Breakthrough in mapping nicotine addiction could help researchers improve treatment
A scientific blueprint to end tobacco
cravings may be on the way after researchers crystallized a protein that
holds answers to how nicotine addiction occurs in the brain.
The breakthrough at the Peter O'Donnell Jr. Brain Institute comes
after decades of failed attempts to crystallize and determine the 3D
structure of a protein that scientists expect will help them develop new
treatments by understanding nicotine's molecular effects.
"It's going to require a huge team of people and a pharmaceutical company to study the protein and develop the drugs, but I think this is the first major stepping stone to making that happen," said Dr. Ryan Hibbs, Assistant Professor of Neuroscience and Biophysics with the O'Donnell Brain Institute at UT Southwestern Medical Center, who co-authored the findings published in Nature.
The protein, called the α4β2 (alpha-4-beta-2) nicotinic receptor, sits on nerve cells in the brain. Nicotine binds to the receptor when someone smokes a cigarette or chews tobacco, causing the protein to open a path for ions to enter the cell. The process produces cognitive benefits such as increased memory and focus but is also highly addictive.
Until the new findings were generated, scientists didn't have a way to examine at atomic resolution how nicotine achieves these cognitive and addictive effects.
Who will benefit?
The expectation is that the 3D structures will help researchers understand how nicotine influences the activity of the receptor and lead to a medication that mimics its actions in the brain.
The finding may also have benefits in creating medications for certain types of epilepsy, mental illness, and dementia such as Alzheimer's, which are also associated with the nicotinic receptor. However, Dr. Hibbs cautioned that testing of any ensuing treatment would likely take many years.
Studies have shown smoking cessation drugs have mixed results in treating nicotine addiction, as have other methods such as nicotine patches and chewing gum.
"I just cannot quit smoking," said Tom Loveless of Dallas, who has tried many times to kick his cigarette habit after becoming addicted 40 years ago while in the Air Force.
He found the study's findings encouraging and hopes one day scientists can find a way to beat nicotine addiction. "I hate what it does to me," said Mr. Loveless, a retired 65-year-old grandfather. "I hate the expense. I hate the odor. It upsets my wife. It isn't worth it."
Motivating Factors
Despite widespread education on the dangers of tobacco use, it still causes nearly 6 million deaths per year worldwide, with smoking the leading cause of preventable death, according to the U.S. Centers for Disease Control and Prevention. Cigarettes alone account for 1 in 5 deaths annually in the U.S.
Those statistics are among the motivating factors for Dr. Hibbs, whose laboratory team began researching how to determine the structure of the receptor in 2012.
The receptor is "a critically important therapeutic target" for addiction and various mental and neurological disorders, said Dr. Joseph Takahashi, Chairman of Neuroscience and Investigator for the Howard Hughes Medical Institute.
"This is a major advance and solves a longstanding problem in crystallizing" the nicotinic receptor, said Dr. Takahashi, who holds the Loyd B. Sands Distinguished Chair in Neuroscience.
How they did it
For years scientists around the globe had concentrated efforts on the receptor found in the electric organ of a torpedo ray, a rich source of nicotinic receptors that yielded a wealth of biochemical information and held promise for obtaining a high-resolution atomic map of the protein.
"But they were never able to get the torpedo protein to crystalize," Dr. Hibbs said, explaining that the protein from the ray proved too unstable and couldn't be genetically modified. "Many very good research groups had tried to do this and failed. We took a different approach."
Instead, UT Southwestern researchers developed a method for mass producing nicotinic receptors by viral infection of a human cell line. The team inserted genes encoding the proteins that make the receptor into the virus, and the infected human cells started producing large amounts of the receptor.
They then used detergent and other purification steps to separate the receptor from the cell membrane and wash away all other proteins. Researchers were left with milligrams of the pure receptor that they mixed with chemicals known to promote crystallization.
The team looked at thousands of chemical combinations before eventually being able to grow crystals of the receptor, bound by nicotine and about 0.2 mm long. Lastly, they used X-ray diffraction measurements to obtain a high-resolution structure of the receptor.
The team's next steps involve determining structures in the absence of nicotine, and in the presence of molecules with different functional effects. Comparisons between structures will allow them to understand better what nicotine does, and how its actions are distinct from those of other chemicals, said Dr. Hibbs, Effie Marie Cain Scholar in Medical Research.
"It's going to require a huge team of people and a pharmaceutical company to study the protein and develop the drugs, but I think this is the first major stepping stone to making that happen," said Dr. Ryan Hibbs, Assistant Professor of Neuroscience and Biophysics with the O'Donnell Brain Institute at UT Southwestern Medical Center, who co-authored the findings published in Nature.
The protein, called the α4β2 (alpha-4-beta-2) nicotinic receptor, sits on nerve cells in the brain. Nicotine binds to the receptor when someone smokes a cigarette or chews tobacco, causing the protein to open a path for ions to enter the cell. The process produces cognitive benefits such as increased memory and focus but is also highly addictive.
Until the new findings were generated, scientists didn't have a way to examine at atomic resolution how nicotine achieves these cognitive and addictive effects.
Who will benefit?
The expectation is that the 3D structures will help researchers understand how nicotine influences the activity of the receptor and lead to a medication that mimics its actions in the brain.
The finding may also have benefits in creating medications for certain types of epilepsy, mental illness, and dementia such as Alzheimer's, which are also associated with the nicotinic receptor. However, Dr. Hibbs cautioned that testing of any ensuing treatment would likely take many years.
Studies have shown smoking cessation drugs have mixed results in treating nicotine addiction, as have other methods such as nicotine patches and chewing gum.
"I just cannot quit smoking," said Tom Loveless of Dallas, who has tried many times to kick his cigarette habit after becoming addicted 40 years ago while in the Air Force.
He found the study's findings encouraging and hopes one day scientists can find a way to beat nicotine addiction. "I hate what it does to me," said Mr. Loveless, a retired 65-year-old grandfather. "I hate the expense. I hate the odor. It upsets my wife. It isn't worth it."
Motivating Factors
Despite widespread education on the dangers of tobacco use, it still causes nearly 6 million deaths per year worldwide, with smoking the leading cause of preventable death, according to the U.S. Centers for Disease Control and Prevention. Cigarettes alone account for 1 in 5 deaths annually in the U.S.
Those statistics are among the motivating factors for Dr. Hibbs, whose laboratory team began researching how to determine the structure of the receptor in 2012.
The receptor is "a critically important therapeutic target" for addiction and various mental and neurological disorders, said Dr. Joseph Takahashi, Chairman of Neuroscience and Investigator for the Howard Hughes Medical Institute.
"This is a major advance and solves a longstanding problem in crystallizing" the nicotinic receptor, said Dr. Takahashi, who holds the Loyd B. Sands Distinguished Chair in Neuroscience.
How they did it
For years scientists around the globe had concentrated efforts on the receptor found in the electric organ of a torpedo ray, a rich source of nicotinic receptors that yielded a wealth of biochemical information and held promise for obtaining a high-resolution atomic map of the protein.
"But they were never able to get the torpedo protein to crystalize," Dr. Hibbs said, explaining that the protein from the ray proved too unstable and couldn't be genetically modified. "Many very good research groups had tried to do this and failed. We took a different approach."
Instead, UT Southwestern researchers developed a method for mass producing nicotinic receptors by viral infection of a human cell line. The team inserted genes encoding the proteins that make the receptor into the virus, and the infected human cells started producing large amounts of the receptor.
They then used detergent and other purification steps to separate the receptor from the cell membrane and wash away all other proteins. Researchers were left with milligrams of the pure receptor that they mixed with chemicals known to promote crystallization.
The team looked at thousands of chemical combinations before eventually being able to grow crystals of the receptor, bound by nicotine and about 0.2 mm long. Lastly, they used X-ray diffraction measurements to obtain a high-resolution structure of the receptor.
The team's next steps involve determining structures in the absence of nicotine, and in the presence of molecules with different functional effects. Comparisons between structures will allow them to understand better what nicotine does, and how its actions are distinct from those of other chemicals, said Dr. Hibbs, Effie Marie Cain Scholar in Medical Research.
Story Source:
Materials provided by UT Southwestern Medical Center. Note: Content may be edited for style and length.
In a piece of good news for people trying to quit smoking,
researchers have crystallized a protein that they hope will show what
happens in the brain when a person becomes addicted to nicotine.
Nicotine is a highly addictive drug.
Scientists expect the findings - published in Nature - to eventually lead to new treatments.
In the United States, 1 in 5 deaths are attributed to smoking, and tobacco use is responsible for nearly 6 million deaths globally every year.
Smoking is the number one cause of preventable death in the U.S., according to the Centers for Disease Control and Prevention (CDC).
Existing drugs, nicotine patches, and chewing gum have had mixed success in helping people to quit using nicotine products.
For decades, scientists have been trying to identify the 3-D structure of a protein known as the alpha-4-beta-2 (α4β2) nicotinic receptor.
Until now, there has been no way to study nicotine's effects on the brain, and how it becomes addictive, at the atomic level.
The current breakthrough should lead to a new understanding of the molecular effects of nicotine.
The α4β2 nicotinic receptor is located on nerve cells in the brain. When a person smokes a cigarette or chews tobacco, the nicotine binds to this receptor. This opens a pathway for ions to enter the cell.
There are cognitive benefits, including an enhancement of memory and focus, but it is also very addictive.
The ray's electric organ is known to be a rich source of nicotinic receptors, and it provided a wealth of key information. However, the close-up view the scientists craved remained elusive.
The present team tried a new strategy; they found a way to produce large numbers of nicotinic receptors by infecting a human cell line with a virus.
They inserted genes into the virus, and these genes encoded the required proteins. The cells that were infected with the virus began to produce large amounts of the receptor.
Using detergent and other methods of purification, the researchers separated the receptor from the cell membrane, and they eliminated all the other proteins. They were left with milligrams of the pure receptor.
Next, they mixed the receptor with chemicals that normally promote crystallization. They looked at thousands of chemical combinations, and they finally succeeded in growing crystals of the receptor.
The crystals were bound by nicotine, and they measured around 0.2 millimeters in length.
To obtain a high-resolution structure of the receptor, the researchers used X-ray diffraction measurements.
The next step will be to look at the structures when there is no nicotine, and when molecules with different functional effects are applied.
Comparing the structures in this way is expected to shed light on how nicotine acts and what it does differently from other chemicals.
Find out how nicotine has been proposed as a possible way to prevent brain aging.
Materials provided by UT Southwestern Medical Center. Note: Content may be edited for style and length.
Nicotine is a highly addictive drug.
In the United States, 1 in 5 deaths are attributed to smoking, and tobacco use is responsible for nearly 6 million deaths globally every year.
Smoking is the number one cause of preventable death in the U.S., according to the Centers for Disease Control and Prevention (CDC).
Existing drugs, nicotine patches, and chewing gum have had mixed success in helping people to quit using nicotine products.
For decades, scientists have been trying to identify the 3-D structure of a protein known as the alpha-4-beta-2 (α4β2) nicotinic receptor.
Until now, there has been no way to study nicotine's effects on the brain, and how it becomes addictive, at the atomic level.
The current breakthrough should lead to a new understanding of the molecular effects of nicotine.
The α4β2 nicotinic receptor is located on nerve cells in the brain. When a person smokes a cigarette or chews tobacco, the nicotine binds to this receptor. This opens a pathway for ions to enter the cell.
There are cognitive benefits, including an enhancement of memory and focus, but it is also very addictive.
Searching for clues in the torpedo ray
For years, teams from around the world have been expecting the torpedo ray to provide the clues they needed to understand how this protein works.The ray's electric organ is known to be a rich source of nicotinic receptors, and it provided a wealth of key information. However, the close-up view the scientists craved remained elusive.
Fast facts about nicotine
The protein from the ray was too unstable. It could not be genetically modified, and it would not crystallize.
- More people in the U.S. are addicted to nicotine than any other drug
- Nicotine may be as addictive as heroin, cocaine, or alcohol
- Nicotine withdrawal can trigger stress, weight gain, and irritability.
The present team tried a new strategy; they found a way to produce large numbers of nicotinic receptors by infecting a human cell line with a virus.
They inserted genes into the virus, and these genes encoded the required proteins. The cells that were infected with the virus began to produce large amounts of the receptor.
Using detergent and other methods of purification, the researchers separated the receptor from the cell membrane, and they eliminated all the other proteins. They were left with milligrams of the pure receptor.
Next, they mixed the receptor with chemicals that normally promote crystallization. They looked at thousands of chemical combinations, and they finally succeeded in growing crystals of the receptor.
The crystals were bound by nicotine, and they measured around 0.2 millimeters in length.
To obtain a high-resolution structure of the receptor, the researchers used X-ray diffraction measurements.
The next step will be to look at the structures when there is no nicotine, and when molecules with different functional effects are applied.
Comparing the structures in this way is expected to shed light on how nicotine acts and what it does differently from other chemicals.
Possible future applications
Study co-author Dr. Ryan Hibbs, assistant professor of neuroscience and biophysics with the O'Donnell Brain Institute at the University of Texas Southwestern Medical Center in Dallas, notes that it could take years to develop and test any treatment."It's going to require a huge team of people and a pharmaceutical company to study the protein and develop the drugs, but I think this is the first major stepping stone to making that happen."Other conditions linked to the nicotinic receptor include some types of epilepsy, mental illness, and dementia - for example, Alzheimer's disease. These, too, could benefit from the discovery.
Dr. Ryan Hibbs
Find out how nicotine has been proposed as a possible way to prevent brain aging.
Cigarette
smoking remains a leading cause of preventable disease and premature
death in the United States and other countries. On average, 435,000
people in the United States die prematurely from smoking-related
diseases each year; overall, smoking causes 1 in 5 deaths. The chance
that a lifelong smoker will die prematurely from a complication of
smoking is approximately 50%.1
Tobacco
use is a major cause of death from cancer, cardiovascular disease, and
pulmonary disease. Cigarette smoking is also a risk factor for
respiratory tract and other infections, osteoporosis, reproductive
disorders, adverse postoperative events and delayed wound healing,
duodenal and gastric ulcers, and diabetes. In addition, smoking has a
strong association with fire-related and trauma-related injuries.
Smoking-caused disease is a consequence of exposure to toxins in tobacco
smoke. Although nicotine plays a minor role, if any, in causing
smoking-induced diseases, addiction to nicotine is the proximate cause
of these diseases.
Currently, about 45 million Americans
smoke tobacco. Seventy percent of smokers say they would like to quit,
and every year, 40% do quit for at least 1 day.2 Some highly addicted smokers make serious attempts to quit but are able to stop only for a few hours.3
Moreover, the 80% who attempt to quit on their own return to smoking
within a month, and each year, only 3% of smokers quit successfully.
Unfortunately, the rate at which persons — primarily children and
adolescents — become daily smokers nearly matches the quit rate, so the
prevalence of cigarette smoking has declined only very slowly in recent
years.2
This
article focuses on nicotine as a determinant of addiction to tobacco
and the pharmacologic effects of nicotine that sustain cigarette
smoking. Tobacco addiction (like all drug addictions) involves the
interplay of pharmacology, learned or conditioned factors, genetics, and
social and environmental factors (including tobacco product design and
marketing)4 (Fig. 1).
The pharmacologic reasons for nicotine use are enhancement of mood,
either directly or through relief of withdrawal symptoms, and
augmentation of mental or physical functions.
Figure 1
The Biology of Nicotine Addiction
BRAIN MECHANISMS
NICOTINIC ACETYLCHOLINE RECEPTORS
Inhalation
of smoke from a cigarette distills nicotine from the tobacco in the
cigarette. Smoke particles carry the nicotine into the lungs, where it
is rapidly absorbed into the pulmonary venous circulation. The nicotine
then enters the arterial circulation and moves quickly from the lungs to
the brain, where it binds to nicotinic cholinergic receptors
(ligand-gated ion channels that normally bind acetylcholine). The
binding of nicotine at the interface between two subunits of the
receptor opens the channel, thereby allowing the entry of sodium or
calcium.5
The entry of these cations into the cell further activates
voltage-dependent calcium channels, allowing more calcium to enter. One
of the effects of the entry of calcium into a neuron is the release of
neurotransmitters.
The nicotinic cholinergic receptor consists of five subunits.6 The mammalian brain expresses nine α subunits (α2 through α10) and three β subunits (β2 through β4). The most abundant receptors are α4β2, α3β4, and α7, the latter of which are homomeric. The α4β2*
receptor (the asterisk indicates that other subunits may be present in
this receptor) is the principal mediator of nicotine dependence. In
mice, disruption of the β2 subunit gene eliminates
the behavioral effects of nicotine; reinserting the gene into the
ventral tegmental area restores behavioral responses to nicotine.7,8 The α4
subunit is an important determinant of sensitivity to nicotine. A
mutation affecting a single nucleotide in the pore-forming region of the
mouse receptor gene makes it hypersensitive to the effects of nicotine.9 Other subunits can form functional receptors. The presence of an α5 subunit combined with α4β2 increases calcium conductance seven times; α5 gene variants also alter nicotine responsiveness in cultured human cells.10,11 The α3β4 subtype probably mediates the cardiovascular effects of nicotine.12 The α7
homomeric receptors are involved in rapid synaptic transmission and
long-term potentiation to dopaminergic neurons at excitatory inputs and
have a role in learning and sensory gating.13–16
NICOTINE AND NEUROTRANSMITTER RELEASE
Stimulation of nicotinic cholinergic receptors releases a variety of neurotransmitters in the brain.5,17
One of them, dopamine, signals a pleasurable experience and is critical
for the reinforcing effects (effects that promote self-administration)
of nicotine and other drugs of abuse, as well as for compelling drives
such as eating.18
Experimentally induced lesions in dopamine-releasing neurons prevent
self-administration of nicotine in rats. Nicotine releases dopamine in
the mesolimbic area, the corpus striatum, and the frontal cortex (Fig. 2).
The dopaminergic neurons in the ventral tegmental area of the midbrain
and in the shell of the nucleus accumbens are critical in drug-induced
reward (both regions have a role in perceptions of pleasure and reward).6,18
Figure 2
Role of the Mesolimbic Dopamine System in Nicotine Activity
Nicotine also augments both glutamate release, which facilitates the release of dopamine, and γ-aminobutyric acid (GABA) release, which inhibits dopamine release.15,16
With long-term exposure to nicotine, some nicotinic cholinergic
receptors become desensitized but some do not. As a result,
GABA-mediated inhibitory tone diminishes while glutamate-mediated
excitation persists, thereby increasing excitation of dopaminergic
neurons and enhancing responsiveness to nicotine.
A
measure of the function of the reward system in rats is the threshold
for electrical self-stimulation in the medial forebrain: a lower
threshold indicates increased responsiveness to rewarding stimuli.
Nicotine lowers the threshold for reward, an effect that can last for
more than 30 days.19
It also increases activity in the prefrontal cortex, thalamus, and
visual system, reflecting activation of corticobasal ganglia–thalamic
brain circuits (part of the reward network), and releases dopamine in
the striatum.20
Other neurotransmitters that may be involved in nicotine addiction are
the hypocretins, neuropeptides produced in the lateral hypothalamus that
regulate the stimulatory effects of nicotine on reward centers in the
brain and modulate self-administration of nicotine in rodents.21
MONAMINE OXIDASE
Constituents
of cigarette smoke other than nicotine contribute to nicotine
addiction. Monoamine oxidases, enzymes located in catecholaminergic and
other neurons, catalyze the metabolism of dopamine, norepinephrine, and
serotonin. Condensation products of acetaldehyde in cigarette smoke with
biogenic amines inhibit the activity of monoamine oxidase type A and
monoamine oxidase type B, and there is evidence that inhibition of
monoamine oxidase contributes to the addictiveness of smoking by
reducing the metabolism of dopamine.22,23
NEUROADAPTATION
With repeated exposure to nicotine, neuroadaptation (tolerance) to some of the effects of nicotine develops.24
As neuroadaptation develops, the number of binding sites on the
nicotinic cholinergic receptors in the brain increases, probably in
response to nicotine-mediated desensitization of receptors.25
Desensitization — ligand-induced closure and unresponsiveness of the
receptor — is believed to play a role in tolerance and dependence: the
symptoms of craving and withdrawal begin in smokers when desensitized α4 β2* nicotinic cholinergic receptors become responsive during periods of abstinence, such as nighttime sleep.26 Nicotine binding of these receptors during smoking alleviates craving and withdrawal.
Cigarette
smoking in amounts that are typical for daily smokers maintains
near-complete saturation — and thus desensitization — of the α4 β2* nicotinic cholinergic receptors.27
Thus, smokers are probably attempting to avoid withdrawal symptoms when
maintaining a desensitized state. By sustaining sufficient levels of
plasma nicotine to prevent withdrawal symptoms, they also derive
rewarding effects from the conditioned reinforcements associated with
smoking, such as the taste and feel of smoke.28
Nicotine withdrawal causes anxiety and stress, both of which are powerful incentives to take up smoking again.29
The negative affect that typifies the response to nicotine withdrawal
probably results in part from a cascade of events involving increased
levels of extrahypothalamic corticotropin-releasing factor (CRF) and
increased binding of CRF to corticotropin-releasing factor 1 (CRF1)
receptors in the brain, thereby activating the CRF–CRF1 receptor system,
which mediates responses to stress. In rats, anxiety-like behavior and
the release of CRF in the central nucleus of the amygdala occur during
nicotine withdrawal.30
CRF causes anxiety, whereas the pharmacologic blockade of CRF1
receptors inhibits the anxiogenic effects of nicotine withdrawal. The
blockade of CRF1 receptors also prevents the increase in
self-administration of nicotine that occurs during abstinence from
forced nicotine administration in rats. Thus, both underactivity of the
dopaminergic system and activation of the CRF–CRF1 receptor system
contribute to the symptoms of nicotine withdrawal that often precipitate
relapse.
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CLINICAL ASPECTS OF NICOTINE ADDICTION
PSYCHOACTIVE EFFECTS OF NICOTINE
Nicotine
induces pleasure and reduces stress and anxiety. Smokers use it to
modulate levels of arousal and to control mood. Smoking improves
concentration, reaction time, and performance of certain tasks. Relief
from withdrawal symptoms is probably the primary reason for this
enhanced performance and heightened mood.31 Cessation of smoking causes the emergence of withdrawal symptoms: irritability, depressed mood, restlessness, and anxiety.32 The intensity of these mood disturbances is similar to that found in psychiatric outpatients.33
Anhedonia — the feeling that there is little pleasure in life — can
also occur with withdrawal from nicotine, and from other drugs of abuse.34
The
basis of nicotine addiction is a combination of positive
reinforcements, including enhancement of mood and avoidance of
withdrawal symptoms (Fig. 3).35 In addition, conditioning has an important role in the development of tobacco addiction.
Figure 3
Molecular and Behavioral Aspects of Nicotine Addiction
CONDITIONED BEHAVIOR
When
a person who is addicted to nicotine stops smoking, the urge to resume
is recurrent and persists long after withdrawal symptoms dissipate. With
regular smoking, the smoker comes to associate specific moods,
situations, or environmental factors — smoking-related cues — with the
rewarding effects of nicotine. Typically, these cues trigger relapse.
The
association between such cues and the anticipated effects of nicotine,
and the resulting urge to use nicotine, constitute a form of
conditioning. Studies in animals show that nicotine exposure causes
changes in the protein expression of brain cells and in their synaptic
connections — a process termed neural plasticity — which underlie
conditioning.36,37 Nicotine also enhances behavioral responses to conditioned stimuli, which may contribute to compulsive smoking.38
Furthermore, studies in nicotine-dependent rats show that conditioned
stimuli associated with nicotine withdrawal increase the magnitude of
withdrawal through an elevation of the brain’s reward threshold.39 Thus, cues associated with nicotine withdrawal can decrease the function of the brain’s reward systems.
The
desire to smoke is maintained, in part, by such conditioning. Smokers
usually take a cigarette after a meal, with a cup of coffee or an
alcoholic drink, or with friends who smoke. When repeated many times,
such situations become a powerful cue for the urge to smoke. Aspects of
smoking itself — the manipulation of smoking materials, or the taste,
smell, or feel of smoke in the throat — also become associated with the
pleasurable effects of smoking.40,41
Even unpleasant moods can become conditioned cues for smoking: a smoker
may learn that not having a cigarette provokes irritability and that
smoking one provides relief. After repeated experiences like this, a
smoker can sense irritability from any source as a cue for smoking.
Functional imaging studies have shown that exposure to drug-associated
cues activates cortical regions of the brain, including the insula (a
structure in the cortex associated with certain basic emotions). Smokers
who sustain damage to the insula (e.g., brain trauma) are more likely
to quit smoking soon after the injury, and to remain abstinent, and are
less likely to have conscious urges to smoke than smokers with brain
injury that does not affect the insula.42
THE TOBACCO ADDICTION CYCLE
Smoking
is a highly efficient form of drug administration. Inhaled nicotine
enters the circulation rapidly through the lungs and moves into the
brain within seconds. Rapid rates of absorption and entry into the brain
cause a strongly felt “rush” and reinforce the effects of the drug. In
animals, rapid administration of nicotine potentiates locomotor
sensitization, which is linked to reward, and neuroplastic changes in
the brain.43
The smoking process also provides rapid reinforcement and allows for
precise dosing, making it possible for a smoker to obtain desired
effects without toxicity. Unlike cigarettes, nicotine medications
marketed to promote smoking cessation deliver nicotine slowly, and the
risk of abuse is low.44
In addition to delivering nicotine to the brain quickly, cigarettes
have been designed with additives and engineering features to enhance
its addictiveness.45
There
is considerable peak-to-trough oscillation in blood levels of nicotine
from cigarette to cigarette. Nevertheless, it accumulates in the body
over the course of 6 to 9 hours of regular smoking and results in 24
hours of exposure. Arteriovenous differences in nicotine concentrations
during cigarette smoking are substantial, with arterial levels up to 10
times as high as venous levels.46
The persistence of nicotine in the brain throughout the day and night
changes the structure and function of nicotinic receptors, stimulating
intracellular processes of neuroadaptation.
The
pharmacologic basis of nicotine addiction is thus a combination of
positive reinforcements, such as enhancement of mood and mental or
physical functioning, and avoidance of withdrawal symptoms when nicotine
is not available. Figure 4 shows a typical daily smoking cycle.47
Figure 4
The Tobacco Addiction Cycle
Smokers
tend to take in the same amount of nicotine from day to day to achieve
the desired effects. They adjust their smoking behavior to compensate
for changes in the availability of nicotine (e.g., when switching from
regular to low-yield cigarettes) to regulate the body’s level of
nicotine.48
Light smokers (those who smoke ≤5 cigarettes per day) and occasional
smokers smoke primarily for the positive reinforcing effects of nicotine
and have minimal or no withdrawal symptoms.49
They smoke primarily in association with particular activities (after
eating a meal or while drinking alcohol), and are less likely to smoke
in response to negative affect. Although withdrawal symptoms may not be
prominent, many light and occasional smokers have difficulty quitting.
Some of them have a high level of dependence, but with pharmacodynamics
that differ from those in heavier smokers.
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GENETICS OF NICOTINE ADDICTION
Studies
in twins have shown a high degree of heritability of cigarette smoking
(≥50%), including the level of dependence and the number of cigarettes
smoked daily.50 These studies have also revealed the heritability of the particular symptoms that occur when a smoker stops smoking.51
Numerous attempts have been made to identify genes underlying nicotine addiction.50
Such studies are problematic because multiple genes and environmental
factors determine complex behavior, and the many different dependence
phenotypes may have different genetic underpinnings. Candidate genes
coding for nicotine-receptor subtypes, dopamine receptors and dopamine
transporters, GABA receptors, opiate and cannabinoid receptors, and
other types of receptors have been associated with different aspects of
smoking behavior.52 Subsequent research, however, has not replicated many of the initial findings.
Recent
genomewide association studies point to several promising genetic
determinants of nicotine dependence. Bierut et al. compared the genomes
of smokers who became dependent on nicotine with the genomes of smokers
who did not.53
Signals from genomewide association studies guided a second-phase
candidate-gene association study by Saccone et al. in which several
strong genetic associations were uncovered.54 Most prominent were genes within the α5/α3/β4
nicotinic cholinergic receptor gene complex on chromosome 15. This and
other genomewide association studies of tobacco addiction have also
identified genes affecting cell adhesion and extracellular matrix
molecules, which are common among various addictions. These findings are
consistent with the idea that neural plasticity and learning are key
determinants of individual differences in vulnerability to nicotine
dependence and other drug addictions.55
Variants associated with nicotine dependence in the α5/α3/β4
gene region (chromosome 15, 15q25) also have a significant association
with the number of cigarettes smoked per day, plasma levels of cotinine
(a biomarker of nicotine intake), urine levels of tobacco-smoke
carcinogens, and the risks of smoking-related diseases.11,56–62
The mechanisms of the associations between these variants and disease
are probably related to the level of dependence and therefore the level
of intake of tobacco-smoke toxins; however, nicotinic cholinergic
receptors also modulate inflammatory responses, angiogenesis, and
apoptosis, and thus account for additional mechanisms through which
nicotine could affect the risk of disease.63
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VULNERABILITY TO ADDICTION
Tobacco use typically begins in childhood or adolescence — 80% of smokers begin smoking by 18 years of age.64
Although two thirds of young people try cigarette smoking, only 20 to
25% of them become dependent daily smokers, usually as adults.65,66
Risk factors for smoking in childhood or adolescence include peer and
parental influences, behavioral problems (e.g., poor school
performance), personality characteristics (rebelliousness, risk taking,
depression, and anxiety), and genetic influences.64
The risk of dependence increases when smoking begins early.64
Studies of the developing brain in animals suggest that nicotine can
induce permanent changes that lead to addiction. Brain changes in
adolescent rats exposed to nicotine are greater than those in exposed
adult rats. Adolescent rats that have been exposed to nicotine have
higher rates of nicotine self-administration as adults, which is
consistent with the idea that early exposure to nicotine increases the
severity of dependence.67,68
Tobacco addiction is highly prevalent among persons with mental illness or substance-abuse disorders.69,70
The mechanisms of this association are likely to include a shared
genetic predisposition, the capacity of nicotine to alleviate some
psychiatric symptoms, and the inhibitory effects of tobacco smoke on
monoamine oxidase.23,71,72
Smoking
behavior in women is more strongly influenced by conditioned cues and
negative affect; men are more likely to smoke in response to
pharmacologic cues, regulating their intake of nicotine more precisely
than women.73 On average, women metabolize nicotine more quickly than men,74
which may contribute to their increased susceptibility to nicotine
addiction and may help to explain why, among smokers, it is more
difficult for women to quit.75
Insofar
as smokers regulate their intake of nicotine to maintain particular
levels throughout the day, those who metabolize nicotine rapidly take in
more cigarette smoke per day than those who metabolize nicotine slowly.
Nicotine is metabolized to cotinine primarily by the liver enzyme
CYP2A6.76 Persons with a genetic basis for slow metabolism (those with variant CYP2A6 genes that are associated with reduced enzyme activity) smoke fewer cigarettes daily than persons with faster metabolism.77
The observation that the fraction of smokers with genetically slow
metabolism in the population of smokers decreases with the increasing
age of the cohort of smokers suggests that those with slow metabolism
are more likely to quit than those with faster metabolism. Rapid
metabolism of nicotine is associated with more severe withdrawal
symptoms and a lower probability of success in quitting during
nicotine-patch treatment.78,79
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