A narrative review on the reinforcing properties of nicotine not directly linked to the “classic” mechanisms of addiction: an addiction that goes beyond addiction| Tabaccologia

Abstract

Tobacco smoke causes a “dopaminergic-accumbal self-administration disorder, having nicotine as the main pharmacological agent”. When smoked, in a few seconds, nicotine reaches specific areas of the brain by selectively binding to its receptors (nAChRs) in brain areas involved in different processes. The underlying mechanisms are common to both natural pleasures and other psychoactive substances, creating a primary reinforcement to continued consumption over time, which favors the onset of a tobacco use disorder (TUD) which, in its most severe and typical form, leads to tobacco addiction. Nicotine simultaneously causes cognitive reinforcement by acting as a “nootropic” substance, especially in people with underlying diseases that are often accompanied by a deficit of cognitivefunctions, even if it is able to improve cognitive performance in healthy non-smokers. Finally, nicotine can amplify a myriad of non-drug related rewards, contributing greatly to the difficulty experienced by smokers trying to quit tobacco smoking. This difficulty is not simply linked to the craving for nicotine and the appearance of withdrawal symptoms due to its deficiency. It is also the fact that other activities are not as rewarding and motivating for smokers in the absence of nicotine. This valuable data must be considered when thinking about new prevention strategies and treatments for the cessation of tobacco smoke.

Introduction

Tobacco contains a psychoactive drug, nicotine: by smoking small quantities of this substance are taken with each puff. It has specific effects, by binding selectively to its receptors (nAChRs) present in specific brain areas, such as the mesolimbic circuit of gratification in different processes [1].

After being smoked and inhaled, nicotine is quickly absorbed by the lungs in a free-base form largely suspended over tiny tar particles. Nicotine reaches the brain in eight seconds, virtually as fast as an intravenous injection. Cigarettes contain 1 to 2% nicotine, approximately, 10-20 mg of nicotine each. Smokers tend to titrate their intake over time, consuming on average about 1 mg of nicotine per cigarette and keeping nicotine levels relatively stable during waking hours. Nicotine can also be absorbed passively; non-smokers who live with a person who smokes 40 cigarettes a day, have urinary levels of cotinine (the main metabolite of nicotine) equivalent to those who smoke about 3 cigarettes a day. As already mentioned, nicotine reaches its peak concentration within a few seconds of inhalation and then drops just as quickly; it therefore acts like many other substances of abuse: the underlying mechanisms are common to physiological pleasures related to the conservation of the species, such as eating, drinking, having sex and caring for offspring. Access to activation of the gratification circuit is one of the factors that lead to “tobacco/nicotine use disorder” (TUD) of which the most severe form is commonly known as “tobacco/nicotine addiction” [2]. Nicotine, more than other substances of abuse, involves receptor systems that modulate neurons of different functional systems in the brain and even neuroendocrine circuits. To this already complex interaction with our body, we must add the multiple reinforcements related to the social, cognitive, and emotional values that smoking assumes for many individuals. In fact, according to data from the World Health Organization, smokers in the world in 2015 were 1 billion and 351 million and, in 2017, about 8 million people died from tobacco-related diseases [3]. This work aims to summarize the recent scientific contributions that have had as their object of study the many reinforcing actions that allow smoking to be, since centuries, one of the most important risk factors for the health and life for humanity.

Materials and Methods

To understand the global effects of nicotine on the smoker, it is useful to consider a didactic subdivision as follows:

1. Effects attributable to the “classical mechanisms of dependence”.
2. Effects related to the “cognitive strengthening properties” of nicotine.
3. “Reward amplifier” effects of nicotine.

To carry out a review on less studied and published aspects of nicotine such as those of points b and c, a wide-ranging narrative review was carried out, also using search engines such as Google Scholar and published works, in indexed and non-indexed scientific journals. The keywords used for searches on the net, in English and in Italian were:

1. Nicotine, nootropic effect, reinforcement, cognitive performance, reward enhancer.
2. Nicotine, nootropic effect, reinforcement, cognitive performance, reward amplification. The articles considered significant for the period 1990 – 2021 have been collected.

Results and Discussion

Effects of nicotine attributable to the “classic mechanisms of addiction”

Nicotine addiction traces the same stages of the cycle of addiction described by Koob and Le Moal [4], the activation of the mesolimbic dopaminergic circuit of gratification. The clinical picture of TUD is similar to that of other substances of abuse: over time following regular consumption, it leads to tolerance, abstinence, psychological dependence, and loss of control. Gradual learning to consumption is established, following repeated associations between smoking, and taking nicotine, not only inducing gratification in different environmental situations, but also creating and reinforcing the memory of consumption. The main effect of nicotine is pleasant, rewarding and reinforces its intake. At this point, however, there is a neuroadaptation to nicotine: prolonged exposure to it can induce a desensitization of nicotinic receptors. The body counteracts it with a compensation, with the increase in the number of receptors themselves. Consequently, discontinuation of use causes a withdrawal crisis already described in the previous paragraph [1,5]. It has been hypothesized that avoidance of the affective components of nicotine withdrawal plays an important role in maintaining addiction to somatic withdrawal symptoms. Smoking behavior is influenced by pharmacological feedback and environmental factors such as sensory stimuli related to smoking, friends who smoke, stress and tobacco advertising. Nicotine levels in the body, in relation to cigarettes smoked, are modulated by the speed of nicotine metabolism, which occurs in the liver, largely by means of the enzyme CYP2A6. Other factors that influence smoking behavior include age, gender, genetics, mental illness, and substance abuse [6,7].

The non-pharmacological factors of smoking, however linked to the dopaminergic mechanisms of addiction, consider individual genetic characteristics, personality, environmental, personal history, and socioeconomic conditions. The pleasant effects of smoking occur in an environmental context rich in stimuli that thus acquire positive conditioned properties effective in reinforcing the conditioning from the cigarette. The environmental context is strongly rooted and influential within every level of the individual and social memory of the smoker [1].

Effects related to the “cognitive strengthening properties” of nicotine”

Nicotine activates the ganglion receptors of the autonomic nervous system including those of the adrenal cortex. However, this activation is only short-lived and is followed by persistent depression of all autonomic ganglia, depending on the dose and mode of administration. In humans, cigarette smoke increases heartbeat and blood pressure. Nicotine stimulates the gastrointestinal tract, but is followed by inhibition, indicating parasympathetic activity. It causes bronchial dilation and stimulates the salivary glands. Nicotine, in a person who has never smoked, can induce vomiting through stimulation of a chemo-receptor zone in the postrema area of the medulla and activation of the vagal and spinal nerves that form the sensory component of the vomiting reflex. In humans, therefore, nicotine has several acute activating, strengthening, and even anxiolytic effects [2,8]. Numerous animal studies have demonstrated the positive strengthening properties on the central nervous system of nicotine in many species. In humans, it produces positive reinforcing effects including mild euphoria, a feeling of increased energy, increased arousal, and reduced appetite. Cigarette smokers report that smoking produces excitement, particularly at the first cigarette of the day, but also relaxation when they are under stress. Nicotine reduces pain and raises its threshold in humans. Nasal spray or low-dose transdermal nicotine has been shown to reduce post-operative pain. These analgesic effects of nicotine can be mediated through the activation of endogenous opioid systems, and the release of beta-endorphins. In fact, endogenous opioid peptides, and their receptor subtypes, have demonstrated anti-nociceptive effects of spinal cord-mediated nicotine [8,9]. The positive reinforcement effects of acute nicotine administration, through smoking, are particularly important for the initiation and maintenance of tobacco smoke which, ultimately, results in an addiction. As mentioned above, nicotine reduces appetite, particularly for sweet foods and carbohydrates and this has been linked to the reason for persevering to smoke in women, and their higher levels of relapse than in men [10]. The appetite reduction is complemented by a decrease in blood insulin levels and alterations in serotonin function. Nicotine also increases the metabolism and oxidation of fats.

Nicotine is able to increase cognitive performance in non-smokers [2]. It is therefore a cognitive enhancer, an effect that defines the action of so-called “nootropic” drugs. This term was coined when the memory-enhancing properties of piracetam were clinically observed [11]. Since then, several drugs have been evaluated in clinical trials or preclinical experiments. Cognitive enhancers (or nootropics) are used in patients suffering from diseases that manifest cognitive deficits such as Alzheimer’s disease (AD) [12], schizophrenia [13], strokes, attention deficit hyperactivity disorder (ADHD) [14], as well as in aging [15]. Many studies highlight an important role of nicotinic α7 acetylcholine receptors (α7nAChR) in these diseases or in the state of senescence, suggesting that modulation of α7nAChRs may represent an effective therapeutic strategy [16-19].

Nicotinic acetylcholine receptors have proven their importance for maintaining optimal performance on a variety of cognitive tasks. In humans, the nicotine-induced improvement in rapid information processing is particularly well documented [20]. In experimental animals, nicotine has been shown to improve learning and memory in a variety of tasks, while mecamylamine, a nicotinic antagonist, has been shown to impair memory performance [21]. Nicotine was found to be effective in alleviating memory deficits resulting from septo-hippocampal tract lesions or aging in experimental animals. Nicotinic receptors are decreased in the cortex of patients with AD. Preliminary studies have shown that some aspects of cognitive impairment in AD can be mitigated by nicotine. Nicotine may prove to be a useful therapeutic treatment for this and other types of dementia [22].

Recent advances in studies on nicotinic agents in humans have begun to define more carefully the cognitive operations that can be influenced by nicotinic stimulation and / or blockade, among which attention is the one most influenced by the activation of the nicotinic receptor. The issue that nicotine can improve attention in normal non-smokers, who do not have any pre-existing attentional damage, was addressed. Adult non-smokers without symptoms of attention deficit hyperactivity disorder (ADHD) were treated with nicotine patches or placebo patches.

The authors found that nicotine administration significantly reduced the number of omission errors in continuous performance activity. No change in omission errors was found. The nicotine patch significantly reduced the variability of response time and increased the measure of composite attention. Overall, this study shows that transdermally administered nicotine can improve attention in non-smokers who do not have pre-existing attentional deficits [23].

Min et al. also studied the effects of transdermal nicotine on attention and memory in non-smoking and nicotine-naive elderly subjects. The results obtained confirm that nicotine, at low plasma levels, can improve short-term verbal memory functions [24]. The selective effects of nicotine on attentional processes have been studied by Mancuso et al., also in smokers [25]. Smokers, who abstained from smoking for at least ten hours before the test, were treated with transdermal patches and tested for the selective effects of nicotine on attention using the Random Letter Generation test, a test to assess the degree of flexibility of attention, and the Stroop test. The authors found that the nicotine patch held six hours alone improved the speed of number generation and processing speed in both the control and interference condition of the Stroop test. The authors conclude that nicotine primarily improves attention intensity characteristics, rather than selectivity characteristics, in accordance with previous studies. Wesnes et al. conducted a study to determine the level of cognitive alterations in smokers abstaining from tobacco smoke. Healthy male volunteers who were housed in a clinical trial facility for 16 days underwent periods of ad libitum smoking and smoking abstinence. According to the authors, the study confirmed previous work showing cognitive decline in smoking abstinence [26].

According to Valentine and Sofuoglu, while the direct positive behavioral reinforcement effect of nicotine has historically been considered the main mechanism driving the development of TUD, the cognitive enhancement effects of nicotine may also contribute significantly to the onset and maintenance of TUD, especially in individuals with pre-existing cognitive deficits. To prove their theory, they conducted a selective review of progress in understanding the effects of nicotine on cognitive function, a discussion of the role of cognitive function in vulnerability to TUD, followed by an overview of the neurobiological mechanisms underlying the cognitive effects of nicotine. Preclinical models and human studies have shown that nicotine has cognitive enhancement effects. Attention, working memory, fine motor skills and episodic memory functions are particularly sensitive to the effects of nicotine. Recent studies have shown that the α4, β2 and α7 subunits of the nicotinic acetylcholine receptor (nAChR) participate in the cognitive enhancement effects of nicotine [27].

Kenny et al. [20] showed in rats that self-administration of nicotine increased the sensitivity of brain reward systems, and that this action persisted for at least 36 days after cessation of nicotine intake. The authors concluded that nicotine acutely stimulated the pathways of gratification by maintaining tobacco consumption habits in a similar way to other drugs of abuse in humans. However, nicotine was able to imprint an indelible “memory” on the brain’s reward pathways by resetting their sensitivity to an increased level, a property that seems unique to nicotine among drugs of abuse. These nootropic effects of nicotine highlight its possible use in the treatment of cognitive dysfunction. Levin et al. [28] examined some specific cognitive functions influenced by nicotinic treatments, including attention, learning, and memory. From the data obtained, the authors hypothesized that nicotinic agonists and nicotine may improve working memory function, learning and attention. Both α4β2 and α7 nicotinic receptors appear to be critical for memory function. The hippocampus and amygdala were found to be important for memory, decreased nicotinic activity in these areas can damage memory function.

The discovery of the behavioral, pharmacological, and anatomical specificity of nicotinic effects on learning, memory, and attention, not only helps the understanding of nicotinic involvement in the basis of cognitive function, but also in the development of possible nicotine-based treatments for cognitive dysfunction [24]. According to Levine et al., the nicotinic agonist ABT-418 was able to improve symptomatology in adults with ADHD. Nicotine-induced attentional improvement was evidenced by magnetic resonance imaging studies where greater activation was detected in the parietal cortex, thalamus and caudate. Nicotine has been shown to improve cognitive function among individuals with psychiatric conditions such as schizophrenia, ADHD, Parkinson’s disease (PD) and AD. In each of these conditions, nicotinic receptors are believed to play a direct or indirect role in the pathophysiology of the condition, as evidenced by post-mortem analyses of brain tissue findings or human neuroimaging. In addition, smoking prevalences are disproportionately high for people with schizophrenia and ADHD. In all the conditions examined, several studies have shown that nicotine can improve attention after both acute and chronic administration. This improvement may be due to several factors, including nicotine stimulation of dopamine release in the striatum or direct stimulation of nicotinic neurons in the thalamus or other brain regions involved in attention, for example, in the anterior cingulate cortex. Activation of nicotinic receptors in brain regions associated with arousal may also have the effect of improving attention. With the great anatomical diversity of nicotinic receptors in the brain, it is reasonable to assume that nicotinic receptors in different locations play different roles in neurocognitive function. Nicotinic pharmacological actions on some of these receptors can have positive effects on cognitive function, while the same actions on the same receptor subtypes in other areas of the brain may have negative actions, while others may not be involved at all. For example, the nicotine agonist effects in the mid-dorsal thalamic nucleus appear to be opposite to the ventral hippocampus and basolateral amygdala regarding working memory function [29].

Ashare et al. [30] studied nicotine withdrawal symptoms associated with prolonged attention discrepancy of working memory. According to the authors, several converging lines of evidence suggest that these deficits may represent a basic dependency phenotype. A better understanding of the mechanisms underlying abstinence-related cognitive deficits can lead to improved tobacco treatment using both pharmacological and behavioral targeted tools, aimed at soothing the cognitive symptoms of nicotine withdrawal.

Heishman et al. published a meta-analysis of the acute effects of nicotine and tobacco smoking on human performance. They conducted research on outcome measures from 41 double-blind, placebo-controlled studies published between 1994 and 2008. In all studies, nicotine was administered, and performance assessed in non-smokers or smoking adults without withdrawal symptoms. The authors found significant positive effects of nicotine in six domains: fine motor skills, attention and accuracy in alert response time, attention and response time in orientation, accuracy of short-term episodic memory, and working memory [31]. Studies on the effects of nicotinic systems and/or nicotinic receptor stimulation in pathological states such as AD, PD [32], ADHD [33], and schizophrenia [34] show the potential therapeutic usefulness of nicotinic drugs.

Tucha and Lange evaluated the effect of nicotine chewing gum in a motor task, that is, on hand movements when writing in smokers and non-smokers. They performed handwriting movement evaluation of 38 smokers and 38 non-smokers performed following chewing gums containing 0 mg, 2 mg, or 4 mg nicotine. Kinematic analysis of writing movements revealed that nicotine could produce absolute improvements in writing. These improvements were more striking in smokers than in non-smokers. The authors concluded that nicotine could increase psychomotor performance to a significant extent [35].

Newhouse et al. conducted a six-month double-blind clinical trial of nicotine use in mild cognitive impairment (MCI). This study showed that transdermal nicotine can be safely administered to non-smokers with MCI for more than 6 months with an improvement in primary and secondary cognitive measures of attention, memory, and mental processing, although not resulting in the assessments on the overall impression evaluated by the clinician [36].

To elucidate the neural correlates of nicotine’s cognitive effects, Kumari et al. examined behavioral performance and blood oxygenation-dependent brain activity, using functional MRI in healthy non-smoking males after nicotine or saline administration. Nicotine, compared to placebo, improved accuracy in all active conditions and produced an increased response in the anterior cingulate, upper frontal cortex and parietal cortex. It also produced an increased response in the midbrain roof in all active conditions and in the para-hippocampal gyrus, cerebellum, and medial occipital lobe during rest. These observations indicate an increase in activity in a distributed neural network in response to assigned tasks by confirming nicotine’s nootropic capabilities [37]. Nicotine addiction is more frequent in psychiatric patients who have on average higher levels of consumption than in mentally healthy subjects [27]. This correlation has been noted for several psychiatric conditions such as schizophrenia [38], attention and hyperactivity disorder [39,40], major depression [41], bipolar disorder [42], anxiety disorders [43], post-traumatic stress disorder [44], antisocial personality disorder [45], obsessive compulsive disorder [46] and multiple dependences [47]. This strong association between smoking and psychiatric diseases may support the hypothesis that psychological and neurobiological attributes that predispose subjects to smoking also predispose them to mental disorders [48]. Moreover, nicotine’s ability to relieve stress and anxiety, improve mood and cognitive function can lead to higher levels of consumption in smokers with psychiatric diagnoses thus giving credence to the hypothesis of the use of nicotine as self-medication [49].

Scipioni et al. published a systematic review of the prevalence of smoking in subjects with an alexithymic personality trait, highlighting between alexithymia and smoking [50].

According to Prochaska tobacco addiction is the most prevalent drug abuse disorder among adults diagnosed with psychiatric illness or illness. The author believes that neurobiological and psychosocial factors contribute to the high rates of tobacco consumption in these patients, including the reinforcing effects of nicotine mood alteration, shared environment or genetic factors, and reduced coping for cessation efforts.

The reinforcing actions of nicotine on the mesolimbic dopamine strengthening pathway in the brain are similar to those of cocaine and amphetamine, contributing to mood enhancement, cognitive enhancement, and reduced appetite [51].

Harris et al. conducted a study of 20 schizophrenics, 10 smokers and 10 non-smokers, who were evaluated following administration of nicotine gum and placebo gum. The battery of repeatable tests for the evaluation of neuropsychological status was administered. Nicotine only affected the attention index; there were no effects on learning and memory, language, or visuospatial/constructive skills [34].

Nicotine as a “reward amplifier”

The rewarding effects of smoking in an environment abundant in stimuli, often biologically neutral, acquire, for the consumer of nicotine, effective positive conditioned properties that reinforce the conditioning of cigarette consumption. So, as seen above, it is not only the release of dopamine caused by nicotine that produces and sustains such an extinction-resistant addiction. In all addictions, it is suitable to consider multimodal causal patterns, and this applies in a particular way to smoking because, after the first cigarettes of the day, nicotinic receptors are largely desensitized and therefore further tobacco consumption should not trigger much dopaminergic activity.

This additional complication comes from evidence, even in animal models, that nicotine can somehow act as a “reward amplifier,” that is, increasing the reward value of other stimuli such as food or pleasurable flavors. For example, a slightly rewarding stimulus such as sensing the aroma of tobacco may become more rewarding if nicotine is present in the CNS. In addition, the dopamine signal is the mediator not only of pleasure and reward, but also of aversion, novelty, expectations, prediction errors, decision-making and in general of information processing from, and to the environment around the tobacco consumer [52]. Other systems and/or substances have been hypothesized to be able to modulate the gratification and addictive effect of nicotine.

Chamitkov et al. conducted an animal study to assess whether nicotine can acquire additional reinforcing properties through associations with other rewards. Rats were placed in the condition of self-administering nicotine or nicotine associated with access to sucrose during the conditioning phase. At the end of the study the authors concluded that, in addition to the multifaceted nature of the nicotine stimulus that includes primary reinforcing effects, conditioned reinforcement effects, and reward-enhancing effects, nicotine may acquire additional reinforcing properties through associations with other rewards. This ability to acquire additional reinforcing properties through associative learning may therefore contribute to the onset and chronicity of tobacco use disorder in humans [53].

Hollander et al. published a paper on the regulation of the rewarding effects of nicotine by hypocretin (orexin) of the insular lobe. Damage to the insular cortex can disrupt tobacco addiction in tobacco users, with spontaneous cessation of the pursuit of tobacco consumption and a persistent decrease in the desire to smoke. Emerging evidence suggests that the transmission of hypocretin (orexin) may play an important role in drug reinforcement processes, but its role in the rewarding actions of nicotine, considered the key addictive component of tobacco smoking, remains largely unexplored. After experimental sessions in rats, the authors concluded that transmission of insular hypocretin plays a role in regulating the motivational properties of nicotine, and therefore may be a key neurobiological substrate necessary to maintain tobacco dependence in human smokers [54].

Merrit et al. used complementary transgenic and pharmacological approaches to test the hypothesis that the endocannabinoid system can modulate the reward capacity and establish nicotine dependence. The authors concluded that endocannabinoids may play a role in nicotine’s rewarding properties and nicotine addiction. Increased levels of endogenous cannabinoids amplify nicotine’s ability to gratify, and disruption of the CB1 receptor signal attenuates nicotine reward and withdrawal [55].

Zeeb et al. experimented in rats with the blocking action of nicotine’s rewarding properties by an agonist of the serotonin receptor 2C (5-HT2C), lorcaserin, also used for the treatment of obesity. The authors state, after completing the experimental sessions, that lorcaserin may be effective in the treatment of obesity and smoking, reducing the value of food reward and nicotine [56].

Berrendero et al. published a review on the involvement of neurotransmitters of the endogenous opioid system in nicotine addiction.

Up-regulation of mu-opioid receptors after chronic nicotine treatment could counteract the development of nicotine tolerance, while down-regulation induced on kappa-opioid receptors appears to facilitate nicotine tolerance. In accordance with these reactions of the endogenous opioid system, the opioid antagonist naltrexone has been shown to be effective for quitting smoking in some subpopulations of smokers [57].

Liechti and Markou published a review on the role of the glutamatergic system in nicotine addiction. The authors highlighted how drugs that reduce glutamatergic transmission decrease the reinforcing effects of tobacco smoke and can prevent relapses to tobacco smoke in humans [58].

Linch and Sofuoglu described the role of progesterone in establishing and consolidating nicotine addiction. In a review, the authors collected clinical and preclinical studies evaluating the role of progesterone in nicotine addiction, especially during initiation of use and in the later stages of addiction. The authors suggest that progesterone plays an important role in the reward given by nicotine. In fact, animal studies show that progesterone can reduce the reinforcing effects of nicotine. The authors observed a higher level of nicotine cravings during estrus. Hormonal regulation of nicotine’s reinforcing effects may be salient during transitional hormonal phases such as adolescence and pregnancy. In conclusion, it is hypothesized that progesterone may facilitate smoking cessation in women with a normal cycle. Cognitive enhancement effects caused by progesterone have also been shown; these improvements were greater in female smokers than in males, suggesting a potential use of progesterone in smoking cessation treatment in women [59].

Barrett et al. studied gender differences in the effects of nicotine’s increased gratification on ethanol reinforcement in rats. The authors, at the end of the experimental sessions, concluded that nicotine increases the reinforcement of ethanol and can, albeit in part, lead to comorbidity between nicotine and alcohol abuse. Males showed signs of a higher ethanol reinforcement value than females in saline conditions, but nicotine administration attenuated this effect by increasing the ethanol reinforcement value in females. Nicotine dose-dependently increases the reinforcing value of alcohol in a way that is clearly influenced by biological sex [60].

Chaudri et al. addressed the problem of complex interactions between nicotine and non-pharmacological stimuli, in the context of the paradigm of drug self-administration in rats. According to them, this has led to new points of view on the paradox that nicotine, having a seemingly weak primary reinforcement, can lead to an extremely robust addiction to tobacco smoke. The authors’ hypothesis is that nicotine acts both as a primary enhancer and as an enhancer of other non-nicotinic reinforcements [61].

Kirshenbaum and Hughes published an assessment of the enhancement of reinforcement by nicotine as a cause of e-cigarette abuse in young adults. Nicotine can act as primary positive reinforcement and as negative reinforcement to relieve withdrawal [62].

Vegliach addresses the aspect of “reward amplifier” and its psychological consequences, beyond the “canonical” boundaries of addiction related to nicotine as the primary pharmacological agent.

According to the author, smoking is a complex and treatment-resistant phenomenon not only because of the involvement of multiple brain structures and neurophysiological lines but also because smoking takes on emotional and affective values replacing childhood regressive structures. Thus, in care settings, the cured-caring relationship must be the main tool with which the strong symbiotic bond that the patient maintains with the cigarette is dissolved [63].

Volkow published in Scientific American a work on why nicotine easily causes such a robust addiction. Although the amount of dopamine released by the cigarette is not remarkable compared to other drugs, the determining fact is that the activity is repeated very often, and in conjunction with many activities. This links the rewards of nicotine to multiple behaviors that we have daily, increasing the pleasure and motivation we derive from them.

Smokers’ brains have learned to smoke, just like riding a bicycle, and it’s incredibly difficult to unlearn that behavior even if it’s linked to tenuous dopaminergic gratification. It is known for many years that nicotine plays a role as a substance of engagement with other addictive substances or behaviors. Cigarette consumption tends to precede initiation to other drugs (gateway effect), and not just because cigarettes are more available. Scientific research shows that nicotine works as a promoter, in animal models, of self-administration of cocaine while the opposite does not happen, cocaine does not act as a gateway for the self-administration of nicotine [64].

Columbia University researchers Denise and Eric Kandel identified a molecular mechanism that underlies the gateway effect of nicotine: Nicotine encourages the expression of FOSB in the gratification circuit, a gene that underlies the learning process mentioned earlier. Thus, nicotine allows other drugs to teach more easily the brain of users to repeat their consumption. Even more interest comes from the fact that nicotine seems to make other more enjoyable activities, not related to drugs [65]. According to studies conducted by Perkins et al., nicotine itself increases the response in humans that is reinforced by certain gratifications (auditory and visual stimuli). These reinforcement-enhancing effects are not due to addiction or withdrawal resolution and can be restored by a small amount of nicotine, such as smoking another cigarette. The authors found that nicotine reduced the rate at which smokers get bored with visual reinforcement. Smoking tobacco or vaping nicotine seem to favor and prolong the pleasure of other daily activities [66].

Conclusions

As seen, tobacco smoke causes a “self-administering dopaminergic-accumbal disorder having nicotine as its main pharmacological agent” [61]. At the same time, nicotine causes cognitive reinforcement by acting as a nootropic substance, especially in people with underlying pathologies that are often accompanied by a deficit in cognitive functions, even if it can improve cognitive performance in healthy non-smokers. Finally, nicotine can amplify gratifications not directly related to smoking, contributing greatly to the difficulty encountered by smokers trying to stop smoking. This difficulty is not simply related to craving and the appearance of withdrawal symptoms, but also to other activities that lose their value for smokers in the absence of nicotine. It is crucial to understand that the interweaving of substances and other behaviors can make addiction to a relatively “light” primary reinforcement drug such as nicotine serious, turning it into a serious problem that endangers the health and lives of millions of people every year.

Clarifying the multiple links that make it difficult to untangle the network of reinforcements that keep the smoker hooked to tobacco smoke make it possible to highlight that all low-burning products and vaporizers containing nicotine that have appeared on the market in recent years, although they reduce the damage on the respiratory system, keep the link of dependence between the user and nicotine intact [52]. Many people are misinformed about the harms related to various forms of tobacco and nicotinic-derived products. To promote confidence in smoking cessation pathways, public health institutions must be clear in presenting the dangers, however diverse, that tobacco and nicotine products cause on individuals who take them, causing a huge expense to health systems as well as a huge burden of suffering in terms of diseases and years of life lost due to smoking [67].

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