible for the effects of nicotinic and NMDA ligands. Finally, an important component of nicotine effects is its ability to stimulate the release of a variety of neurotransmitters including acetylcholine, dopamine, norepinephrine and serotonin.52 This cascade of neurotransmitter release can have effects on a wide variety of neurobehavioral functions.

With increased understanding of the molecular biology of the nicotinic acetylcholine receptor (NAR), new molecules are being developed which have enhanced selectivity for nicotinic receptor subtypes, or which may be allosteric modulators of nicotinic receptor functioning. ABT-418 is a potent and selective NAR ligand which appears to be relatively selective for the alpha-4-beta-2 NAR subtype.53 Studies of the cognitive effects of ABT-418 in animal models showed positive effects on inhibitory avoidance, restored performance in septal-lesioned rats and enhanced primate performance on delayed matching-to-sample tasks.54 Other nicotinic agonists under development include GTS-21, an anabasine derivative which may have activity at alpha-7 NARs and may be neuroprotective. S-1663 appears to be selective for alpha-3-beta-4/2 NARs and may selectively enhance dopamine release and reduce neuroleptic-induced catalepsy. Novel selective nicotinic agonists may offer significant therapeutic advantages over nicotine itself.

Research is continuing in a number of directions to promote a better understanding of the role of nicotinic mechanisms in both CNS and peripheral disease states and to develop selective nicotinic agonists for clinical trials. Such efforts may open up a new era in nicotine pharmacology.
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