Kimberly Burnham, IMTC, PhD Candidate

Essays and articles written by Kimberly Burnham, whose interests include Integrative Manual Therapy (IMT), CenterIMT, Neurodegenerative Disorders, Parkinson's Disease, Vision, VisionIMT, Eye Disorders, Travel, Languages, PhD Candidate, Westbrook University, Connecticut School of Integrative Manual Therapy.

Name:
Location: Bloomfield, Connecticut, United States

Monday, June 28, 2004

Smoking, Nicotine, The Basal Ganglia and their Relationship with Parkinson’s and Ulcerative Colitis

Smoking can at once be considered a serious killer in the United States and potentially beneficial in a wide array of conditions. Nicotine has been shown to be beneficial in ulcerative colitis, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, schizophrenia, neuropsychiatric motor disorders, sleep apnea, and attention deficit disorder.

"Although tobacco smoking has long been associated with diseases of the lungs and cardiovascular system, numerous studies have demonstrated a negative association between tobacco smoking and ulcerative colitis, and the neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD). The evidence suggests that nicotine--the main pharmacologically active ingredient of tobacco--appears to be responsible for this effect. Pure nicotine has no known carcinogenic properties......There is ample clinical evidence to suggest that nicotine could be beneficial in the treatment of some patients with diseases. Pharmacologically, nicotine acts on cholinergic (nicotinic-specific) receptors which are depleted in AD and PD. Nicotinic receptors also interact closely with several neurotransmitters including dopamine, which is implicated in both Parkinson’s and Gilles de la Tourettes's syndrome." (Birtwistle, 1996).

In 1996, Baron also noted, that "cigarette smoking is an established risk factor for cancer and cardiovascular disease, and is the leading cause of avoidable disease in most industrialized countries.......Preliminary data suggest that there may be inverse associations of smoking with uterine fibroids and endometriosis, and protective effects on hypertensive disorders and vomiting in pregnancy are likely. Smoking has consistently been found to be inversely related to the risk of endometrial cancer, but cancers of the breast and colon seem unrelated to smoking. Inverse associations with venous thrombosis and fatality after myocardial infarction are probably not causal, but indications of benefits with regard to recurrent aphthous ulcers, ulcerative colitis, and control of body weight may well reflect a genuine benefit." (Baron, 1996).

With so many positive and negative effects of smoking and nicotine, is it wise to encourage people to start smoking? Many people would agree that it would be better to find a way to balance the cholinergic system and regulate nicotinic receptors without increasing smoking or nicotine use..

In Integrative Manual Therapy (IMT), rather than recommend smoking, therapist use hands on treatment to shift the symptoms and affect the underlying neuroendocrine dysfunctions in ulcerative colitis, Parkinson’s and much more.

IMT therapists working with someone with ulcerative colitis will focus on hands-on ways to decrease the inflammatory process and stimulate healing in the colon tissue. Some of the techniques used include templates, physical functional medicine and biomechanical techniques to decrease the effects of inflammation, improve blood flow and recovery. There is also a focus on the basal ganglia and those neural structures involved in the regulation of nicotinic receptors in the central nervous system as well as the colon.

The following information on the effects of nicotine and nicotinic receptors on basal ganglia related diseases, such as Parkinson’s can also be used by IMT therapists to improve the symptoms of neurodegenerative disorders.

"Nicotine acts on nicotinic cholinergic receptors, which demonstrate diversity in subunit structure, function, and distribution within the nervous system, presumably mediating the complex actions of nicotine described in tobacco users. .... The metabolism of nicotine is now well characterized in humans. A few individuals with deficient C-oxidation of nicotine, unusually slow metabolism of nicotine, and little generation of cotinine have been described. Nicotine affects most organ systems in the body, although its contribution to smoking-related disease is still unclear." (Benowitz, 1996)

"A variety of mechanisms for potentially beneficial effects of smoking have been proposed, but three predominate: the 'anti-estrogenic effect' of smoking; alterations in prostaglandin production; and stimulation of nicotinic cholinergic receptors in the central nervous system" (Baron, 1996)

"Nicotine fairly specifically binds to the cholinergic nicotinic gating site on cationic ion channels in receptors throughout the body. This action stimulates the release of a variety of neurotransmitters including especially catecholamines and serotonin." (Jarvik, 1991)

The relationship between smoking and the colon is not so straight forward. Smoking seems to improve ulcerative colitis but makes Crohn’s disease worse.

"Nicotine is probably the principal active ingredient in smoking responsible for the association; trials have shown it to be of some benefit in ulcerative colitis." (Thomas, 2000). Ulcerative colitis, a kind of inflammatory bowel disease with unknown cause, affects 1-2 million people in the United States. Current research is focusing on "potential unconventional treatments - transdermal nicotine, heparin, melatonin, DHEA, probiotics, fiber, dietary changes, botanicals, essential fatty acids, and other nutrients - that may be considered in conjunction with conventional approaches or as part of a comprehensive alternative treatment protocol." (Head, 2003).

Recently researchers suggested, a relationship between the mucosal barrier function in the colon and the central nervous system, including muscarinic and nicotinic receptors. "The results suggest that in vivo, the permeability increase induced by a moderate concentration of bile acid is to a large extent mediated by a neural mechanism involving muscarinic and nicotinic receptors. This mechanism may be a link between the central nervous system and colonic mucosal barrier function." (Sun, 2004).

The distribution of serotonin-containing cells (SC cells) in the human alimentary tract was studied ... No serotonin containing cells could be observed in the nonmucosal parts of the alimentary tract and in the squamous cell epithelium of the esophagus. The richest SC cells were observed in the upper portion of the small intestine (namely the duodenum and the jejunum). The rectum was relatively rich in the distribution of SC cells. They moderately distributed in the terminal ileum and the pyloric and cardiac gland region of the stomach. The ascending, transverse, descending and sigmoid colon and the fundic gland region of the stomach showed poor distribution of SC cells. The basal-layer of the mucosa contained generally richer SC cells than the superficial-layer of the mucosa throughout the alimentary tract except for the esophagus. In the pyloric gland region of the stomach, the rectum and the upper portion of the small intestine, often a few SC cells were observed in the basal part of several glands in the transverse section. In contrast, SC cells could be rarely identified in other parts of the alimentary tract even in the basal part of the mucosa. And it was characteristic that SC cells distributed fairly even in the mucosa of the sigmoid colon." (Sekizuka, 1975).

The way that nicotine improves ulcerative colitis is still not well known but research has implicated nicotinic acetylcholine receptors (nAChRs) in the colon. "The presence of nAChRs in colonic epithelium may be pertinent to the beneficial effect of nicotine in ulcerative colitis, but since neither smoking nor nicotine treatment is associated with any change in the expression of epithelial alpha3 nAChRs, the effect may be due to functional changes in the receptor. The decreased number of alpha3 nAChRs in UC compared with controls may be related to an increased cell turnover in UC." (Richardson, 2003).

Of course smoking is not without its problems. "The excessive use of tobacco products has been associated with various lesions in the oral cavity. Tobacco-associated lesions include tooth stains, abrasions, smoker's melanosis, acute necrotizing ulcerative gingivitis and other periodontal conditions, burns and keratotic patches, black hairy tongue, nicotinic stomatitis, palatal erosions, leukoplakia, epithelial dysplasia and squamous-cell carcinoma." (Mirbod, 2000) While, "magnetic resonance imaging (MRI) studies have demonstrated large-scale brain abnormalities in cigarette smokers, such as ventricular enlargement and atrophy. Converging lines of evidence point to functional differences between smokers and nonsmokers in specific brain regions, namely the lateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and thalamus. .... Smokers and nonsmokers differed in regional gray matter in brain areas previously linked with nicotine dependence. These findings might reflect effects of chronic smoking, predisposing traits that lead to smoking, or some combination of these factors." Brody, 2004). Integrative Manual Therapy, including techniques to affect the subcortical tissue and Manual Pattern Recognition (MPR) can be used to focus on these areas of the brain.

There are some interesting studies on the use of nicotine in treating Parkinson’s and Alzheimer’s.

"CYP2E1 metabolizes ethanol and can generate toxic intermediates. CYP2E1 also bioactivates tobacco smoke and other procarcinogens and several hepatotoxins ....... These data suggest that nicotine may increase CYP2E1-induced toxicity and contribute to cross-tolerance in smokers and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis,)." (Howard, 2001) "CYP2E1...can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver diseases and cancer. .....Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity." (Micu, 2003). IMT work with the liver and immune system is also helpful for neurodegenerative diseases as well as imbalances of the colon.

One of the other problems with encouraging people to smoke in order to decrease their chances of developing Parkinson’s is that smoking increases the risk of strokes and vascular dementia. "Vascular dementia is the second most common type of dementia. The subcortical ischaemic form (SIVD) frequently causes cognitive impairment and dementia in elderly people. SIVD results from small-vessel disease, which produces either arteriolar occlusion and lacunes or widespread incomplete infarction of white matter due to critical stenosis of medullary arterioles and hypoperfusion (Binswanger's disease). Symptoms include motor and cognitive dysexecutive slowing, forgetfulness, dysarthria, mood changes, urinary symptoms, and short-stepped gait. These manifestations probably result from ischaemic interruption of parallel circuits from the prefrontal cortex to the basal ganglia and corresponding thalamocortical connections ..... The main risk factors are advanced age, hypertension, diabetes, smoking, hyperhomocysteinaemia, hyperfibrinogenaemia, and other conditions that can cause brain hypoperfusion such as obstructive sleep apnoea, congestive heart failure, cardiac arrhythmias, and orthostatic hypotension. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)and some forms of cerebral amyloid angiopathy have a genetic basis." (Roman, 2002).

On the other hand smoking marijuana, seems to increase cerebral blood flow. "The effects of smoking marijuana on regional cerebral blood flow (rCBF) and cognitive performance were assessed in 12 recreational users in a double-blinded, placebo-controlled study..... Increased rCBF was observed in orbital and mesial frontal lobes, insula, temporal poles, anterior cingulate, as well as in the cerebellum. The increases in rCBF in anterior brain regions were predominantly in "paralimbic" regions and may be related to marijuana's mood-related effects. Reduced rCBF was observed in temporal lobe auditory regions, in visual cortex, and in brain regions that may be part of an attentional network (parietal lobe, frontal lobe and thalamus). These rCBF decreases may be the neural basis of perceptual and cognitive alterations that occur with acute marijuana intoxication. There was no significant rCBF change in the nucleus accumbens or other reward-related brain regions, nor in basal ganglia or hippocampus, which have a high density of cannabinoid receptors." (O’Leary, 2002)

"Several drugs of abuse, including nicotine, are thought to exert their reinforcing effects through actions on the mesolimbic dopamine system.....studies suggest that chronic administration of addictive drugs may lead to impaired dopamine neurotransmission in the nucleus accumbens......This suggests that there is a reduction in dopamine D1 receptor density in the ventral striatum of human cigarette smokers relative to nonsmokers, which implies that the postsynaptic mesolimbic dopamine system may be chronically underactive in smokers, either as an antecedent or consequence of addiction to cigarettes. Such a hypodopaminergic state may play an important role in sustaining nicotine-seeking behavior. Alternatively, an inherited reduction in dopamine receptors in the striatum may be associated with an increased risk of addictive behavior. (Dagher, 2001).

So on one hand smoking reduces the number of dopamine recptors and on the other hand, "smoking is related to greater dopamine activity in the human basal ganglia. Nicotine-induced dopamine activity may be a relevant mechanism in dependence on cigarette smoking." (Salokangas, 2000)

In any case nicotine does affect the basal ganglia. "Accumulating evidence indicates that nicotinic receptors play a role in basal ganglia function. Furthermore, nicotine administration may be neuroprotective in animal models of nigrostriatal degeneration, while cigarette smoking is inversely correlated with Parkinson's disease. Because nicotinic receptors are decreased in Parkinson's disease, these observations may suggest that nicotinic agonists are beneficial in this disorder. .... As an approach to evaluate neuroprotective effects of nicotine against nigral neuron damage, we used mesencephalic neurons in culture, treated with a selective dopaminergic neurotoxin. The results show that nicotine pretreatment protected against dopaminergic nigral neural degeneration. These data suggest that nicotinic receptor ligands may be useful in Parkinson's disease therapy." (Quik, 2000).

"Smokers had significantly lower brain monamine oxidase B (MAO B) than non-smokers .....Reductions were observed in all brain regions. Low brain MAO B in the cigarette smoker appears to be a pharmacological rather than a genetic effect since former smokers did not differ from non-smokers. Brain MAO B inhibition by cigarette smoke is of relevance in light of the inverse association between smoking and Parkinson's disease and a high prevalence of smoking in psychiatric disorders and in substance abuse. Though nicotine is at the core of the neuropharmacological actions of tobacco smoke, MAO B inhibition may also be an important variable in understanding and treating tobacco smoke addiction. (Fowler, 1998)

"Parkinson's disease (PD) is one of the most frequent disorders of the basal ganglia. From epidemiological studies there is a controversial discussion on the question whether tobacco smoking is correlated with a decreased incidence of PD........... High dosage nicotine treatment significantly increased the MPTP-induced loss of body weight and resulted in a significantly decreased striatal dopamine content and an increased dopamine turnover in comparison with the MPTP-treated controls at day 15. However, the lower dosage of nicotine did not significantly alleviate the MPTP-induced effects, although some parameters showed a slight tendency in this direction. These results demonstrate that in vitro nicotine has radical scavenging properties which might suggest neuroprotective effects. In vivo experiments with nicotine, however, showed that a low dosage of nicotine did not alleviate the MPTP-induced dopamine depletion, but a large dosage even enhanced it. (Ferger, 1998).

‘Reports of a reduction in the risk of developing Parkinson's disease and Alzheimer's disease in tobacco smokers, together with the loss of high-affinity nicotine binding in these diseases, suggest that consequences of nicotinic cholinergic transmission may be neuroprotective. ..... The ratio of homovanillic acid to dopamine, an index of dopamine turnover, was reduced in elderly smokers compared with age matched non-smokers (P<0.05) in both the caudate and putamen. Dopamine levels were significantly elevated in the caudate of smokers compared with non-smokers (P<0.05). .....These findings suggest that chronic cigarette smoking is associated with a reduction of the firing of nigrostriatal dopaminergic neurons in the absence of changes in the numbers of dopamine receptors and the dopamine transporter. Reduced dopamine turnover associated with increased numbers of high-affinity nicotine receptors is consistent with attenuated efficacy of these receptors in smokers. A decrease in striatal dopamine turnover may be a mechanism of neuroprotection in tobacco smokers that could delay basal ganglia pathology. (Court, 1998)

"The three responses (R1, R2, and R3) of the electrically elicited blink reflex (BR) obtained in four normal human subjects were investigated before and after smoking both a filtered and an unfiltered cigarette. ....... The action of nicotine on central pathways located at the interneuronal network of the brainstem, basal ganglia, and C fiber structures involved with this reflex seems to be the most likely mechanism for these findings." (Leon, 1997)

Beyond smoking there are other chemicals that can affect dopamine production and receptor sites. "Many complaints of Gulf War veterans are compatible with a neurologic illness involving the basal ganglia. .....Controlling for age, renal clearances of creatinine and weak organic anions, handedness, and smoking did not substantially alter the associations. The reduction in functioning neuronal mass in the left basal ganglia of these veterans with Gulf War syndrome seems to have altered central dopamine production in a lateralized pattern. This finding supports the theory that Gulf War syndrome is a neurologic illness, in part related to injury to dopaminergic neurons in the basal ganglia." (Haley, 2000)

Gilles de la Tourette syndrome (TS) is a neuropsychiatric spectrum disorder of unknown etiology. While several studies have provided evidence that nicotine causes an improvement, only anecdotal reports suggest that alcohol and marijuana influence the symptomatology. ...... marijuana influences an assumed interaction between cannabinoid and dopamine receptors and, by this, influences the dopaminergic processes in basal ganglia and motor activity. (Muller-Vahl, 1997)

There are also links between smoking and bruxism, another involuntary movement disorder "In the past, morphological factors, like occlusal discrepancies and the anatomy of the bony structures of the orofacial region, have been considered the main causative factors for bruxism. Nowadays, these factors play only a small role, if any. Recent focus is more on the pathophysiological factors. For example, bruxism has been suggested to be part of a sleep arousal response. In addition, bruxism appears to be modulated by various neurotransmitters in the central nervous system. More specifically, disturbances in the central dopaminergic system have been linked to bruxism. Further, factors like smoking, alcohol, drugs, diseases and trauma may be involved in the bruxism aetiology. Psychological factors like stress and personality are frequently mentioned in relation to bruxism as well. However, research to these factors comes to equivocal results and needs further attention. Taken all evidence together, bruxism appears to be mainly regulated centrally, not peripherally. (Lobbezzo, 2001)

"Nicotine produces profound behavioral effects in humans, but little is known about the sites of its action. There is a hypothesis that frontal lobe and limbic/cingulate cortical structures might be the sites. In this study, we examined the effects of cigarette smoking on feeling and cerebral blood flow (CBF) in human subjects. ...... Arterial nicotine increased up to the levels 8 times higher than before smoking. The increases of blood pressure and pulse rate were minimal. Arterial carbon dioxide level and hematocrit did not change. Feeling after smoking was variable in individual subject. In 8 subjects with a relatively high feeling, CBF increased mainly in the frontal lobe, hippocampus, uncus, thalamus and caudate nucleus. CBF did not change in the parietal, temporal and occipital lobes, and in the putamen, insula, brainstem and cerebellum. In two subjects with uncomfortable feeling, CBF did reduce in the whole brain. The CBF increase in frontal lobe and limbic structures seems to be secondary to nicotine-induced neuronal activation in each structure. Mesocorticolimbic dopamine system, which is believed to influence learning, memory or emotional performance, appears to be a target for nicotine. The CBF reduction in the whole brain might be due to cerebral vasoconstriction or be secondary to a systemic hypotension. (Nakamura, 2000)

Ulcerative colitis is associated with changes in colon physiology and motilities. "Patients with ulcerative colitis have abnormal rectal motility. AIM: To compare the contractile properties of rectal smooth muscle from patients with ulcerative colitis and controls. ....... Ulcerative colitis tissue has an increased sensitivity to carbachol and this is not due to denervation; it may result from increased calcium release from intracellular stores since contraction due to membrane depolarization is not altered. Modulation of this pathway could potentially be used to alter rectal motility in patients with ulcerative colitis." (Cook, 2000)

There are also indications that nicotine has an anti-inflammatory effect. "Recent advances in the therapy of inflammatory bowel disease specifically directed against the inflammatory and immune mechanisms include an impressive and often overwhelming cornucopia of anti-inflammatory agents, immunomodulators, antibiotics, biologicals, topical therapies, nicotine, heparin, and nutritional supplements." (Katz, 1999)

"To clarify the hypothesis that nicotine exerts its anti-inflammatory effect in UC through selective inhibition of T-cell-derived cytokine synthesis, we studied in vivo effects of nicotine on cytokine production by human non-adherent mononuclear cells isolated from peripheral blood in a randomized, double-blind, placebo-controlled trial. ...... The beneficial effect of transdermal nicotine in ulcerative colitis may be mediated by a selective inhibition of the IL-2 production by mucosal mononuclear cells, which could result in diminished cell proliferation and consequently a reduction in the inflammatory process." (van Dijk, 1998)

There are some interesting case reported on the effect of smoking on involuntary movement. "A 65-year-old hypertensive man was admitted because of abnormal involuntary movements which had an onset one month prior to the admission......he noted that smoking induced choreic movement in his left side transiently. The involuntary movement ceased soon after upon stopping smoking. ... Our observation may indicate that the inhibition of the subthalamic nucleus as the result of the decrease of the putaminal output to the external segment of the globus pallidus will induce hemiballism. The effect of smoking on his involuntary movements can be understood as a result of increase in the dopamine release from the nigrostriatal terminals induced by nicotine. (Mochizuki, 1993)

Smoking can also affect neuroleptic metabolism. ""The authors' goal was to study the relationship between smoking status and clinical characteristics in schizophrenic patients. ...... .....Cigarette smokers receive significantly higher neuroleptic doses, in part because of a smoking-induced increase in neuroleptic metabolism. Smoking is also associated with significant reduction in levels of parkinsonism. Smoking status is a significant factor that should be considered in assessment of neuroleptic dose requirements and neuroleptic side effects. (Goff, 1992).

There are also some links between nicotine and adrenal function. "One important neuroendocrine action of nicotine in the male rat is an increase in the secretion of corticosterone which is seen upon acute and acute intermittent exposure to nicotine. ....... Available evidence indicates that corticosterone can modulate dopamine transmission in the basal ganglia via glucocorticoid receptors within the nucleus accumbens and neostriatum, and via glucocorticoid receptor immunoreactivity in nigrostriatal and mesolimbic dopamine pathways. Through concerted pre- and postsynaptic actions glucocorticoids may decrease dopamine transmission, especially that mediated by D2 receptors in these regions. In view of the hypothesis that the mesolimbic dopamine pathways mediate the euphoric effects of nicotine, the secretion of corticosterone induced by nicotine in the smoking male may substantially influence the mood elevating activity of nicotine. Thus, individual smoking habits may depend on the ability of nicotine to induce corticosterone secretion, which obviously would also vary with the degree of stress. The glucocorticoids may in a similar way influence the arousal action of nicotine because of the high number of glucocorticoid receptors present both in noradrenaline cell bodies of the locus ceruleus and within the entire cerebral cortex." (Fuxe, 1990).

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