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Chapter 12: Nicotine and Caffeine

 General information and learning issues:
 In chapter 11, we have learned those stimulants like cocaine, amphetamine, and methamphetamine, which are relatively limited because they are illegal except for limited medical purposes. In this chapter, we are continuing to introduce more stimulant drugs that are legally consumed;
 The most commonly used stimulant (and the most widely consumed drug) in the world are nicotine and caffeine, that are found in cigarettes, coffee, tea, soft drinks, chocolate, and drugs, including pain relievers, diet pills, and cold and allergy medications;  In this chapter, we are discussing the properties of these two substances, their mechanisms of action, and their potential for abuse.

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 Practice and significance of learning issues:
 Caffeine is addictive. People who consume it regularly develop a tolerance for it;

 Caffeine causes physical dependence, producing withdrawal symptoms including anxiety, headaches, and fatigue when its use is discontinued;
 People who stop using caffeine also experience a craving for it - psychological dependence;  Nicotine is consumed in smoking, which has well been suggested to be closely associated with lung cancer;

 Nicotine withdrawal symptoms include anxiety, irritability, insomnia, depression, headaches, mood swings, difficulty concentrating, and changes in appetite.

Nicotine
 Nicotine is an alkaloid found in tobacco leaves;  Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann, who considered it a poison. Its chemical empirical formula was described by Melsens in 1843, its structure was discovered by Garry Pinner in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904 – history of finding.  What we are concerned is about its action as a stimulant in mammals and is the main factor responsible for the dependence-forming properties of tobacco smoking – reinforcing properties.  According to the American Heart Association, the nicotine addiction has historically been one of the hardest addictions to break. The pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine – Smokers are actually the nicotine dependent!  Nicotine forms salts with acids that are usually solid and water soluble, which easily penetrates the skin – features of pharmacokinetics;  Free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 35 °C in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked - features of pharmacokinetics;  The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves – pharmacological actions of nicotine;  Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major (70-80%) metabolite is cotinine.

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the rapidly repeated. which is approximately twice as fast as when the drug is administered IV. The amount of available nicotine depends mainly on features of the smoker's behavior such as the number of puffs and the length of each puff.  A typical smoker takes about 10 total puffs on a cigarette at intervals of approximately 30-60 s. Each puff delivers a small burst of nicotine to the brain. Thus smoking a cigarette is the quickest and most efficient method of delivering nicotine to the brain.  Levels of nicotine in the arterial blood circulation following smoking are important index of reflecting how much of the drug is reaching the brain.  It enters the smoker's lungs mainly on tiny particles called tar.Nicotine (continued)  Features of pharmacokinetics and its contribution to withdrawal and dependence 3  The typical cigarette contains between 6-11 mg of nicotine. 10 puffs per cigarette yields 300 separate “hits" of nicotine each day. puff-by-puff drug delivery that occurs during smoking permits the user unmatched control over both the pattern of intake and the dose. the arterial concentration falls to the same level as the venous concentration.  Arterial nicotine rises more rapidly and reaches a much greater peak than the concentration in venous blood. If the person smokes 30 cigarettes per day. . although no more than 1-3 mg actually reaches the bloodstream of the smoker. and along with nicotine.  Within a few min. a complex mixture of hydrocarbons that are known to be carcinogenic. Moreover.  The rapid transit of nicotine to the brain is thought to powerfully reinforce smoking behavior.  The nicotine first reaches the brain in about 7 s. where the drug produces its reinforcing effects. these sensory qualities contribute significantly to the reinforcing effects of smoking. Tar is an important contributor to the taste and smell of cigarette smoke.

and β. 4 . some of them bind nicotine with a much higher affinity than others. However. because of tolerance that has also developed over the same time period.β2x3) in the CNS/PNS.  In the brain. see Chapter 6).β. since each dose builds on the re’sidual nicotine left over from that day's previous cigarettes.and three β-subunits are thought to be a high-affinity nAChR.  Mechanisms of Nicotine Action (pharmacology):  Nicotine works mainly by activating nicotinic cholinergic receptors (nAChRs). yet at the same time the nicotine tolerance built up over the previous day partially dissipates. it is typically around 2 h.(α4X2. several different varieties of each subunit are present in the brain. this does not cause greater and greater effects.Nicotine (continued)  Although the elimination (drug clearance) half-life of nicotine varies among individuals (related at least partially to differences in the level of CYP2A6).  Mild nicotine withdrawal emerges during the overnight period while the smoker is sleeping. one of the two basic subtypes of acetylcholine (ACh) receptor.δ.γ.  Despite the fact that all of these receptors are considered nicotinic because of their basic structure and function.  Because of these two processes.  Frequent smoking leads to ever increasing peak levels of nicotine across the day. two α. However. This requires that the user smoke repeatedly over the day to avoid withdrawal symptoms due to falling blood nicotine levels (a sustained level of nicotine is needed to avoid withdrawal responses).  nAChRs are ionotropic receptors comprising five separate protein subunits with only α. and that these subunits are somehow different from those found on muscle cells (αx2. the individual awakens the next morning with a strong craving for a cigarette but also may experience the strongest or best response that he will have all day.

the receptors function by enhancing neurotransmitter release from the terminal.  Peripherally. striatum.  Some nAChRs are located presynaptically. that is. on nerve terminals. At this location.  The high-affinity nAChRs are commonly thought to possess two α. and monoamine-containing nuclei such as the substantia nigra.  This causes a depolarization block.and three β-subunits. and within this general category the most common type of receptor contains a mixture of α4.  High doses of nicotine lead to a persistent activation of nicotinic receptors and a continuous depolarization of the postsynaptic cell. leading to a fast excitatory response by the cell. 5 .Nicotine (continued)  High-affinity nAChRs are found in many parts of the CNS. ventral tegmental area (VTA) . hippocampus. including the cerebral cortex. and the cell cannot fire again until the nicotine is removed.  Some nAChRs also allow significantly a mounts of Ca2+ to enter the cell. a high dose of nicotine exerts a biphasic effect that begins with stimulation of nicotinic cholinergic functions but then turns to a nicotinic receptor blockade. This biphasic action accounts for the features of nicotine poisoning. thalamus. such receptors are found in the ganglia of the autonomic (parasympathetic and sympathetic) nervous system.  When nicotine binds to a nicotinic receptor. thereby stimulating Ca2+dependent second messenger functions. and the raphe nuclei. Thus. This depolarizes the cell membrane.and β2-subunits.  Behavioral and Physiological Effects  Nicotine elicits different mood changes in smokers compared to nonsmokers:  The mood-altering effects of nicotine depend on whether the subject is an abstinent smoker or a nonsmoker. it opens a channel that allows sodium (Na+) ions to flow into the cell across the plasma membrane. locus coeruleus.

Nicotine (enhanced recognition)  In temporarily abstinent smokers (regular or established) .  Cognitive enhancement by nicotine is also indicated by the drug's effects on electroencephalogram (EEG) activity. particularly those involving attentional demands. This effect is likely due to relief from nicotine withdrawal symptoms. lightheadedness or dizziness. Although this is mediated in large part by the muscarinic cholinergic receptors.  In contrast. Much of this enhancement appears to be due to alleviation of withdrawal-related deficits. and sometimes nausea.  If you either smoke now or have ever smoked in the past.  There is some indication that nicotine has positive effects on cognitive performance even in nonsmokers. . nicotinic receptors could also be involved. particularly those involving attentional demands. you may recall having experienced some of these same effects when you tried your first cigarette. nicotine given to nonsmokers more often elicits feelings of tension.  Nicotine enhances cognitive function:  ACh plays an important role in certain aspects of cognitive functioning. administration of pure nicotine usually 6 increases calmness and relaxation.  Administration of nicotine to abstinent smokers also leads to enhanced performance on various cognitive tasks.  Nicotine injection decreased reaction times of both smokers and non-smokers in a task requiring sustained visual attention. arousal.  Abstinent smokers given nicotine show enhanced performance on many kinds of cognitive tasks.

 Using a mutant mouse strain that lacks the β2-receptor subunit. The nicotine-treated animals showed better working memory as indicated by a greater number of arm entries before they committed their first error (going into a previously entered arm). 7 . However. nicotine produced increased retention in the wild-type mice as indicated by greater latency to enter the dark compartment. 4.Nicotine (enahnced recognition)  Nicotine enhances working memory (short-term. Compared to vehicle treatment. Since the β2-subunit is most commonly found along with α4.2 mg/kg) or placebo and then were tested for their performance in the radial arm maze. receptors may be critical for the memory-enhancing effects of nicotine.19) Rats received an acute injection of either nicotine (0. No such effect was observed in the mutant (β2-subunit knockout) mice. nicotine had absolutely no effect on memory in the β2 knockout mice. the involvement of particular nicotinic receptor subtypes on the behavioral and physiological effects of nicotine is studied. this finding raises the possibility that α4β2. requires to make a correct response quickly) of rats in the radial arm maze (see Fig. Wild-type (genetically normal) mice showed enhanced retention of a one-trial passive avoidance task when given a low dose of nicotine immediately after the learning trial (one-time only).

since β2 knockout mice show little selfadministration of nicotine. demonstrating that these effects are mediated by nicotinic cholinergic receptors.  High-affinity nicotinic receptors. Firing rates of a representative neuron in the VTA (A) and another neuron in the substantia nigra (B) are shown by the amplitude of the rate histogram. when activated. Smoke containing approximately 100 μg of nicotine was inhaled several times for 2 minutes during each trial (shaded area).  Lesioning the dopaminergic innervation of nucleus accumbens with 6-OHDA significantly attenuated nicotine self-administration.  Several subtypes of nicotinic receptors are probably involved in the activation of DA neurons and the elicitation of behavioral reinforcement. Tobacco smoke caused a substantial increase in VTA neuronal firing that returned to baseline within a few minutes. A smaller but still noticeable effect also occurred for cells in the substantia nigra. Activation of midbrain dopamine neuron by tobacco smoke Rats were connected to an artificial respirator through which tobacco smoke (TS) could be delivered. which causes increased DA release in the NA. . Note that prior intravenous (lV) infusion of the selective nicotinic receptor antagonist mecamylamine (lower righthand part of each graph) completely blocked the effects of tobacco smoke on dopaminergic neuron firing.  Nicotine-induced activation of DA neurons in VTA and subtantia nigra is evident by way of directly inhaling cigarette smoke.Nicotine (reinforcing properties)  Nicotine's reinforcing effects are mediated by activation of the mesolimbic dopamine system: 8  The mesolimbic dopamine (DA) pathway from the VTA to the nucleus accumbens (NA) plays a key role in nicotine's reinforcing effects (reward response).  Among these may be receptors that contain the β2-subunit. located in the VTA stimulate the firing of dopaminergic neurons.

 If a sufficient dose has been ingested. . Activation of the adrenal glands and sympathetic ganglia leads to symptoms of physiological arousal such as tachycardia (increased heart rate) and elevated blood pressure. Consequently. The action of nicotine on parasympathetic ganglia increases hydrochloric acid secretion in the stomach. which sometimes leads to chronic diarrhea that is especially harmful to individuals vulnerable to colitis. abdominal pain. nicotine can activate elements of both the sympathetic and parasympathetic systems to cause a wide spectrum of physiological manifestation. particularly if the smoker has high blood pressure to begin with. who weighs an average of 8-10 pounds less than gender. and weakness. This mild physiological arousal is thought to contribute to the reinforcing features of smoking. administration of artificial respiration. One consequence that many cigarette smokers find desirable is the constraining effect of nicotine on body weight. confusion. vomiting and diarrhea. death may occur from respiratory failure. 1.  Treatment involves an attempt to remove the nicotine from the victim's stomach (if the nicotine has been swallowed). 2. salivation. There is also increased muscle contraction in the bowel. This effect of nicotine has been attributed to an increase in metabolic rate combined with appetite suppression. a chronic irritability of the colon.and age-matched nonsmokers. The same effects could increase the smoker's risk for cardiovascular disease and cerebrovascular accidents (strokes). But what would you believe? Would you recommend smoking for weigh control? 9  Nicotine is a toxic substance that can be fatal at high doses:  Nicotine is a toxic substance that can cause dangerous symptoms such as nausea.Nicotine (physiological effects)  Nicotine produces a wide range of physiological effects:  Nicotinic receptors are abundantly expressed in autonomic ganglia. which exacerbates or contributes to the formation of stomach ulcers. and dealing with drug-induced shock. and quitting smoking usually results in weight gain. 3.

teeth chatter.  Typical nicotine withdrawal symptoms include gasps. If it develops a long-term exposure.  Laboratory studies have found that many effects of nicotine administration are attenuated (tolerance) in smokers compared to non-smokers. ptosis (drooping eyelids).  Nicotine dependence in smokers can be seen by either stopping chronic administration of nicotine (such as 1-2 weeks’ infusion of nicotine) or giving a nicotinic receptor antagonist. or clammy hands) in nonsmokers.Chronic Nicotine (tolerance)  Chronic exposure to nicotine induces tolerance and dependence: 10  Repeated exposure to nicotine can lead to tolerance and. in the dependent animals (dependence). in some cases. within the brain) and peripheral (outside of the brain) nicotinic receptors.  Subcutaneous injection of a high dose of nicotine elicited an aversive reaction consisting of at least some symptoms of mild nicotine toxicity (nausea.  Current evidence suggests that the nicotine abstinence syndrome is mediated by a combination of central (that is. like mecamylamine. because DA release in the NA is inhibited during mecamylamine precipitated nicotine withdrawal. palpitations. The peripheral receptors might be those located within autonomic ganglia. shakes or tremors. but no such reaction in smoker (tolerance). headache. stomachache. dizziness.  Nicotinic receptors in the VTA play a significant role in nicotine withdrawal and that this role at least partially involves changes in the NA’s DA release. whereas the central component of nicotine withdrawal may involve receptors in the VTA. the chronic tolerance occurs. and withdrawal symptoms can be elicited by injecting mecamylamine directly into the VTA of nicotine-dependent rats (but not known further mechanisms). reduced locomotor activity. It is only present in smokers and others who use tobacco frequently. . sweating. and increased startle reactivity. sensitization.

and then Asians. about 14% of college graduates are smokers. For individuals 18 years or older.  The prevalence of cigarette smoking is inversely related to level of education. although it can be seen from the figure that this gender difference is not present within the l2-to-17 -year age group. Hispanics and African Americans. .  Males are generally more likely to smoke than females.  Across different ethnic groups. compared to 32% of high school graduates and 35% of people without a high school diploma.  Tobacco use varies significantly by age. followed by whites. the highest rate of smoking occurs in Native Americans. with the highest incidence in the 18-to-25-year age range.Chronic nicotine (smoking)  Cigarette Smoking  How many smokers during nearly 100 yrs?  Who are they? 11 Yearly per capita cigarette consumption in the US from 1900 to 1998 for individuals 18 years of age or older  Approximately 30% of the population age 12 years or older is tobacco users.

counteracting stress and/or boredom.  Generally.  Moreover.Chronic nicotine (smoking)  Cigarette smokers progress through a series of stages in their smoking behavior:  Most smokers pick up the habit during adolescence.  Most investigators agree that smokers pass through several different stages on their way to eventual nicotine dependence . stage changes are usually toward heavier cigarette use.development. and simple curiosity . There are many theories about why teenagers take up smoking .reasons. 12 . including the health consequences . unless an individual is actively attempting to quit. improving self-image and enhancing social acceptance (assuming that one's friends are already smokers). young people tend to emphasize the positive elements of smoking while disregarding or denying the negative aspects. there can be movement in both directions along the continuum from occasional to regular smoking.start.reasons.  However.  Some of the hypothesized reasons include establishing feelings of independence and maturity (by defying parental wishes or societal norms).

 However. It is well established that smoking intensity is increased when smokers of regular cigarettes switch to a brand that is low in nicotine and tar. That is the nicotine obtained through smoking has the beneficial effects of increasing mood control and enhancing concentration. which argues that the positive effects experienced when smoking actually constitute the alleviation of withdrawal effects such as irritability. Smoking behavior itself. and poor concentration (passive). even a brief abstinence of a few hours leads to craving and a growing urge to smoke. These feelings correlate with a drop in nicotine levels in the individual's bloodstream.Chronic nicotine (smoking)  Why do smokers smoke? 13  Smoking and stress: Based on the reports by the smokers that smoking causes relaxation. 5. lettuce-based cigarettes) have never been commercially successful. 3. which hypothesizes a nicotine resource model. the abstinent symptoms last? The next figure presents time course analysis of tobacco withdrawal symptoms and the effects of nicotine replacement therapy from one study that examined the time course of withdrawal symptoms as well as the ability of nicotine gum to prevent such symptoms. which are based on standardized smoking by a machine. and hunger and weight gain. and increased ability to concentrate. This change in smoking behavior increases nicotine yields well beyond those specified by the Federal Trade Commission (FTC). if yes. anxiety. insomnia. 2. anxiety. the deprivation reversal model. Cigarettes devoid of nicotine (for example. For habitual smokers who meet the criteria for nicotine dependence.  The role of nicotine in smoking (one of the most critical factors causing addiction/dependence): 1. The much longer abstinence that occurs when people try to quit smoking leads to a more complex abstinence syndrome characterized not only by tobacco craving but also by irritability. Delivery of nicotine is obviously one of the key factors in smoking. Withdrawal from regular tobacco use leads to significant abstinence symptoms that are thought to result primarily from removal of nicotine from the person's system. accumulated evidence favors an alternative model. impatience. alleviation of stress. difficulty concentrating. restlessness. These are still debated. .  Will and how long. 4.

it is found that about 20-25% of the subjects still reported significant symptoms at the 4-week time point. 4. Most of these symptoms are due to nicotine dependence. These and other experimental results indicate that the nicotine-induced abstinence syndrome is not the only reason that most regular smokers find it so difficult to quit their habit. However. but the average levels of most symptoms were at or near baseline at 4 weeks. BL) and then again 1 and 4 weeks later. more than 2/3 of the subjects were back smoking at a 6-month follow-up test despite lacking the typical withdrawal symptoms. 3. the fact is more complicated according to other studies. However. even with the nicotine gum. Nicotine gum clearly prevented almost all of the withdrawal symptoms except for hunger and weight gain. 1. 2. Placebo data suggest that the abstinence syndrome from tobacco is relatively shortlasting. 14 .Chronic nicotine (smoking) Regular smokers who wanted to quit smoking were randomly assigned to either a nicotine gum or placebo gum group. symptom ratings were obtained before the beginning of treatment (baseline. 5. Most abstinence symptoms were still present at 1 week post cessation. The figure illustrates data for those subjects who were abstinent at the 4-week test point compared to those who failed to quit (Nonquiters) during the study.

a 10-year smoker has had over 1 million "learning trials" in which a mouthful of cigarette smoke was paired with one of those bursts of nicotine.  The MAO-B in both brain and peripheral organs is decreased in smokers. since it is not found after the smoking of a single cigarette (acute). namely the taste and smell of cigarette smoke. Brain imaging studies using positron emission tomography (PET) found a large reduction in the activities of both monoamine oxidase A (MAO-A) and MAO-B in smokers compared to nonsmokers (see the figure).  One factor is the sensory aspects of smoking.Chronic nicotine (smoking)  It is interesting that some individuals.  Since MAO is an enzyme that plays a critical role in metabolizing DA. 15  The role of other factors in smoking:  Although withdrawal symptoms (critically due to nicotine) undoubtedly play an important role in maintaining the smoking habit in dependent smokers. it is possible that smoking not only causes DA release (acute) but also slows its breakdown (chronic).  One additional factor is a pharmacologically unrelated to nicotine. As these organs are exposed to catecholamines (CA) via the circulation as well as from sympathetic nerve endings. Assuming 30 cigarettes per day and 10 puffs per cigarette. can smoke small numbers of cigarettes regularly without becoming dependent.  Chippers do develop tolerance but might not be dependence. called chippers.  This effect is not produced by administration of pure nicotine (nicotine-like drug is given. . which demonstrates a separation between the processes underlying nicotine tolerance and dependence.  For these reasons. it is likely that the sensory aspects of smoking help maintain this behavior under conditions where direct nicotine reinforcement is minimal due to receptor desensitization (not sure yet desensitized due to chronic?). other factors also contribute to this habit. not smoking) and therefore must be caused by other substances present in cigarette smoke. however. a deficiency in MAO-B could result in adverse consequences due to augmented CA activity throughout the body.  MAO inhibition seems to require repeated cigarette use.

and so on. the motivation to quit. . However. including tar. the success rate is very low due to addiction to nicotine is so powerful.  A variety of behavioral and pharmacological approaches for treating tobacco dependence are available.  Cigarette smoking increases the risk for many life-threatening illnesses. whether or not the smoker lives and/or works in a smoking environment. and the strong association between cigarette smoking and lung cancer has been known for well over 30 years.  Even if a given therapeutic program claims a high success rate for its clients.  Tar contains a number of identified carcinogens. stroke. the intensity of the abstinence syndrome. such claims are meaningless unless there is careful follow-up for months and years to ascertain long term abstinence. and atherosclerosis. but it is important to recognize that the success rate of any treatment approach is influenced by numerous variables.  Smokers are at increased risk for heart attack.  Pregnant smokers in particular should try to stop or at least cut back on their smoking habit. which delays the infant's development and puts him at risk for other complications. including several kinds of cancer as well as cardiovascular disease.  The deleterious (harmful) effects of smoking stem from a combination of factors. and possibly also nicotine.  Behavioral and pharmocologicaI strategies are used to treat tobacco dependence:  Surveys indicate that 70-75% of current smokers in the US would like to quit smoking. and about 4045% of daily smokers actually attempt to quit each year. Smoking can also lead to other respiratory diseases such as emphysema and chronic bronchitis.Chronic nicotine (smoking)  Smoking is a major cause of illness and premature death: 16  It has been estimated that one-third to one-half of smokers die prematurely due to their exposure to tobacco. such as the duration of smoking behavior and number of cigarettes smoked daily. carbon monoxide gas that is produced by the burning of tobacco. Smoking during pregnancy is the leading cause of low birth weight.

Habitrol. but it does reduce the amount of use. However. o Levying of high taxes on tobacco products. Pharmacological interventions: The most common pharmacological intervention for smoking cessation is nicotine replacement. Nicotrol). where absorption is minimal and there is substantial first-pass metabolism in the liver. and nicotine lozenges (Commit Lozenges). This has the advantage that nicotine can be absorbed by the buccal mucosa (mucous membranes lining the mouth) rather than the gastrointestinal tract. particularly those that provide social support and/or coping-skills training to their clients. nicotine nasal spray (Nicotrol NS). This approach is based on several premises: o The difficulty associated with smoking cessation is significantly related to nicotine withdrawal symptoms.  This was later followed by the transdermal nicotine patch (Nicoderm. nicotine inhaler (Nicotrol Inhaler). 17 . o Various self-help programs involving books or manuals are used by smokers. o Mandated health warnings on cigarette packages by the Surgeon General. o There are safer ways for individuals to obtain nicotine than by smoking.  Nicotine replacement was first accomplished by formulating a special nicotine-containing chewing gum (nicotine polacrilex). o Individual or group counseling programs provided by health professionals. o Blocking (or at least reducing) these symptoms by maintaining a certain circulating level of nicotine can assist in terminating smoking. these may not prevent people from starting to use these products.Chronic nicotine (treatment) Behavioral interventions: Strategies for directed toward discouraging young people from beginning tobacco use or giving it up if it is already habitually used: o Anti-smoking appeals.

combination treatments such as nicotine gum plus the patch or the nicotine inhaler plus the patch may be more effective than either treatment alone in helping some smokers quit their habit. a number of studies have shown that success rates are increased when behavioral or psychosocial (supportive) therapy is provided along with nicotine replacement. . it should not be surprising that a combined therapeutic approach gives the smoker the best chance of quitting. Second. Given the complex nature of nicotine addiction and the smoking habit.Chronic nicotine (treatment)  Below lists some of the advantages and disadvantages of each nicotine delivery vehicle: 18  Two other points should also be noted with respect to nicotine replacement therapy: First.

the combination of bupropion and the patch did not reduce symptoms below the level achieved with either treatment alone. The intensity of withdrawal symptoms was rated and compared to baseline (pretreatment) scores for the first 6 days after quitting (A). nicotine patch alone. an unusual antidepressant medication thought to act by inhibiting DA and norepinephrine reuptake. which shows that sustained release bupropion is as effective as the nicotine patch in reducing nicotine withdrawal symptoms in newly abstinent smokers. and the drug is now available for smoking cessation in the form of a sustained-release preparation. All treatment groups showed reduced withdrawal symptoms compared to the placebo group.Chronic nicotine (treatment)  In addition to nicotine replacement therapy. 19  Formal studies confirmed the efficacy of bupropion. bupropion plus nicotine patch. or placebo. bupropion. . and then at weekly intervals for a total of 9 weeks (B). Efficacy of bupropion treatment in reducing symptoms of smoking withdrawal Subjects were enrolled in a smoking cessation program in which they received bupropion alone. is reported to reduce cravings and were able to quit smoking without additional therapeutic intervention. However.

 Tea leaves contain significant amounts of both caffeine and a related compound called theophylline. 20 . you are consuming caffeine at least partly for its pharmacological properties as a stimulant. which are the seeds of the plant Coffea arabica.  The major source of caffeine is coffee beans. it is virtually completely absorbed from the gastrointestinal tract within 30-60 min.  Caffeine absorption begins in the stomach but takes place mainly within the small intestine. but the average value is about 4 hours.  The typical caffeine content of various foodstuffs and over-the-counter drugs is shown in Table.Caffeine  While you are drinking a cup of coffee or tea.  Basic Pharmacology of Caffeine  Caffeine is normally consumed orally through the beverages in which it is present. The plasma half-life of caffeine varies substantially from one person to another. people who drink coffee repeatedly over the course of a day experience gradually rising plasma caffeine concentrations.  Consequently. Under this condition.

at low doses. These metabolites account for almost all caffeine excretion. caffeine does more than just increase our arousal.  Compared to placebo. and enhanced sociability. At high doses of caffeine.  The rate of plasma clearance is stimulated by smoking and reduced when smoking is terminated.5% through the feces. particularly since caffeine is anxiogenic (anxiety provoking) at high dose. including feelings of well-being. approximately 95% of caffeine metabolites are eliminated through the urine. .  Caffeine is converted to a variety of metabolites by the liver. caffeine administration significantly increased alertness. and decreased reaction times on a focused attention task.  In humans.  The resulting increase in plasma caffeine levels could contribute to cigarette withdrawal symptoms in heavy coffee drinkers. caffeine has stimulant effects as shown by increased locomotor activity. humans do not show behavioral depression like rodents but rather experience feelings of tension and anxiety. and then tested a second time. because it seems that high level of caffeine in the blood evokes more smoking to clear more caffeine. enhanced energy or vigor. as only 1-2% of an administered dose is excreted unchanged.  Following figure shows the results of one such study in which college students were tested on a variety of mood and performance measures. this effect is reversed and animals actually show reduced activity. given a beverage containing either 40 mg of caffeine or no drug (decaffeinated placebo).Caffeine (continued)  Most of this caffeine is then cleared from the circulation during sleep. At high doses. 2. reduced tension. Moreover. self-confidence.  Humans receiving low or intermediate doses of caffeine report a variety of positive subjective effects. and the remainder through other bodily fluids such as saliva. increased work motivation. increased alertness and ability to concentrate. 21  Behavioral and Physiological Effects  Acute subjective and behavioral effects of caffeine depend on dose and prior exposure:  Animal studies show that.  People ingest caffeine mostly for its stimulating and fatigue-reducing effects.

Caffeine (continued)  Some of caffeine's subjective effects may be related to its peripheral physiological actions.  The most important clinical use of caffeine is in the treatment of newborn infants who show apneic episodes (periodic cessation of breathing). Therapeutic uses of caffeine:  Caffeine is a constituent of several over-thecounter analgesic agents. particularly in individuals who are especially sensitive to the drug's cardiovascular effects. particularly epinephrine release.  These include increased blood pressure and respiration rate. and stimulation of catecholamine. Caffeine can be lifesaving in these babies by regularizing their breathing.  There is growing concern that even though the influence of caffeine on blood pressure is generally small. It is suggested that caffeine is mildly effective in the treatment of (nonmigraine) headache either alone or acting synergistically with aspirin or acetaminophen (the active ingredient in Tylenol). chronic caffeine use may represent a risk factor for heart disease or stroke. enhanced water excretion (diuresis). 22 .

insomnia.  Caffeinism is caused due to chronic ingestion of excessive amounts of caffeine. including headache and lethargy or fatigue.  Chronic caffeine consumption may be a risk factor for certain physiological disorders. however. .  For those of you who are regular caffeine users. The figures show withdrawal symptoms if caffeine is withheld for a prolonged period of time. Caffeine withdrawal symptoms rapidly appeared during abstinence.  However. nervousness. which is characterized by restlessness.  Caffeine withdrawal symptoms and resulting craving may be experienced. perhaps you have occasionally been forced to miss your morning cup of coffee or tea. and these may last a few days but then dissipate. the symptoms gradually disappeared over the course of several days. During the second phase (middle panel).Caffeine (continued)  Regular caffeine use leads to tolerance and dependence: Studies show that regular caffeine use does lead to tolerance and dependence. caffeine administration was reinstated. You might experience at least a few psychological and/or physical symptoms. 23 Time course of caffeine withdrawal in regular users During the first phase of the study (left panel). and physiological disturbances including tachycardia (increased heart rate) and gastrointestinal upset. In the third phase (right panel). then you are dependent on caffeine. placebo capsules were substituted for caffeine without the knowledge of the subjects. subjects were maintained on 100 mg of caffeine daily in capsule form while abstaining from all dietary sources of caffeine. this common drug dependence is harmless except in a small percentage of individuals who have extremely high levels of caffeine intake. If so.

other evidence does not seem to verify caffeine-induced activation of cAMP is done by inhibition of phosphodiesterase) !!!??? c. Figure on right illustrates idealized concentration-response functions for the various cellular effects of caffeine. phosphodiesterase inhibitors that differ in their chemical structure from caffeine or theophylline are actually behavioral depressants rather than stimulants!!!??? 2. Such activation can occur at brain caffeine concentrations. it has been less attention. In addition. the enzyme that breaks down cAMP (increase in cAMP?). but the caffeinism’s dependence is not as severe as seen in other drugs. b. but are insufficient to inhibit phosphodiesterase (in other words. a. a. 24  Mechanisms of Action  It is clear that caffeine does not directly influence catecholamine systems in the manner of the psychomotor stimulants amphetamine and cocaine. This led to the theory that the behavioral activation produced by caffeine or theophylline was caused by a buildup of brain cAMP concentrations. even into the toxic range associated with caffeinism. stimulation of Ca2+ release within cells. and blockade of A1 and A2 receptors for a substance called adenosine. The levels of caffeine associated with one or a few cups of coffee. Thus. The other effects require much higher doses. only the adenosine receptor blockade would come into play. b. including blockade of GABAA receptors. .Caffeine (continued)  It is generally believe that relief from withdrawal is a major factor in chronic coffee drinking. When the biochemistry of the second messenger cyclic adenosine monophosphate (cAMP) was first beings studied. but how else might it work? 1. investigators discovered that caffeine and theophylline are inhibitors of cAMP phosphodiesterase. Several other cellular actions of caffeine have been identified.

It can be released into the brain extracellular fluid.  Caffeine most potently blocks the A1 and A2A receptor subtypes.  It is not yet very clear whether adenosine plays a role in feelings of drowsiness or sleepiness in humans. the cell can no longer identify adenosine because caffeine is taking up all the receptors. and A3). However. which are therefore thought to mediate most of the behavioral effects of caffeine in laboratory animals. they are “speeding up” due to the receptors are bound by caffeine. If it does.  There is now overwhelming evidence that blockade of adenosine receptors underlies caffeineinduced behavioral stimulation – caffeine might have a blocking effect on adenosine receptors. then one can see how that first cup of coffee in the morning helps shake off the lingering sleepiness of the previous night.Caffeine (continued)  Adenosine and its receptors:  Adenosine in the brain seems to serve a neurotransmitter-like function. As a result. because it blocks the receptors. . A2B. or how a mid-afternoon coffee break brings workers back to an alert state during a post-lunch period of drowsiness. Instead. it does not slow down the cell's activity like adenosine would. Extracellular adenosine levels in the basal forebrain are significantly elevated during prolonged wakefulness. the neurons are not slowing down because of the adenosine's effect. where it acts on several different types of identified and specific adenosine receptors in nerve cell membranes (A1. which causes drowsiness (a sleepy feeling) by slowing down neuronal activity. or how that late-night cup of coffee keeps you awake unless you are already tolerant to caffeine. caffeine looks like adenosine that binds to the adenosine receptor. A2A. indicating this substance is responsible for the drowsiness that occurs following a period of sleep deprivation – long-term wakefulness is a trigger for getting sleep.  To a nerve cell. 25  Adenosine binds to adenosine receptors. Accordingly.

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