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I POSITIVE ASPECTS OF NICOTINE USE Tobacco use has spread around the world since Columbus was offered dried tobacco leaves at the House of the Arawaks on October 11, 1492 (1). There are many reasons why tobacco products have gained such wide usage around the world, but one of the more important is that tobacco contains a unique substance- nicotine. Nicotine is an alkaloid with a tertiary amine structure composed of a pyridine and a pyrrolidine ring. The liver is the primary organ of nicotine metabolism but some metabolism also occurs in the lung . Cotinine and nicotine-N-oxide are the major metabolites. Cotinine is a particularly interesting metabolite as it has a relatively long half-life (18 to 20 hours) compared to nicotine (2 hours) (2). This long half-life results in a plasma cotinine to plasma nicotine ratio of approximately 10 in smokers (3). Cotinine is also significantly less toxic than nicotine. The LD50 value for (-)-cotinine as determined by intraperitoneal administration in mice is 930 ± 35 mg/kg. The comparable LD50 value for (-)-nicotine is 9.99 ± 1.05 mg/kg (4). Nicotine has been shown to exert several beneficial effects in humans. The beneficial effects include enhanced mental performance, decreased anxiety, reduced aggression, increased tolerance to pain, and body weight control. This article will summarize some of the research that has been conducted on the effects of nicotine and discuss the developing area of nicotine- degenerative brain disease research. A distinction has been made between smoking effects and nicotine effects because they sometimes differ. Improvements in Mental Performance Several studies with humans have demonstrated that smoking facilitates the recall of learned material from long-term memory (5,6). This result is consistent with an extensive animal literature indicating that nicotine facilitates learning in a variety of situations (7). In addition to enhancing the retrieval of stored material, nicotine has also been shown to improve rapid information processing. This has been measured by determining the ability of subjects to recognize correct sequences of numbers rapidly presented on a video screen. Both speed and accuracy at this task have been improved by nicotine tablets (8). Smoking has also been shown to decrease the time interval between the onset of a stimulus and the peak of the P300 brain wave. The P300 brain wave is an index of the speed of perceptual information processing that, unlike manual reaction time, does not reflect response (motor)-related processes (9). Vigilance tasks measure the ability of subjects to detect and respond to infrequent signals which occur unpredictably across a sustained interval of time. Administration of nicotine tablets has been shown to improve the ability of both smokers and nonsmokers to perform vigilance tasks, e.g., monitoring a clock (10,11). Nicotine has also been shown to reduce distraction as measured by a significant dose dependent reduction in Stroop interference (8).

Stroop interference refers to the performance decrement produced by color/word incompatability. An example of this phenomena would be the word red printed in green, the subject being required to report the color of the letters (12). Several different tests have demonstrated a beneficial effect of nicotine on temporal resolution in the visual modality. The Critical Flicker Fusion (CFF) Threshold test measures the frequency at which a flickering light source appears to stop flickering. This test is similar to the Two-Flash Fusion (TFF) Threshold test which measures the ability of a subject to discriminate between two successive flashes of light. In 1968, Warwick and Eysenck (13) reported that low levels of nicotine reduced both the CFF and the TFF threshold. These results have been interpreted as a nicotine- induced improvement in the processing of visual information. Positive Psychological and Emotional Effects In addition to improvements in mental performance, nicotine has been shown to exert several positive psychological and emotional effects. Anxiety induced by having subjects attempt to solve a difficult puzzle was reduced by smoking a "usual -nicotine" delivery cigarette. No reduction in anxiety was seen in subjects after smoking zero-nicotine cigarettes. These same subjects were also exposed to freezing water for 5 minutes. Pain endurance and awareness thresholds were measured and the McGill Pain Questionnaire was administered. After smoking a "usual-brand" cigarette, all five subjects displayed increased pain awareness thresholds, four of five showed increased pain endurance, and three of five reported decreased perception of pain (14). Several laboratories have reported a reduction in aggression in animals after administration of nicotine. Silverman (15) reported that a nicotine dose of 25 milligrams per kilogram of body weight selectively and reversibly reduced aggression in rats. Nicotine has been reported to suppress the biting attack induced in squirrel monkeys by tail shock (16,17). Other studies have demonstrated reduced aggression in rats (18-20) and in cats (21). The relevance of these studies to humans is not known as there may be species differences in the effects of nicotine on aggression (22,23), although there is some evidence that nicotine also reduces aggression in humans. Ganter (24) recently tested the effectiveness of nicotine in counteracting the aggression enhancing effect of alcohol. She determined the amount of shock that 40 male undergraduates selected for their "opponent" to receive during a competitive reaction-time task while under the influence of either nicotine, alcohol, or nicotine and alcohol. Intoxicated subjects given nicotine set significantly lower shocks for their competitors than intoxicated subjects who were not given nicotine. Body Weight Control Nicotine may also play a role in body weight control. As a

group, smokers weigh less than nonsmokers (25-29). Smokers who stop smoking frequently gain weight until they weigh approximately as much as nonsmokers (30,31). Data from both human and animal experiments have suggested that nicotine is the factor responsible for this smoking-associated weight control. Grunberg (32) has reported that nicotine consumption is accompanied by a decreased appetite for sweet-tasting high caloric foods. In addition, animal studies have demonstrated that nicotine administration can reduce body weight without a reduction in food intake (33-37). These results suggest that nicotine may lower body weight by increasing energy expenditure through changes in metabolic rate. Therefore, the observation of increased metabolic rate in smokers (38-41) may be due to nicotine consumption. Lowered Blood Pressure Although the acute administration of nicotine raises blood pressure and elevates heart rate, chronic administration may result in a slightly lowered blood pressure. Hutchinson and Emley (42) received a U.S. patent in 1988 entitled "Method For Treating Hypertension With Nicotine". In this patent, Hutchinson and Emley describe the reduction of systolic and diastolic blood pressures in mildly hypertensive squirrel monkeys after administration of low doses (0.002, 0.005, or 0.01 mg/kg/day) of nicotine tartrate in the drinking water. Evidence from both animal studies and a human epidemiology study suggests that this nicotine-induced lowering of blood pressure may be the result of the buildup of cotinine. McKennis and Bowman (43) described cotinine as an antispasmodic and blood pressure-lowering agent in a 1962 Australian patent. These authors were able to lower the blood pressure of dogs after acute administration of cotinine. In addition, the increase in blood pressure following administration of nicotine was blocked by pre- treatment with cotinine. Connor (44) subchronically dosed rats with cotinine at the level experienced by human cigarette smokers. After 7 days, statistically significant decreases in systolic blood pressure were observed. Benowitz (45) recently reported a significant inverse correlation between serum cotinine and systolic and diastolic blood pressure in a cross-sectional study of 288 normotensive bus drivers. For smoking bus drivers, the average decrease in blood pressure was 10.7 and 7.0 mm mercury for systolic and diastolic blood pressures, respectively. This decrease could not be accounted for by age, body weight, or alcohol consumption. Epidemiology studies have generally reported that smokers have slightly lower blood pressures than nonsmokers (46). This association may be due to the blood pressure lowering effects of cotinine. Parkinson's Disease Parkinsonism is a clinical syndrome characterized by four major symptoms: tremor at rest, rigidity, bradykinesia, and loss

of postural reflexes. Bradykinesia is defined as a paucity of automatic and spontaneous movements with difficulty in initiating voluntary movement. Parkinsonism can be etiologically categorized into three groups: (1) the idiopathic disorder referred to as Parkinson's disease, (2) secondary or acquired parkinsonism, and (3) "parkinsonism-plus" syndromes where additional neurologic findings are present. Most Parkinsonism is caused by the degeneration of dopaminergic melanin-containing neurons in the substantia nigra region of the brain. Approximately 1 million people in the United States suffer from Parkinsonism (47). Baron (48) reviewed 16 epidemiologic studies which examined the relationship between smoking and Parkinson's disease. He reported that the results of these studies suggest that cigarette smokers have about half the risk of developing Parkinson's disease as nonsmokers. Hertzman et al. (49) also recently reported an odds ratio of 0.54 for the development of Parkinson's disease in cigarette smokers. Some authors have debated the validity of the association because of the lack of a clear dose-response relationship (50,51). It should be noted that it is very difficult to collect quantitative smoking data. Therefore, a dose-response relationship is more difficult to determine than a "yes or no" association. Several different hypotheses have been proposed to explain the inverse association between smoking and Parkinson's disease. The first is that the nicotine in cigarette smoke facilitates dopamine release and dopaminergic neural transmission throughout the nervous system thereby relieving the dopamine deficit associated with the disease. Support for this hypothesis has been provided by several lines of evidence gathered from animal studies. Clarke et al. (1985) demonstrated that nicotine exerts a direct excitatory action on the dopaminergic neurons of the substantia nigra pars compacta in rats. Fuxe et al. (1990) and Anderson et al. (1981a,b) also conducted rat studies. Fuxe et al. (1990) reported that chronic nicotine treatment increases dopamine levels and reduces dopamine utilization in substantia nigra after a partial di-mesencephalic hemitransection. Anderson et al. (1981a,b) demonstrated that administration of nicotine or exposure to cigarette smoke enhanced the utilization of dopamine in the neostriatum. In addition, Waller and Waller (1989) reported enhanced motor performance following subchronic administration of nicotine to aging mice. The second hypothesis that has been proposed is that cigarette smoking may protect the brain from a neurotoxin. Interest in a neurotoxic etiology for Parkinson's disease was generated by the observation that chronic parkinsonism can be induced in humans by ingestion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Reference 5 and 6 in Sayre). Monoamine oxidase in the brain metabolizes MPTP to the 1-methyl-4-phenylpyridinium cation (MPP+). The high-affinity dopamine uptake pump accumulates MPP+ in the dopamine producing cells of the pars compacta of the substantia nigra. Cell death due to compromised energy production results, thereby leading to dopamine deficiency. Cigarette smoking may prevent the metabolic activation of an MPTP-like compound to an active neurotoxin. Whole cigarette smoke has been shown to inhibit monoamine oxidase activity in tissue

slices of rat lung (Yu et al., 1987). Carr and Basham (1990) have reported that cigarette smoke condensates inhibit monoamine oxidase A and B in a concentration-dependent manner in mouse brain tissue homogenates. In addition, chronic nicotine treatment may lead to increased survival of nigrostriatal dopaminergic neurons after lesioning with MPTP (Janson et al., 1989). In contrast, Carr and Rowell (1990) reported that while smoke exposure was found to reduce the decrease in striatal dopamine and metabolite levels caused by MPTP, tissues from smoke-treated mice were able to metabolize MPTP to MPP+. Based upon this observation, these authors suggested that the apparent protective effect of cigarette smoke may not be due to inhibition of cerebral monoamine oxidase. Perry et al. (1987) have also reported that mice given MPTP and exposed to cigarette smoke experienced an equivalent depletion of striatal dopamine as did mice treated only with MPTP. However, the time course over which these studies have been conducted leaves unexamined the possibility that a small amount of a lipophilic inhibitor could build up in the brain over a long period of time and provide a protective effect. The MPTP observation has led several researchers to conduct epidemiology studies on associations between Parkinson's disease and exposure to putative environmental neurotoxins. Tanner et al. (1989) conducted a case-control study on one hundred patients and 200 controls in Beijing. They reported that occupational or residential exposure to industrial chemicals, printing plants, or quarries elevated the risk of Parkinson's disease. Ho et al. (1989) studied a group of Parkinson's patients in Hong Kong. These authors found that subjects who had been exposed to herbicides and pesticides were at an increased risk for Parkinson's disease. Koller et al. (1989) also investigated the relationship between herbicide and pesticide use, well water use, and farming and Parkinson's disease by performing a case-control study on 95 patients and 95 matched controls. Parkinson's disease patients had an increase in the mean number of years of drinking well-water, mean number of years in a rural residence, and mean number of exposure years to herbicides and pesticides. The environmental neurotoxin hypothesis has been criticized because of a lack of clustering of cases (Veiregge et al., 1988; Barker, 1989). However, clustering of cases would not necessarily be expected if either the exposure were localized or a genetic predisposition in the presence of neurotoxin exposure were required to develop the disease. Several studies have been conducted to determine whether there are genetically determined metabolic differences between Parkinson's disease patients and controls that would influence the activation of pre-neurotoxins to neurotoxins. Ladero et al. (1989) reported no differences in metabolic phenotype determined by the ability to acetylate sulphamethazine between 100 patients with Parkinson's disease and 93 age-matched normal control subjects. Factor et al. (1989) have suggested that there are no alterations of P450-mediated metabolism of acetaminophen in Parkinson's patients. Barbeau et al. (1985) and Poirier et al. (1987) have reported that Parkinson's patients are poor metabolizers of debrisoquin, but Comella et al. (1987) saw no effect in a smaller study. Ferrari et al. (1986) has also observed

defective metabolism of phenytoin to p-hydroxy-phenyl-phenyl- hydantoin in one Parkinson's patient and his family. If P450 metabolism is involved, smoking could exert a protective effect by inhibiting metabolic activation of toxins either in the liver or in the brain. Nicotine is a relatively weak inducer of P450 and would not be expected to play an important role in this process (Don's paper). Several groups of Japanese researchers have been examining an alternative environmental neurotoxin hypothesis: that Parkinson's disease could result from the long-term ingestion of small amounts of one or more dietary neurotoxins. The carcinogenic heterocyclic amines, 3-amino-l,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-l-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), are formed during the cooking process from the pyrolysis of tryptophan. Naoi et al. (1989) have reported that Trp-P-1 and Trp-P-2 accumulate in clonal rat pheochromocytoma PC12h cells and reduce catecholamine synthesis. They demonstrated the involvement of the dopamine uptake system by showing that the specific dopamine uptake inhibitors, nomifensine and mazindol, reduced the entry of dopamine into the cells. Since Trp-P-1 and Trp-P-2 are neurotoxic and cross the blood brain barrier, Naoi et al. (1989) have speculated that these common food mutagens might play a role in the etiology of Parkinson's disease. Makino et al. (1988) and Niwa et al. (1989) have reported the presence of nanogram/gram quantities of 1,2,3,4-tetrahydro-isoquinoline (TIQ) and 1-methyl-1,2,3,4- tetrahydroisoquinoline (1MeTIQ) in a number of foods including cheese, milk, eggs, and bananas. TIQ and 1MeTIQ have been detected in both normal human and Parkinson's brains (Ohta et al., 1987). Daily injections of TIQ (50 mg/kg per day, s.c. for 11 days) produced parkinsonism in marmosets (Nagatsu and Yoshida, 1988). Whether a lifetime dose of small amounts of these dietary neurotoxins could induce parkinsonism in susceptible individuals is unknown. There are at least two potential mechanisms by which smoking could affect the development of Parkinson's disease induced by a dietary neurotoxin. First, smokers may not consume as much of the dietary neurotoxin as nonsmokers due to differences in dietary preference. Smokers consume a diet significantly higher in saturated fat and lower in fruits and vegetables than nonsmokers (ETS). Nicotine may play a role in dietary preferences as Grunberg (32) has reported that nicotine consumption is accompanied by a decreased appetite for sweet-tasting high calorie foods. Second, cigarette smoke contains a large variety of quinolines and isoquinolines. One or more of these smoke components could competitively inhibit the neurotoxic action of structurally similar compounds like TIQ and 1MeTIQ. The third hypothesis that has been proposed to explain the inverse association between smoking and Parkinson's disease is that individuals destined to develop Parkinson's disease do not develop the smoking habit because of an enhanced sensitivity to the negative effect of repeated nicotine on dopamine metabolism in the nucleus accumbens. Repeated exposure to nicotine has been shown to decrease dopamine turnover in the nucleus accumbens of rats (Maker et al. 1987). Hypothetically, certain individuals could experience

greater decreases in dopamine than others after chronic nicotine ingestion and therefore not enjoy smoking. Alzheimer's Disease Anatomical, physiological, and pharmacological evidence has implicated the cholinergic system of the brain in memory function (52). The cholinergic system is severely compromised in Alzheimer's disease (AD) brains. AD brains have been shown to be deficient in the acetylcholine (ACh) synthesizing enzyme choline acetyltransferase (ChAT). In addition, deficiencies in the uptake of high affinity choline (Ch) and in the synthesis and release of ACh have been measured (53). These deficiencies correlate with the loss of memory function associated with AD. The cholinergic receptor system of the human brain is also severely altered in AD. Giacobini et al. (52) surveyed the results from eight nicotine receptor studies conducted on autopsy material taken from the frontal cortex of AD patients. Six of the studies showed nicotine receptor decreases from 44 to 65%. Desarno (54) has measured comparable decreases in biopsy material. At least two different groups have experimented with nicotine as a treatment for AD. Newhouse et al. (55) administered i.v. nicotine to six Alzheimer's patients and observed a decrease in intrusion errors during cognitive testing at the 0.25 ug/kg/min dose. Prominent behavioral side effects were noted including a significant dose-related increase in anxiety and a depressive effect. Sahakian et al. (56) administered i.v. nicotine to seven Alzheimer's patients and reported that "nicotine can improve attention and information processing in DAT patients, as well as in normal young adults, but does not affect performance on our tests of short-term memory". The preliminary results obtained in AD patients after nicotine injection are consistent with nicotine's effect on the acetylcholine system. Beani et al. (57) have reported that nicotine evokes increased ACh release, increased D-aspartate release, and reduced GABA outflow in unanaesthetized animals. They have hypothesized that "such an imbalance between excitatory and inhibitory signals certainly increases cortical excitability..." and that "the increased efficacy of the excitatory inputs may explain the favourable effects of nicotine in maintaining the awake state and in facitlitating the memory processes". Since AD patients suffer from deficiences in nicotine receptor number (and possibly function), the upregulation of nicotinic receptors that occurs as a result of chronic exposure to nicotine has been hypothesized to be of potential benefit in AD. However, upregulation of nicotinic receptors may occur as a counterbalance to desensitization. Desensitization is induced by prolonged or repeated exposure to agonists and results in inactivation of the receptor's ion channel (58). Therefore, the functionality of upregulated receptors in Alzheimer brain is unknown at this time. Epidemiology studies on the relationship between smoking and AD may help elucidate the potential role of nicotine or nicotine- like compounds in the treatment of AD. Several studies have been

conducted, but no clear relationship has emerged. At least two studies have reported a negative association between smoking and AD. Appel (59) published the observation that there were very few smokers in thirty AD patients that he was studying. Grossberg et al. (60) found a negative association between smoking and AD in a group of 144 AD patients. Several studies have reported no association between smoking and AD. In a Japanese cohort, Urakami et al.( 61) reported that in a group of 77 patients (16 men, 61 women) there were 12 male smokers, but only one female smoker. These authors believed their results showed "no association between smoking and AD". No association was also reported by Graves et al. (62), Amaducci et al. (63), and French et al. (64). Shalat et al. (65) reported a positive association, but this study used Veteran Administration (VA) patients. Most AD researchers will not use VA patients because of possible confounding from underreporting of alcohol use. The lack of a clear epidemiological relationship is not surprising given the complexity of the problem. An accurate diagnosis of Alzheimer's disease must be obtained. Patients with multi-infarct dementia should be excluded by CT scan. A lifetime smoking history must be taken in addition to information about current smoking habits. A study reported by Barclay and Kheyfets (66) illustrates the potential importance of obtaining longterm tobacco use information in studies of this type. These authors examined tobacco use by next-of-kin interview in 272 patients with "probable" AD by NIH criteria. This cohort reported a history of relatively heavy tobacco use in the past, but most subjects had stopped smoking "long before the onset of cognitive symptoms". These authors hypothesized the following, "The loss of desire to smoke and the lack of withdrawal symptoms after stopping tobacco use precede the onset of cognitive symptoms in Alzheimer's disease by many years, and raise the possibility that alterations in central nicotinic receptors may be a preclinical change in patients later developing Alzheimers disease". Whether continuation of smoking would have delayed the onset of AD in these patients is unkown. Conclusions Several positive benefits of nicotine use have been discussed in this article- enhancement of mental performance, reduction of anxiety and aggression, body weight control, and possible amelioration of the symptoms of Parkinson's and Alzheimer's diseases. The smoker is aware of some of these benefits, e.g., anxiety reduction, performance enhancement, and body weight control. Other benefits like the reduction in risk for the development of Parkinson's disease are hidden. Are the benefits of nicotine use the same for all individuals? Results from several large studies comparing personality characteristics of smokers and nonsmokers would argue that the answer is "no". Warburton (67) has reveiwed the literature on the personality characteristics of smokers. His review summarizes evidence that suggests that compared with nonsmokers, smokers tend

to be more extraverted, more constitutionally anxious, and may have a higher need for achievement. Nicotine's unique ability to combine performance enhancement with anti-anxiety and anti- aggression actions may provide the smoker with a coping mechanism that addresses these personality traits. References 1. International Agency for Research on Cancer. Worldwide use of smoking tobacco. In: IARC Monographs on the Carcinogenic Risk of Chemicals to Humans, Volume 38, Tobacco Smoking, February 1985, Lyon. 2. Benowitz NL. Pharmacokinetics and pharamacodynamics of nicotine. Chapter 1 in: The Pharmacology of Nicotine, eds., MJ Rand and K Thurau, IRL Press, Oxford, Washington D.C., 1987. 3. Teeuwen HWA, Aalders RJW, Van Rossum JM, Maes RAA. Simultaneous estimation of nicotine and cotinine levels in biological fluids using high-resolution capillary-column gas chromatography combined with solid phase extraction work-up. Chapter 2 in: Clinical Pharmacokinetics of Nicotine, Caffeine, and Quinine. Nijmegen, 1988. 4. Borzelleca JF, Bowman ER, McKennis H. Studies on the respiratory and cardiovascular effects of (-)-cotinine. J. Pharmacol. Exp. Ther. 137: 313-318, 1962. 5. Andersson K. Effects of cigarette smoking on learning and retention. Psychophamacologic 41: 1-5, 1975. 6. Mangan GL and Golding JF. The effects of smoking on memory consolidation. Journal of Psychology 115: 65-77, 1983. 7. Battig K. Smoking and the behavioral effects of nicotine.

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