Nicotine

The Reward Pathway

Among the more than 9000 components of tobacco smoke, about 70 are known carcinogens. The most studied component of tobacco smoke is nicotine, which is the major psychoactive ingredient in tobacco smoke and the component most associated with tobacco dependence. Like many drugs associated with abuse and dependence, nicotine ingestion stimulates a rapid increase in dopamine in the nucleus accumbens and the ventral tegmental area, typically within 10 seconds of smoking a cigarette. Under normal circumstances, the nucleus accumbens and ventral tegmental area are activated by food, social affiliation, and sexual activity, all of which are linked to survival ( Fig. 23.2A ).

The key component of the reward pathway within the mesocorticolimbic system is the neurotransmitter dopamine, the pathways of which project from the nucleus accumbens and ventral tegmental area to the prefrontal cortex, the amygdala, and the olfactory tubercle ( Fig. 23.2B ). At the same time that dopamine is released from the ventral tegmental area, a signal is sent to the amygdala, which stamps-in the positive associations of pleasure with the environmental cues that were presented at the time, as well as the delivery of the reinforcing dopamine in the accumbens shell. This means that previously neutral stimuli, such as a brand of cigarette, a package, a vaporizing device, or even a painful burn on the throat (termed, “throat hit”) are now associated with reinforcement. Repeat appearances of cues such as the cigarette, the logo, or even the locations in which one has smoked will trigger the craving and expectation of reward—and when the anticipatory firing of dopamine is not met with actual delivery, it leads to frustration and continued or intensified craving.

Although dopamine appears to be the final common neurotransmitter of this pathway, other neurotransmitter systems such as γ-aminobutyric acid, glutamate, cholinergics, and anticholinergic are believed to be involved in the activation of the reward pathway and the sustainability of substance sue.

Nicotine affects the reward pathway by more than one mechanism; for example, in animal studies, dopamine antagonists or the destruction of dopaminergic neurons in the nucleus accumbens results in a decrease of nicotine self-administration in laboratory animals. Nicotinic acetylcholine receptors (nAChRs) are a subtype of cholinergic receptors present throughout the central nervous system (CNS) and exert varying effects (excitatory, inhibitory, or modulatory) depending on their location in the brain. In turn, nAChRs have an impact on the activity of several neurotransmitters, including dopamine, norepinephrine, serotonin, glutamate, and γ-aminobutyric acid, and of endogenous opioid peptides. Prior research has focused primarily on dopamine as a main determinant of nicotine and other drug addictions, as well as the effect of nicotine on the nucleus accumbens and the similarity of that to other addictive drugs. However, the cholinergic mechanism is also obviously an important determinant and the role of glutamate is ubiquitous to any CNS process ( Fig. 23. 2C ). The endogenous opioid, or endorphin, system is also involved in nicotine dependence, and naloxone can precipitate withdrawal in nicotine-dependent individuals. Most recently the emphasis is shifting to include most if not all the other major neurotransmitter systems in the brain. Finally, cannabinoid-1 (CB ₁ ) receptors also seem to be involved in nicotine dependence and the activation of dopaminergic neurons in the mesocorticolimbic system, highlighting once more the importance of broadening the horizon and scope of our research efforts to include other systems in addition to dopamine and the reward pathway, and other downstream effects of nicotine addiction.

Neuronal Adaptation

Most if not all substances of abuse and dependence initially produce desirable and pleasant effects. However, not everyone who uses these substances goes on to chronically use them, and not all long-term substance abusers become dependent or addicted to them. Genetic, environmental, and cultural factors may all interact to predispose some individuals to substance use and subsequent dependence/addiction.

The pleasurable sensation produced by reward pathway activation is associated with acute use of the substance, whereas repeated administration of nicotine over months or years is likely to lead to increased tolerance and withdrawal in the absence of nicotine. Tolerance and withdrawal are the physiological hallmarks of dependence, and they may be reflecting the neuroadaptive effects occurring within the brain. Of interest, the chronic use of drugs appears to cause a generalized decrease in dopaminergic neurotransmission, likely in response to the intermittent yet repetitive increases in dopamine-inducing presynaptic downregulation of dopamine as a compensatory mechanism for supraphysiological levels of signaling ( Fig. 23.3 ). Using and withdrawing from drugs also increase the levels of corticotropin-releasing factor (CRF), which is associated with the activation of central stress pathways. In vivo animal studies utilizing microdialysis during withdrawal from ethanol, cocaine, nicotine, or tetrahydrocannabinol showed an increase in extracellular CRF. Of interest, the direct injection of a CRF antagonist into the amygdala reversed some of the symptoms of withdrawal (i.e., anxiogenic behaviors).

Two neuroadaptive models have been used to explain how changes in reward function are associated with the development of substance dependence: sensitization and counter adaptation. The sensitization model postulates that there is an increased desire for the drug without a corresponding increase in pleasure, and often with a decrease in pleasure, following intermittent but administration of a drug. This is in contrast to the pharmacological tolerance to a substance, which occurs after continuous exposure to a drug. Sensitization can be thought of as the increase in wanting a drug after intermittent use and can facilitate the transition from occasional use to chronic use and tolerance. This phenomenon is well described and summarized in a paper by Nora Volkow, titled: “Decreased Reward Sensitivity and Increased Expectation Sensitivity Conspire to Overwhelm the Brain’s Control Circuit.”

The counteradaptation model postulates that the initial positive feelings of reward resulting from the use of a drug are followed by an opposing rather than synchronous development of tolerance that is manifested by the appearance of withdrawal associated with the lack of the substance. The positive rewarding effects diminish gradually with sustained use, whereas tolerance for the effect of a drug takes longer to dissipate after stopping the use; a cycle of escalating drug use may follow after each cessation and consequent withdrawal. When the neurotransmitter system of the reward pathway is overactivated through escalating drug use, the system may not be able to maintain an increasingly pleasurable response to the drug. The individual is motivated to escalate the amount of use, to compensate for not delivering the reward that was expected based-on previous experience. This is evidenced in microdialysis experiments that have documented decreases in dopaminergic and serotonergic transmission in the nucleus accumbens after chronic and escalating use. Increase in CRF and concomitant decrease in neuropeptide Y during substance withdrawal (including nicotine) are associated with increases in anxiety. In turn, during substance withdrawal, activation of norepinephrine pathways stimulates additional CRF, possibly resulting in an amplification of arousal and stress, and even neurotoxic effects if this amplification of arousal and stress are long-lasting.

Of course, the two previous models are not mutually exclusive. One aspect of withdrawal that expands the concept of negative reinforcement is the effects of withdrawal on the brain’s prefrontal control circuit, and the depletion of inhibitory capacity. The state of withdrawal alters the ability of the individual to resist drug-related opportunities, and cigarettes are no exception. The brain needs to have sufficient “energy” to inhibit drug cravings, and this has been a point of practical wisdom in mutual help groups, which warn that individuals who are tired are at greater risk of relapse.

Other models of nicotine addiction have been proposed, based on mechanisms associated with cognitive control and reinforcement learning, particularly the negative reinforcement associated with the reduction in negative affect that may follow smoking after a period of abstinence (withdrawal). These models are discussed in detail later in this chapter.

Cognitive Impairment

Although much of the focus of previous research has been related to nicotine’s effects on reward processes and mesolimbic dopamine neurotransmission, a growing body of literature suggests that nicotine’s noradrenergic and dopaminergic effects on attention, information processing, and affective regulation may be of considerable importance in understanding the maintenance of a nicotine use disorder. Neurological deficits common to attention and substance use disorders, such as impaired performance, lack of motivation, decreased working memory, and impaired executive function, have been well documented in both children and adults who have these disorders. Current lines of investigation suggest that overlapping interrelated brain areas are responsible for explaining the attentional and executive impairments common to the two disorders. The involvement of two areas, in particular the prefrontal cortex and anterior cingulate cortex, highlights the commonalities between drug dependence and attentional disorders, including nicotine and neurophysiological deficits related to cognitive dysfunction. It also may be that nicotine causes a distinct problem with decision-making, as evidenced by smokers’ performance on the Iowa Gambling Task. Stopping smoking can partially reverse these deficits. Longitudinal studies will be needed to determine how much of the decision-making deficit was preexisting (and predisposed the individual to substance use), and how much was an effect of the drug. Likewise, it is important to see if group differences between current and former smokers are due to acute drug-effects, or represent a different set of neurobiological characteristics in those who have been able to quit and those who have not.

The prefrontal cortex regulates goal-directed behavior, thought, and affect by using working memory to provide representational knowledge about past or future events and integrating this information into a plan for action or to exercise inhibitory control over inappropriate actions or thoughts. In attentional/cognitive disorders these processes are impaired and manifested in symptoms that involve poor attention, planning, impulse control, and monitoring of one’s behavior. Disentangling the direct relationship of these processes to a substance use disorder is difficult, because these individuals also have neurochemical deficits in the mesolimbic dopamine system. Studies indicate that the right prefrontal cortex in humans is particularly important in the inhibition of activity (i.e., Stop or Go-No Go tasks). The orbital and ventral prefrontal cortex may also have a similar inhibitory effect in the affective domain, thus permitting appropriate social behaviors. In attention-deficit/hyperactivity disorder (ADHD), for example, the anterior cingulate cortex has been implicated in the regulation of the motivational aspects of attention as well as in the regulation of response selection and inhibition. Thus researchers have begun to characterize ADHD as a disorder with deficits in inhibitory processes involving frontal cortical structures. Notably, there is a significant relationship between a history of ADHD and smoking. If a person must mentally manipulate information and make a response, the anterior cingulate cortex (with its connections to the prefrontal cortex) becomes active. This area become particularly active in tasks where inhibitory control or divided attention are necessary.

The importance of the inhibitory role of these structures in drug dependence has also been highlighted by several researchers. Drug-addicted individuals, including smokers, continue to use drugs even when faced with negative consequences and diminished reward, suggesting an apparent loss of control. The failure to regulate (i.e., inhibit) this drive points to a dysfunction within the prefrontal cortex and related areas including the anterior cingulate and orbitofrontal cortices. These prefrontal dysfunctions may themselves be caused by deficits in the limbic structures, or exacerbated by them. As shown in Fig. 23.3 , the resulting persistence of the behavior is not necessarily due to continued reinforcement by the drug (mesolimbic dopamine) but rather to the enhanced saliency of the drug and drug cues that have been firmly established (learned) in memory during the acquisition of dependence. During maintenance of substance use disorders, these super-salient drug-related cues, including the effects of priming doses from the first amount of administration, overcome the inhibitory control of the prefrontal cortex that might normally inhibit the response to take the drug due to perceived costs (consequences) with decreasing hedonistic properties. The expectation of reward is maintained by the brain as it releases significant dopamine when approaching an opportunity to use a substance, even if the actual hedonic enjoyment of that substance has decreased with the development of tolerance. This causes the individual to escalate their use, and sometimes attempt to recreate the level of stimulation that they have previously experienced, and will forever remember that state when presented with cues to use (often termed “euphoric recall”). The development of tolerance occurs over time and leads to the individual needing to consume an increasing amount of the drug, particularly because the effects of the first use of the drug remain the ones that are expected and predicted by the user.

Preclinical studies suggest that the impairment in prefrontal cortex function may be related to significant dendritic branching and spine density resulting from repeated drug administration, thus amplifying the signal of salient events. Moreover, abstinence from the drug significantly reduces the efficiency of the prefrontal cortex to process information in working memory, thereby interfering with its regulatory function. Such effects might be mediated by the negative affect associated with nicotine withdrawal, and when present, reduce the probability that a smoker may exercise an appropriate coping response and increase the probability of relapse. There is electroencephalography (EEG) evidence supporting persistent frontal lobe dysfunction among smokers using tasks related to working memory (P300). Neuhaus and colleagues found a hypoactivation of the anterior cingulate, orbitofrontal, and prefrontal cortices among both current and former smokers compared to never smokers, suggesting that the dysfunctional activation patterns found in smokers may not completely remit after quitting; a fact that may increase their vulnerability to relapse. It remains to be seen whether this is an effect of smoking, or a preexisting risk factor that led these individuals to be more likely to smoke.

A model by Curtin, Baker, and colleagues attempts to address the conditions under which cognitive control mechanisms affect the processing of motivationally relevant information (i.e., smoking cues) and the execution of situationally appropriate behavior. The model holds that once dependence is established, drug use motivation is frequently driven by implicit processes that are largely automatic and outside of the user’s awareness (contextual cueing involving the hippocampus and amygdala, and discrete cueing involving the basolateral amygdala). These implicit processes are developed and maintained by negative and positive reinforcement learning.

In the case of negative reinforcement, internal states associated with negative affect or drug withdrawal can engage motivational systems and drug use behavior in an attempt to ameliorate these aversive states. This involves such processes as the central amygdala cascade occurring with withdrawal, and the release of CRF, which has direct effects on brain structures and also involves engagement of the wider hypothalamus-pituitary-adrenal (HPA) axis. Activation of the habenula, which occurs when there is a reward prediction error, also further dampens the ventral tegmental area (VTA) to positive stimuli and facilitates inhibitory avoidance. In addition, there is evidence that the endorphin (endogenous opioid) system mediates certain aspects of nicotine dependence.

With positive reinforcement, environmental cues and positive mood states previously associated with rewarding drug effects can increase approach motivation. The model postulates that these learned associations trigger subcortical, “bottom-up” processes that can influence drug-seeking behavior implicitly by engaging appetitive or avoidance motivational systems. Thus the drug user may frequently engage in drug-use behaviors for reasons that are outside of conscious awareness, and each use will reinforce the strength of the circuit.

Although the model proposed by Curtin et al. holds that drug sensitization is largely maintained by the implicit influence of learned associations on motivation, the authors also speculate about circumstances in which drug use comes under explicit or cognitive control. Cognitive control can be defined as the effortful application of attentional resources to meaningful information and tasks. Cognitive control is crucial to learning as it is activated when an organism encounters unexpected outcomes, unfavorable outcomes, or response errors. In this model, cognitive control is important because it is elicited during response conflict, which can occur when the user attempts to regulate the craving and drug-seeking behaviors that result from exposure to conditioned cues. Ultimately, cognitive control is what allows a drug user to engage in less well-learned alternatives to drug-seeking behavior when drug craving and approach motivation is activated. However, it is during instances of response conflict and engagement of cognitive control mechanisms that drug craving will be most acutely experienced by the drug user. If there are clear processing deficits engendered in the management of response conflict (also pertinent to error monitoring in the anterior cingulate cortex), then behavioral resistance to the increased craving is also diminished.

Effect on Comorbid Substance Use

All substances use, share, and activate the same underlying neuronal pathways of reward and reinforcement; nicotine may be strengthening the circuits involved in the maintenance of all-drug taking behaviors. Such that these circuits are primed to carry-out addictive behaviors for substances that the nicotine users subsequently experiment with and use regularly, the brain effects of nicotine use mean that individuals are often craving when they are in withdrawal, which can begin within hours of cessation of use. It is unknown what effect this may have on alcohol consumption or other drug use, and traditionally clinical recommendations have often proceeded from the assumption that it will be too difficult for individuals to simultaneously quit nicotine and other substances of abuse as that might incur increased risk of relapse to the other substance. However, the data continue to accumulate against that concept. It seems that quitting smoking (tobacco use) while in treatment either has no impact or, in some studies, has a favorable impact on the ability to quit and stay quit from other substances. Therefore it is important to systematically assess for tobacco use disorder while people come in for treatment of other substance use disorders and offer them assistance to quit.

Because nicotine is one of the earliest drugs to be used, it is important to assess whether use by youth has a gateway effect toward other substances of abuse. For “gateway effect,” the order of the substance may not be as important, but rather that the use of one substance leads to greater vulnerability for the subsequent use and addiction to other substances. The tobacco gateway seems to open quickly for urban adolescent smokers, who demonstrate a very high rate of concomitant substance use in a recent study. The uptake of cannabis seems to be much greater for youth with preexisting nicotine dependence, with the route of administration being an important variable, as smoking had greater risks than chewing tobacco. Furthermore, there is strong evidence that the relationship between cannabis and nicotine is bidirectional, with cannabis use being one of the strongest predictors of the subsequent onset of daily nicotine use after controlling for other variables.

The effects of nicotine cessation on other substances of abuse have been studied, even in high-risk groups like adolescents diagnosed with ADHD and substance use disorders. Still the cessation of nicotine did not increase the rate of relapse to other substances. Furthermore, the addition of smoking cessation to an established cannabis intervention did not adversely affect quit rates. In recent years there has seemed to be an increase in the number of adolescents and young adults who are moving away from tobacco and nicotine dependence to use other substances, which ultimately could make the costs to society even greater. Conversely, not ceasing the use of other substances does increase the uptake of nicotine use.

Nicotine and Negative Affect

Relative to some other substances of abuse (e.g., cocaine), negative reinforcement plays a more powerful role in the maintenance of tobacco use disorders. Negative reinforcement is the process of strengthening a behavior by having an aversive state removed after the behavior is performed, such as the smoking of a cigarette to avoid nicotine withdrawal. One of the most fundamental aspects of nicotine dependence involves its neuroregulatory function on mood. The negative emotions involve decreased experience of reward, increased perception of threat, increased activation of what Panskepp termed the “rage system,” and increased sensations of tension (possibly with relative disinhibition of locomotor activity). The experience of frustrated nonreward recruits more motivation and energy for reward seeking, and increases the probability of reward attainment. To resist this frustration, an individual would need to have a good level of inhibition and an ability to tolerate negative affect.

The relationship between negative affect and the ability to sustain cessation of smoking behavior plays a prominent role in theories of nicotine dependence. It has been theorized that individuals addicted to a substance learn to detect internal cues that negative affect is approaching as drug levels fall within the body. To prevent the onset of these negative feelings, the addicted person self-administers the drug, although often this process proceeds without conscious awareness. The longer the individual is without the drug, the more likely these negative feelings are to enter conscious awareness, providing direct reinforcement that taking the drug relieves negative affect ( Fig. 23.4 ). This relationship has driven the development of new pharmacological and behavioral approaches to treatment. The experience of negative affect is a significant contributor to the risk of relapse, and negative affect reduction is cited by many smokers as an important reason to smoke. This is, of course, a fool’s errand, as the negative affect is not truly relieved, but simply postponed. Newer approaches such as the ecological momentary assessment are helpful tools for tobacco researchers to look at the day-to-day, moment-to-moment correlates of smoking that could lead to the targeting of specific moments and tailoring strategies to forestall the resumption of tobacco consumption. Improving the understanding of the psychobiological and genetic mechanisms associated with the modulation of mood by nicotine will help us better understand the mechanisms of nicotine dependence and the relationship between these mechanisms and treatment success (see Fig. 23.4 ).

The term “negative affect” refers to a composite index of many negative mood states, including feelings of depression, dysphoria, irritability, and nervousness, and is usually measured by Likert-type scales such as the Positive and Negative Affect Scale (PANAS), Profile of Mood States (POMS), or other similar adjective checklists. Research on the relationship between negative affect and smoking behavior has included evaluation of the effects of a past history of major depression, which may serve as a marker for vulnerability to future depressed mood, and evaluation of the effects of precessation and postcessation negative affect.

Indeed, the presence of negative affect following cessation has been found to characterize over 50% of all smoking lapses, with 19% of all lapses occurring under conditions of extreme negative mood. Negative affect appears to be the component of nicotine withdrawal that most profoundly influences relapse and the trajectory of nicotine withdrawal symptoms. The expectation that nicotine will produce desirable emotional consequences has also been shown to inversely predict cessation success. In addition to postcessation negative affect, precessation levels of negative affect, have been shown to predict cessation outcome. Negative affect following a quit attempt has been related to treatment failure and relapse across a variety of treatment modalities.

When a smoker quits using tobacco, the above biological, cognitive, and behavioral aspects of dependence may increase the risk of relapse. However, many factors are associated with an increased risk for relapse after quitting smoking, including the availability of cigarettes, an increase in psychological stressors, and a triggering of conditioning factors (cues). Visual cues can be seeing people smoking or going to a location where one used to smoke or obtain cigarettes. Such factors may trigger the enduring adaptational changes that occurred in the brain during the period of nicotine consumption and subsequent addiction. The amygdala is very slow to forget, if it ever does, positively reinforced cues, in a term called incubation of drug craving.