Nicotine dependence – human and animal studies, current pharmacotherapies and future

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Review

Nicotine dependence – human and animal studies, current pharmacotherapies and future

perspectives

Magdalena Zaniewska, Edmund Przegaliñski, Ma³gorzata Filip

Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Correspondence:Magdalena Zaniewska, e-mail: zaniew@if-pan.krakow.pl

Abstract:

Nicotine dependence is a disease of constantly growing importance. This mini-review describes the effects of nicotine in humans and focuses on the various laboratory animal models developed to study the dependence-related behavioral effects of nicotine. In addition, we outline the current therapeutic approaches designed to substitute nicotine from cigarette smoke with safer compounds or to relieve symptoms of nicotine withdrawal during smoking abstinence. Since several pharmacotherapies have failed to be effica- cious in all patients, we also assess the clinical effectiveness of newer agents in relation to existing drugs.

Key words:

nicotine, drug discrimination, self-administration, reinstatement of seeking behavior, sensitization, rat, clinical trials, nicotine pharmacotherapy

Abbreviations: ACh – acetylcholine, DA – dopamine, EMEA – European Medicines Agency, FDA – Food and Drug Admin- istration, GABA –g-aminobutyric acid, Glu – glutamate, 5-HT – serotonin, IARC – International Agency for Research on Cancer, NA – noradrenaline, nACh – nicotinic acetylcholine, NRT – nicotine replacement therapy

Introduction

Addiction is a chronic disease of the central nervous system, characterized by loss of control over taking addictive substances that leads to compulsive drug- seeking and drug-taking behaviors. The disease is characterized by relapses that can be triggered even

after a very long period of abstinence and is accompa- nied by psychic, somatic and vegetative disturbances.

Addiction is associated with the distortion of the reward system, an important functional system of the brain that is physiologically responsible for feeding, water intake, and sexual and aggressive behaviors [42]. The neuroanatomical localization of the reward system is the ventral tegmental area, which contains dopaminergic neurons that send projections to the nu- cleus accumbens, amygdala and other limbic structures of the brain forming the mesolimbic pathway, and to the prefrontal cortex via the dopamine (DA) mesocortical pathway [3, 42].

The reward system can be stimulated by different chemical substances that produce feelings of pleasure and euphoria and, when taken frequently, lead to ad-

Pharmacological Reports 2009, 61, 957965 ISSN 1734-1140

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Nicotine

Nicotine is an alkaloid found in the leaves of the to- bacco plant (Nicotiana); cigarettes are manufactured from the two species N. tabacum and N. rustica. The first indications of tobacco use by humans (smoking of dried tobacco leaves in a clay pipe called a tobaga by American Indian tribes) were discovered in the 15th century, after the landing of Columbus and his crew in the Caribbean. In the 16th century, tobacco was already known in the Iberian Peninsula, and its further spread through Europe was due to a French physician and diplomat, Jean Nicot de Villemain, who recommended the use of nicotine as medication.

Trace amounts of nicotine are found also in potatoes, tomatoes and sweet pepper [1]. Nicotine content in tobacco leaves approximates 1.5 % of their dry weight.

A cigarette contains 8.4 mg of nicotine on average, of which 1–3 mg is absorbed in humans through the in- halation of the smoke [64, 74].

Nicotine was isolated from tobacco in 1828; its structure was established 15 years later, and it was synthesized in 1904 [1].

Naturally occurring nicotine is an optically active compound. Tobacco contains mostly the (S) enantiomer ((-)-nicotine), which has a stronger biological effect and is metabolized more slowly in the organism than the (R) enantiomer ((+)-nicotine) [64] (Fig. 1).

Nicotine present in tobacco smoke is inhaled to the lungs, where it is absorbed into the circulation and is

delivered to the central nervous system and other tis- sues within a few seconds. Nicotine can also be absorbed in the digestive tract, mainly in the small intes- tine, as a result of swallowing saliva, and also from the skin surface [64, 74]. The highest nicotine concen- trations have been found in the brain, lungs and spleen [64, 74]. The half life of nicotine in the blood is about 120 min in humans, 55 min in rats and 10 min in mice [74, 77]. Nicotine biotransformation occurs principally in the liver; much less is metabolized in the lungs and brain [64, 74]. The main metabolite, cotinine, is formed in the reaction catalyzed by an en- zyme CYP2A6 belonging to the cytochrome P450 family. Other metabolites include nicotine N’-oxide, trans-3’-hydroxycotinine, 5’-hydroxycotinine, cotinine N-oxide, 3-pyridyloacetic acid and nornicotine. A small fraction (5–10%) of nicotine is excreted by the kid- neys in unmetabolized form [64, 74].

Apart from nicotine, tobacco smoke contains other substances (> 4,000 compounds) (Tab. 1). They include the following compounds: crotonaldehyde, benzo(a) pyrene, formaldehyde, cresol, methanol, naphthylamine,

Fig. 1. Structural formula of nicotine ((-)-1-methyl-2-(3-pyridyl) pyrrolidine; CH_"N)

Tab. 1.Composition of cigarette smoke

Components of cigarette smoke

Gaseous compounds Solid compounds

– carbon monoxide and dioxide – volatile N-nitrosamines

– nitriles and other nitrogen compounds – volatile hydrocarbons, alcohols, ketones – pyridine alkaloids (e.g., nicotine, nornicotine) – amines

– organic bases

– pyridine alkaloids (e.g., nicotine, nornicotine, anabasine)

– polycyclic aromatic hydrocarbons: e.g., pyrene, benzo(a)pyrene, benzoanthracene – metal ions and radioactive compounds (e.g., potassium, calcium, selenium, cadmium,

polonium, arsenic) – phenols – organic acids – N-nitrosamines

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dimethylnitrosamine, toluene, carbon monoxide and dioxide; all of them have been classified by the Inter- national Agency for Research on Cancer (IARC) as toxic and/or carcinogenic substances. There are also free radicals, harmful radioactive compounds and heavy metals in the cigarette smoke. It is worth mentioning that besides nicotine, tobacco smoke contains also other pharmacologically active alkaloids like nornicotine, anabasine, nicotirine, anatabine, cotinine and harmane [64, 73, 74]. Data from the literature indicate that the above compounds enhance the functional effects of nicotine and increase the risk of addiction [74].

Smoking cigarettes causes, apart from strong addiction, a number of cancers (affecting lung, esopha- gus, mouth, kidney, stomach, pancreas, bone marrow) and diseases of the respiratory (chronic obstructive lung disease, emphysema, asthma, respiratory tract in- fections), digestive (stomach and duodenal ulcer) and cardiovascular (ischemic heart disease, atherosclero- sis, heart attack, cerebral stroke) systems [74].

Despite the mutagenic and carcinogenic properties of cigarette smoke, the number of cigarette smokers in Poland has been estimated at 10 million people who smoke 90 million cigarettes a day [cf. 7].

Nicotine effects in humans

In humans, nicotine affects the peripheral and central nervous systems; its effects are strictly dose-dependent [74].

Peripheral effects of nicotine are attributed to the stimulation (low doses) or inhibition (high doses) of autonomic system ganglia (sympathetic and parasym- pathetic) and neuromuscular fibers. The most characteristic effects of lower doses of nicotine include an increase in blood pressure, tachypnea, gastric hyper- secretion or vasoconstriction. The use of higher doses induces the opposite effects, mostly hypoperistalsis and hypotension [74].

In the central nervous system, low doses of nicotine produce neuronal stimulation, thereby increasing vigilance, learning abilities and memory performance, while the higher doses cause feelings of pleasure, dis- torted perception, photophobia, tiredness, and deficits in concentration and memory [39, 48, 62].

Extremely high nicotine doses can lead to acute intoxication, manifested by paleness, sweating, nausea, diarrhea, headache, dizziness, muscular tremor and

confusion. In severe cases, loss of consciousness, convulsions and even death, due to respiratory center depression, may follow [58]. The lethal nicotine dose in non-smokers is 50–100 mg, while in smokers it is higher because of the development of tolerance.

Numerous studies have demonstrated the strong addictive liability of nicotine, a major component in tobacco [53]. Nicotine addiction is a complex process which in humans is comprised of the development of addiction, nicotine craving and relapses that can occur even after a very long abstinence period [44] (Tab. 2).

The development of addiction is closely associated with the rewarding and subjective effects of nicotine, while relaxation, decreased appetite, alleviation of stress and weariness symptoms, and mood elevation are other reasons why a smoker would want to have another cigarette. Social pressure (smokers’ company) and genetic factors are also important [33, 39, 44, 51, 62, 70]. It is worth emphasizing that even a single small dose of nicotine (smoking one cigarette) can induce a desire for the next cigarette, which quickly leads to addiction [25]. Notably, young smokers are the most vulnerable to quick development of addiction.

One of the crucial elements of nicotine addiction is development of tolerance, which forces a chronic smoker to smoke cigarettes more frequently. Such people also exhibit tolerance to the side effects of nicotine (nausea, vomiting, dizziness and headache) that are observed after a single nicotine use in naive smokers [74].

Abrupt nicotine withdrawal induces aversive abstinence symptoms. A smoker desperately striving to relieve these negative symptoms smokes another cigarette [51]. The withdrawal symptoms appear within the first several hours after smoking the last cigarette and in many smokers last up to 6 months [35, 51].

They include somatic (physical) and affective signs (Tab. 2). The most frequent somatic symptoms are bradycardia and increased appetite, while the most common affective symptoms are nicotine craving, depressed mood, dysphoria, irritability, anxiety, and dif- ficulties concentrating [4, 41]. It is worth noting that in nicotine dependence, smoking-associated environmental cues (e.g., cigarette commercials or seeing other people smoking) are a significant factor contrib- uting to the increased risk of relapse.

Epidemiological data indicate that smoking tobacco is very characteristic of poly-drug users also us- ing alcohol or cocaine, as well as in patients with schizophrenia, depression or attention deficit hyperac- tivity disorder [48, 57, 64].

Nicotine in human and animal research

Magdalena Zaniewska et al.

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Besides the above-mentioned harmful effects of nicotine, there are some clinical reports suggesting that this alkaloid shows a certain neuroprotective effect in Parkinson’s and Alzheimer’s disease, has therapeutic action in Huntington’s disease and Touret- te’s syndrome, reduces attention deficit in Alzheimer’s disease patients and schizophrenics, and also allevi- ates emotional disturbances and decreases pain perception [48, 62, 64].

Behavioral effects of nicotine in animals

A single nicotine dose produces changes in animal behavior and other effects resulting from the activation of specific receptors. In particular, nicotine increases locomotor activity in rodents [15, 75, 78]. However, it is worth emphasizing that the locomotor effects of nicotine are dependent on the dose (low doses produce a biphasic effect of initial hypomotility followed

tine was shown to decrease the body temperature in animals, to induce analgesic effects in the hot plate and tail flick tests and to enhance cognitive functions in rodents by improving attention, learning and memory [5, 6, 22, 47, 74]. Nicotine also produces “antidepressant-like” effects in the forced swim test (FST) in rodents [59, 65, 71] and effects characteristic of anxiolytic drugs, though in the latter case, the results are inconsistent [13, 60].

Recent data indicated that repeated nicotine treatment induces symptoms of addiction in animals [41, 44]. In particular, as in humans, addiction in animals has three distinguishable phases: development of addiction, abstinence signs and relapses (Tab. 2).

Different phases of nicotine dependence can be studied in various animal models. The rewarding effects of nicotine are examined in the self-administration procedure [17] and the conditioned place preference [43, 45]. Repeated nicotine treatment elic- its also subjective effects allowing the animals to dis- criminate between nicotine and its vehicle in the drug discrimination test [44, 67].

In animals, the withdrawal syndrome can be evoked by abrupt cessation of nicotine treatment or administration of an appropriate receptor antagonist after a period of nicotine self-administration or chronic nicotine passive administration (injections or osmotic minipumps) [41, 49, 51]. The somatic effects of withdrawal, e.g., forelimb tremor, head twitches, jumps and piloerection, appear immediately after the antagonist treatment [5, 41, 63]. The affective signs of nicotine withdrawal (e.g., anhedonia) in animals are investigated by analysis of the brain stimulation reward threshold for different brain structures in the in- tracranial self-stimulation model [40, 51]. Withdrawal from repeated nicotine treatment in animals also trig- gers “depressive-like” behaviors, manifested by an increased immobility time in the FST or “anxiogenic”

effects, such as shortening the time spent on the open arms in the elevated plus maze test [11].

Nicotine craving caused by the intake-associated environmental cues induces drug-seeking behavior and relapses in nicotine self-administration, place preference or conditioned locomotor activity models/tests [43, 45, 78].

Relapses and nicotine-induced permanent neu- roadaptive changes in the brain are modeled by, re-

Humans Animals

Addiction development - rewarding effects (feeling of satisfaction)

- subjective effects (pleasant experiences)

Addiction development - rewarding effects

- subjective effects

Withdrawal symptoms - somatic

bradycardia, gastrointestinal disturbances, constipation, increased appetite, body weight gain, nausea, headache, muscular pain, tiredness

Withdrawal signs - somatic tremor of the whole

body/forelimbs, head twitches, wet dog shakes, jumps, gasps, escape attempts, genital grooming, scratching, yawning, paw licks, mastication/teeth chattering, piloerection, muscular spasms, muscle relaxation - affective

nicotine craving, depressed mood, anxiety, irritability, nervousness, aggression, concentration deficits, insomnia

- affective

anhedonia, “depressive-like”

behavior, nicotine craving, anxiety

Relapses induced by - nicotine

- stress or environmental cue

Relapses induced by - nicotine

- stress or environmental cue

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spectively, the reinstatement of extinguished instru- mental response (pressing the lever associated with previous nicotine self-administration) of the animals to the priming dose of nicotine or nicotine-associated cue, or enhancement (sensitization) of locomotor activity in animals that were receiving repeated inter- mittent treatments of this substance [51, 56].

Mechanism of nicotine action

The mechanism of the pharmacological action of nicotine is based on the stimulation of nicotinic acetylcholine (nACh) receptors that are ion channel per- meable to monovalent (Na⁺, K⁺) and divalent (Ca⁺⁺) cations. These receptors belong to the ionotropic receptor family [77]. The nACh receptor is a pentamer composed of four types of subunits:a, b, g and d. In adults, the g subunit is replaced by the e subunit. Each subunit of the nACh receptor contains four transmem- brane domains. The subunits of the nACh receptor form different hetero- or homomeric combinations [38].

In mammals, nACh receptors are localized in the central nervous system, autonomic ganglia, at neuromuscular junctions, on immune cells, keratinocytes, and intestinal and pulmonary mucosa [38]. Neuronal nACh receptors in mammals are formed by eight types of a (a₂–a₇anda₉–a₁₀) and three types of b (b2–b4) subunits [38].

In the central nervous system, nACh receptors are localized on acetylcholine (ACh)-synthesizing neurons (somatodendritic receptors) and their terminals in many brain structures [28, 37, 69]. The nACh receptors can also function as pre- and postsynaptic receptors present on other neurons. It was shown that the stimulation of somatodendritic and presynaptic nACh heteroreceptors elevates the release of different neurotransmitters, while activation of postsynaptic nACh receptors mediates fast excitatory transmission [38, 62]. The nACh heteroreceptors are localized on the serotonin (5-HT) endings, mainly in the striatum and hypothalamus, on DA terminals in the striatum, and on endings of glutamatergic neurons in the midbrain and of g-aminobutyric acid (GABAergic) neu- rons in the ventral tegmental area [3, 9, 37, 51, 62, 63, 68]. Moreover, these receptors are present on DA and GABA neurons in the ventral tegmental area and sub- stantia nigra [3, 9, 37, 51, 62, 63].

Nicotine exhibits variable affinity for nACh receptors containing subunitsa4b2,a3b2ora6b2(Tab. 3).

The studies performed so far have demonstrated that nACh receptors composed ofa_4,a₅,a₆andb₂subunits, and alsoa7homomeric pentamers, play an important role in the functional effects of nicotine [9, 28, 38, 62, 63].

Nicotine, by acting on its specific receptor, evokes changes in the cell membrane electrical potential, thus causing membrane depolarization and formation of an action potential [38, 77]. In vitro studies have shown that nicotine activates the spinal GABAergic and the hippocampal glutamatergic neurons [37]. Nicotine, administered systemically or iontophoretically, activates the midbrain DA neurons and prolongs their fir- ing time [9, 62]. In addition, the modulating effects of nicotine on 5-HT neurons of the dorsal raphe nuclei have been described [54].

Acute systemic nicotine administration elevates synaptic release of many neurotransmitters in animals, including ACh, glutamate (Glu), GABA and monoamines such as DA, noradrenaline (NA) and 5-HT [38, 62]. In addition, an increased release of opioid peptides, such as b-endorphin and met- enkephalin, has been reported in the rat brain and the striatum, respectively [23, 24]. Nicotine augments hormone secretion in rat blood, increasing the con- centrations of corticosterone, adrenocorticotropic hormone, prolactin, antidiuretic hormone (vasopressin) and growth hormone [18, 50, 52, 64]. Nicotine was also documented to enhance nerve growth factor syn-

Tab. 3.Affinity of nicotine for the nACh receptor subunits

nACh receptor containing subunits

Affinity of nicotine K_E(nM)

References

Humans Rodents

ab --- 3.6–12 [61]

ab_" 9,900 83–112 [61]

a_!b 14 47 [61]

a_!b_" 187 100–475 [61]

a_"b 1–4.6 0.8–10 [61]

a_"b_" 6,690 40–74 [61]

a_$b --- 3.8 [12]

a_$b_!b_"a_# --- 156 [61]

a_% 2,000 130–15,000 [61]

Abbreviations: nACh nicotinic acetylcholine; --- not studied

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Current pharmacotherapies for nicotine addiction

The search for an efficient pharmacotherapy for nicotine addiction has lasted many years. However, the fact that addiction is a complex disease makes the task more complicated. Currently, the substitution strategy involving nicotine replacement therapy (NRT) in the form of chewing gum, patches, sublingual tablets, na- sal spray or inhaler (Nicotinell, Nicorette, Niquitin) has been approved by the US Food and Drug Admin- istration (FDA) and European Medicines Agency (EMEA) for the treatment of nicotine dependence. The NRT aims to replace nicotine delivered in cigarette smoke and is safer for the organism due to the lack of harmful substances present in cigarette smoke [30, 64].

Substitution therapy does not work satisfactorily for all cigarette smokers, so bupropion (Zyban) is often used in smoking cessation therapy [26, 27]. This drug inhibits the reuptake of DA and NA [2]. By increasing the level of these monoamines in the synaptic cleft, it may effectively prevent relapses of nicotine use and cigarette smoking [36]. Double-blind studies performed on smokers in recent years have demonstrated that bupropion sustained-release prolongs nicotine abstinence [21].

Another drug used in smoking cessation therapy is cytisine (Tabex). The mechanism of action of this plant-derived alkaloid is associated with partial activation of the a4b2 nACh subtype receptors that evokes a moderate DA release, thereby decreasing nicotine craving when nicotine is absent, while attenuating its rewarding effects when it is present [77].

A promising strategy of nicotine dependence therapy utilizes varenicline (Champix), which, like cytisine, is a partiala4b2nACh subtype receptor agonist, but also a full a₇ subtype receptor agonist [10, 26, 27, 55]. Varenicline has higher than nicotine affinity for thea₄b₂nACh subtype receptor and was shown to alleviate nicotine craving and to attenuate the feelings of pleasure associated with smoking [8, 76].

The so-called second choice treatment drugs in nicotine dependence pharmacotherapy include nortriptyline (Allergon) and clonidine (Iporel), which

while the second is a hypotensive drug that functions as ana₂-adrenoceptor agonist, used in smoking cessation therapy to relieve excessive irritability during nicotine withdrawal.

The use of current pharmacotherapies is often limited by the side effects observed in many patients. The adverse effects of NRT or cytisine are typical for acute intoxication with nicotine (e.g., headaches, gastric problems, nausea) or may include other ailments such as local irritation (nicotine patches, inhalers or aerosols) [8, 34]. The use of bupropion is associated with appearance of tachycardia, headaches, nausea, hypotension, dry mouth, gastrointestinal disturbances, insomnia and muscular tremor [36], while the use of nortriptyline or clonidine may cause dry mouth, sleepiness and tiredness [34, 36]. It should also be mentioned that varenicline produces many fewer side effects than other anti-nicotine therapies [8, 34].

The above-mentioned drugs, besides causing adverse effects limiting their use, have low clinical effi- cacies [30]. Therefore, there is still an urgent need to find new therapeutic strategies for the treatment of nicotine dependence, especially those that are devoid of adverse reactions and more effective than current options [29–31]. Intensive clinical trials of “mixed”

preparations composed of different drugs/substances affecting the ACh system, i.e., varenicline or mecamylamine (a noncompetitive nACh receptor antagonist) in combination with NRT, or treatment with the above ACh compounds and bupropion (DA and NA reuptake inhibitor) are underway [19].

Early clinical and/or preclinical trials are focusing on the neurotransmitters other than ACh. The following compounds are under examination: a DA D₃recep- tor antagonist – trans-N-[4-[2-(6-cyano-1,2,3,4-tetra- hydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinoline- carboxamide (SB-277011-A), a NA reuptake inhibitor – reboxetine, GABA_Breceptor agonists – baclofen and (3-amino-2(S)-hydroxypropyl)methylphosphinic acid (CGP 44532), a monoaminooxidase A inhibitor – mo- clobemide, a monoaminooxidase B inhibitor – selegiline, a metabotropic Glu receptor subtype 5 (mGluR5) antagonist – 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an opioid receptor antagonist – naltrexone, a corticotropin- releasing factor₁ receptor antagonist – butyl-ethyl-[2,5-dimethyl- 7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin- 4-yl]amine (CP-154,526) and a cannabinoid₁receptor

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antagonist – rimonabant (Acomplia) [4, 19, 30]. Un- fortunately, the use of rimonabant for smoking cessation therapy can be limited due to its adverse effects, such as depression episodes, anxiety and increased risk of suicidal attempts, which have been observed in overweight patients treated with this drug [14, 46].

Rimonabant was withdrawn from the market in many European countries [20] and, despite its efficacy in preclinical studies on nicotine dependence [16], it will not probably be considered as a potential therapeutic option in this type of addiction. On the other hand, since nicotine withdrawal is associated with an increased appetite and body weight gain, treatment has been proposed that combines rimonabant with NRT, e.g., nicotine patches [66].

The studies on vaccines that induce anti-nicotine antibodies and decrease the amount of nicotine reach- ing the brain (after its systemic administration) thereby attenuating its rewarding effects, are also worth mentioning [53]. The results of clinical studies on NicQb, NicVAX or TA-NIC vaccines seem to raise increasing hopes that such treatment strategy may be a successful one [53].

Conclusions

The currently available knowledge about nicotine dependence is still growing and is partly based on data from the laboratory animal models. The lack of effectiveness and adverse effects associated with the use of currently available anti-nicotinic drugs support the notion that researchers must continue to seek more effective pharmacological treatments.

Acknowledgements:

This paper was supported by the statutory funds from the Department of Pharmacology, Institute of Pharmacology Polish Academy of Sciences (Kraków) and by the Foundation for Polish Science to M.Z.

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Received:

July 24, 2009; in revised form: November 23, 2009.