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Physiology of Behavior 11th Edition
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Neil R. Carlson
Prepared by Grant McLaren, Edinboro University of Pennsylvania
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Drug Abuse
Chapter 18
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Drug Abuse
• Common Features of Addiction
• A Little Background
• Positive Reinforcement
• Negative Reinforcement
• Craving and Relapse
• Section Summary
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Drug Abuse
• Commonly Abused Drugs
• Opiates
• Stimulant Drugs: Cocaine and Amphetamine
• Nicotine
• Alcohol
• Cannabis
• Section Summary
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Drug Abuse
• Heredity and Drug Abuse
• Section Summary
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Drug Abuse
• Therapy for Drug Abuse
• Section Summary
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Common Features of Addiction
• The term addiction derives from the Latin word addicere, “to sentence.”
• Someone who is addicted to a drug is, in a way, sentenced to a term of involuntary
servitude, being obliged to fulfill the demands of his or her drug dependency.
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Common Features of Addiction
A Little Background
• Long ago, people discovered that many substances found in nature—primarily leaves,
seeds, and roots of plants, but also some animal products—had medicinal qualities.
• They discovered herbs that helped to prevent infections, that promoted healing, that
calmed an upset stomach, that reduced pain, or that helped to provide a night ’s sleep.
• They also discovered “recreational drugs”—drugs that produced pleasurable effects
when eaten, drunk, or smoked. The most universal recreational drug, and perhaps the
first one that our ancestors discovered, is ethyl alcohol.
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Common Features of Addiction
A Little Background
• Our ancestors also discovered other recreational drugs.
• Some of them were consumed only locally; others became so popular that their cultivation
as commercial crops spread throughout the world.
• For example, Asians discovered the effects of the sap of the opium poppy and the
beverage made from the leaves of the tea plant, Indians discovered the effects of the
smoke of cannabis, South Americans discovered the effects of chewing coca leaves and
making a drink from coffee beans, and North Americans discovered the effects of the
smoke of the tobacco plant.
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Common Features of Addiction
A Little Background
• Many of the drugs they discovered were actually poisons that served to protect the plants
from animals (primarily insects) that ate them.
• Although the drugs were toxic in sufficient quantities, our ancestors learned how to take
these drugs in amounts that would not make them ill—at least, not right away.
• The effects of these drugs on their brains kept them coming back for more.
• Table 18.1 lists the most important addictive drugs and indicates their sites of action.
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Table 18.1, page 616
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Common Features of Addiction
Positive Reinforcement
• Addictive drugs have reinforcing effects.
• That is, their effects include activation of the reinforcement mechanism.
• This activation strengthens the response that was just made.
• If the drug was taken by a fast-acting route such as injection or inhalation, the last
response will be the act of taking the drug, so that response will be reinforced.
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Common Features of Addiction
Role in Drug Abuse
• When appetitive stimuli occur, they usually do so because we just did something to make
them happen—and not because an experimenter was controlling the situation. The
effectiveness of a reinforcing stimulus is greatest if it occurs immediately after a response
occurs. If the reinforcing stimulus is delayed, it becomes considerably less effective. The
reason for this fact is found by examining the function of instrumental conditioning:
learning about the consequences of our own behavior. Normally, causes and effects are
closely related in time; we do something, and something happens, good or bad. The
consequences of the actions teach us whether to repeat that action, and events that
follow a response by more than a few seconds were probably not caused by that
response.
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Common Features of Addiction
Role in Drug Abuse
• As we saw in Chapter 4, drug users prefer heroin to morphine not because heroin has a
different effect, but because it has a more rapid effect.
• In fact, heroin is converted to morphine as soon as it reaches the brain. But because
heroin is more lipid soluble, it passes through the blood–brain barrier more rapidly, and its
effects on the brain are felt sooner than those of morphine.
• The most potent reinforcement occurs when drugs produce sudden changes in the
activity of the reinforcement mechanism; slow changes are much less reinforcing.
• A person taking an addictive drug seeks a sudden “rush” produced by a fast-acting drug.
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Common Features of Addiction
Neural Mechanisms
• As we saw in Chapter 13, all natural reinforcers that have been studied so far (such as
food for a hungry animal, water for a thirsty one, or sexual contact) have one
physiological effect in common: They cause the release of dopamine in the nucleus
accumbens (White, 1996).
• This effect is not the only effect of reinforcing stimuli, and even aversive stimuli can
trigger the release of dopamine (Salamone, 1992).
• But although there is much that we do not yet understand about the neural basis of
reinforcement, the release of dopamine appears to be a necessary (but not sufficient)
condition for positive reinforcement to take place.
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Common Features of Addiction
Neural Mechanisms
• Addictive drugs—including amphetamine, cocaine, opiates, nicotine, alcohol, PCP, and
cannabis—trigger the release of dopamine in the nucleus accumbens (NAC), as
measured by microdialysis (Di Chiara, 1995).
• Different drugs stimulate the release of dopamine in different ways.
• The details of the ways in which particular drugs interact with the mesolimbic
dopaminergic system are described later, in sections devoted to particular categories of
drugs.
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Common Features of Addiction
Neural Mechanisms
• The fact that the reinforcing properties of addictive drugs involve the same brain
mechanisms as natural reinforcers indicated that these drugs “hijack” brain mechanisms
that normally help us adapt to our environment.
• It appears that the process of addiction begins in the mesolimbic dopaminergic system
and then produces long-term changes in other brain regions that receive input from these
neurons (Kauer and Malenka, 2007).
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Common Features of Addiction
Neural Mechanisms
• The first changes appear to take place in the ventral tegmental area (VTA).
• Saal et al. (2003) found that a single administration of a variety of addictive drugs
(including cocaine, amphetamine, morphine, alcohol, and nicotine) increased the strength
of excitatory synapses on dopaminergic neurons in the VTA in mice.
• This change appears to result from insertion of additional AMPA receptors into the
postsynaptic membrane of the DA neurons (Mameli et al., 2009).
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Common Features of Addiction
Neural Mechanisms
• At first, the potential addict experiences the pleasurable effects of the drug, which
reinforces the behaviors that cause the drug to be delivered to the brain (procuring the
drug, taking necessary steps to prepare it, then swallowing, smoking, sniffing, or injecting
it).
• Eventually, these behaviors become habitual, and the impulse to perform them becomes
difficult to resist.
• The early reinforcing effects that take place in the ventral striatum (namely, in the NAC)
encourage drug-taking behavior, but the changes that make the behaviors become
habitual involve the dorsal striatum.
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Common Features of Addiction
Neural Mechanisms
• As we saw in Chapter 8, an important role of the dorsal striatum is establishment of
automatic behaviors—the type of behaviors that are impaired in people with Parkinson’s
disease, which is caused by disruption of dopaminergic input to this region.
• Studies with monkeys performing a response reinforced by infusion of cocaine over a
long period of time show a progression of neural changes, beginning in the ventral
striatum (in the NAC) and continuing upward to the dorsal striatum (Letchworth et al.,
2001; Porrino et al., 2004, 2007).
• A study with rats found that infusion of a dopamine antagonist into the dorsal striatum
suppressed lever presses that had been reinforced by the illumination of a light that had
been paired with intravenous injections of cocaine Vanderschuren et al. (2005).
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Common Features of Addiction
Neural Mechanisms
• An experiment by Belin and Everitt (2008) suggests that the neural changes responsible
for addiction follow a dorsally cascading set of reciprocal connections between the
striatum and the ventral tegmental area.
• Anatomical studies show that neurons in the ventral NAC project to the VTA, which sends
dopaminergic projections back to a more dorsal region of the NAC, and so on.
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Common Features of Addiction
Neural Mechanisms
• This back-and-forth communication continues, connecting increasingly dorsal regions of
the striatum, all the way up to the caudate nucleus and putamen.
• Belin and Everitt found that bilateral infusions of a dopamine antagonist into the dorsal
striatum of rats suppressed responding to a light that had been associated with infusions
of cocaine, but that unilateral infusions had no effect.
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Common Features of Addiction
Neural Mechanisms
• They also found that a unilateral lesion of the NAC had no effect on responding.
• However, they found that a lesion of the NAC on one side of the brain combined with
infusion of a dopamine antagonist into the dorsal striatum on the other side of the brain
suppressed responding to the light. (See Figure 18.1.)
• These results suggest that the control of compulsive addictive behavior is established by
interactions between the ventral and dorsal striatum that are mediated by dopaminergic
connections between these regions and the VTA.
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Figure 18.1, page 618
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Common Features of Addiction
Neural Mechanisms
• The alterations that occur in the NAC and later in the dorsal striatum include changes in
dopamine receptors on the medium spiny neurons, which are the source of axons that
project from both of these regions to other parts of the brain.
• Increases are seen in dopamine D1 receptors, which cause excitation and facilitate
behavior, and decreases are seen in dopamine D2 receptors, which cause inhibition and
suppress behavior.
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Common Features of Addiction
Neural Mechanisms
• A study by Witten et al. (2010) found that one of the neural changes in the NAC caused
by cocaine intake involves acetylcholinergic interneurons.
• ACh neurons comprise less than one percent of the neurons in the NAC, but these
neurons have a powerful effect on the activity of the medium spiny neurons located there.
• Witten and her colleagues found that cocaine increased the firing of the interneurons, and
that inhibiting the firing of these neurons by optogenetic methods blocked the reinforcing
effect of cocaine.
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Common Features of Addiction
Neural Mechanisms
• Functional-imaging studies by Volkow and her colleagues (reviewed by Volkow et al.,
2011) provide evidence that addiction involves the dorsal striatum in humans, as well as
in other animals.
• The investigators found that when cocaine addicts are given an injection of
methylphenidate (a drug with effects like those of cocaine or amphetamine), they show a
much smaller release of dopamine in the NAC or dorsal striatum than do nonaddicted
people.
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Common Features of Addiction
Neural Mechanisms
• However, when addicted people are shown a video of people smoking cocaine, they
showed an increased release of dopamine in the dorsal striatum.
• Thus, the response to the drug itself is diminished in addicts, but the response to cues
associated with the drug is augmented—in the dorsal striatum. (See Figure 18.2.)
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Figure 18.2, page 619
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Common Features of Addiction
Neural Mechanisms
• These results are consistent with those of studies with animals cited above: The release
of dopamine in the NAC leads to acquisition of a drug addiction, but changes in the dorsal
striatum are responsible for the establishment of the drug-taking habit.
• In addition, in addicted individuals, dopamine is released in the dorsal striatum —not by
the drug itself, but by stimuli associated with procuring and taking the drug, including
places where the drug was taken and people with whom it was taken.
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Common Features of Addiction
Neural Mechanisms
• So when people first take an addictive drug, they experience pleasurable effects.
• If they continue to take the drug and become addicted, their compulsion to take the drug
is not motivated by the pleasurable effects, but by drug-related cues that give rise to the
urge to perform drug-seeking behaviors.
• As Volkow and her colleagues note, drug addicts are aroused and motivated when they
are seeking a drug but are withdrawn and apathetic when they are in a drug-free
environment, engaged in activities not related to drug taking.
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Common Features of Addiction
Neural Mechanisms
• Most people who are exposed to addictive drugs do not become addicted (Volkow and Li,
2005).
• The likelihood of becoming addicted is a function of heredity, age (adolescents are most
vulnerable), and environment (such as access to drugs and stressful life events) .
• The role of heredity is discussed in a later section of this chapter.
• The role of the prefrontal cortex in judgment, risk taking, and control of inappropriate
behaviors may explain why adolescents are much more vulnerable to drug addiction than
are adults.
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Common Features of Addiction
Neural Mechanisms
• Adolescence is a time of rapid and profound maturational change in the brain—
particularly in the prefrontal cortex.
• Before these circuits reach their adult form, adolescents are more likely to display
increased levels of impulsive, novelty-driven, risky behavior, including experimentation
with alcohol, nicotine, and illicit drugs.
• Addiction in adults most often begins in adolescence or young adulthood.
• Approximately 50 percent of cases of addiction begin between the ages of 15 and 18, and
very few begin after age 20.
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Common Features of Addiction
Neural Mechanisms
• In addition, early onset of drug-taking is associated with more severe addiction and a
greater likelihood of multiple substance abuse (Chambers, Taylor, and Potenza, 2003).
• In fact, Tarter et al. (2003) found that ten- to twelve-year-old boys who scored the lowest
on tests of behavioral inhibition had an increased risk of developing substance use
disorder by age nineteen.
• Some regions of the prefrontal cortex have inhibitory connections with the striatum, and
increased activity of these regions is correlated with resistance to addiction.
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Common Features of Addiction
Neural Mechanisms
• Presumably, the increased vulnerability of adolescents to drug addiction is related to the
relative immaturity of inhibitory mechanisms of their prefrontal cortex.
• The final development of neural circuits involved in behavioral control and judgment,
along with the maturity that comes from increased experience, apparently helps people
emerging from adolescence to resist the temptation to abuse drugs.
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Common Features of Addiction
Neural Mechanisms
• Two peptides, orexin and MCH, play a crucial role in the reinforcing effects of drugs.
• As we saw in Chapters 9 and 12, orexin (also called hypocretin) plays an important role in
control of sleep stages and food-seeking behavior.
• Orexin is synthesized in neurons in the lateral hypothalamus and released in many parts
of the brain, including those that play a role in addiction, such as the VTA, NAC, and
dorsal striatum.
• Administration of addictive drugs or presentation of stimuli associated with them activate
orexinergic neurons, and infusion of orexin into the VTA reinstates drug seeking that was
previously extinguished.
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Common Features of Addiction
Neural Mechanisms
• The second peptide, MCH (melanin-concentrating hormone), is also synthesized in the
lateral hypothalamus, and—as we saw in Chapter 12—stimulates hunger and reduces
metabolic rate.
• MCH receptors are found in several places in the brain, including the NAC, where it is
found on neurons that also contain DA receptors.
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Common Features of Addiction
Neural Mechanisms
• Chung et al. (2009) found that stimulating both DA receptors and MCH receptors
increased firing of NAC neurons, and that administering a drug that blocks MCH receptors
decreased the effectiveness of cocaine or cocaine-related cues on the animals’ behavior.
• A targeted mutation against the MCH receptor gene had the same effect. Cippitelli et al.
(2010) found that MCH played a similar role in alcohol intake.
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Common Features of Addiction
Negative Reinforcement
• A behavior that turns off (or reduces) an aversive stimulus will be reinforced.
• This phenomenon is known as negative reinforcement, and its usefulness is obvious.
• Negative Reinforcement
• the removal or reduction of an aversive stimulus that is contingent on a particular
response, with an attendant increase in the frequency of that response
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Common Features of Addiction
Negative Reinforcement
• It is worth pointing out that negative reinforcement should not be confused with
punishment.
•
Both phenomena involve aversive stimuli, but one makes a response more likely, while
the other makes it less likely.
• For negative reinforcement to occur, the response must make the unpleasant stimulus
end (or at least decrease).
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Common Features of Addiction
Negative Reinforcement
• For punishment to occur, the response must make the unpleasant stimulus occur.
• For example, if a little boy touches a mousetrap and hurts his finger, he is unlikely to
touch a mousetrap again.
• The painful stimulus punishes the behavior of touching the mousetrap.
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Common Features of Addiction
Negative Reinforcement
• People who abuse some drugs become physically dependent on the drug; that is, they
show tolerance and withdrawal symptoms.
• As we saw in Chapter 4, tolerance is the decreased sensitivity to a drug that comes from
its continued use; the user must take larger and larger amounts of the drug for it to be
effective.
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Common Features of Addiction
Negative Reinforcement
• Once a person has taken an opiate regularly enough to develop tolerance, that person
will exhibit withdrawal symptoms if he or she stops taking the drug.
• Withdrawal symptoms are primarily the opposite of the effects of the drug itself.
• The effects of heroin—euphoria, constipation, and relaxation—lead to the withdrawal
effects of dysphoria, cramping and diarrhea, and agitation.
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Common Features of Addiction
Negative Reinforcement
• Most investigators believe that tolerance is produced by the body’s attempt to
compensate for the unusual condition of heroin intoxication.
• The drug disturbs normal homeostatic mechanisms in the brain, and in reaction, these
mechanisms begin to produce effects opposite to those of the drug, partially
compensating for the disturbance.
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Common Features of Addiction
Negative Reinforcement
• Because of these compensatory mechanisms, the user must take increasing amounts of
heroin to achieve the effects that were produced when he or she first started taking the
drug.
• These mechanisms also account for the symptoms of withdrawal: When the person stops
taking the drug, the compensatory mechanisms make themselves felt, unopposed by the
action of the drug.
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Common Features of Addiction
Negative Reinforcement
• Although positive reinforcement seems to be what provokes drug taking in the first place,
reduction of withdrawal effects could certainly play a role in maintaining someone’s drug
addiction.
• The withdrawal effects are unpleasant, but as soon as the person takes some of the drug,
these effects go away, producing negative reinforcement.
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Common Features of Addiction
Negative Reinforcement
• Negative reinforcement could also explain the acquisition of drug addictions under some
conditions.
• If a stressed person is suffering from some unpleasant feelings and then takes a drug that
eliminates these feelings, the person’s drug-taking behavior is likely to be reinforced.
• For example, alcohol can relieve feelings of anxiety.
• If a person finds himself in a situation that arouses anxiety, he might find that having a
drink or two makes him feel much better.
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Common Features of Addiction
Craving and Relapse
• Why do drug addicts crave drugs?
• Why does this craving occur even after a long period of abstinence?
• Even after going for months or years without taking an addictive drug, a former drug
addict might sometimes experience intense craving that leads to relapse.
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Common Features of Addiction
Craving and Relapse
• Clearly, taking a drug over an extended period of time must produce some long-lasting
changes in the brain that increase a person’s likelihood of relapsing.
• Understanding this process might help clinicians to devise therapies that will assist
people in breaking their drug dependence once and for all.
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Common Features of Addiction
Craving and Relapse
• One of the ways in which craving has been investigated in laboratory animals is through
the reinstatement model of drug seeking.
• Animals are first trained to make a response (for example, pressing a lever) that is
reinforced by intravenous injections of a drug such as cocaine.
• Next, the response is extinguished by providing injections of a saline solution rather than
the drug.
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Common Features of Addiction
Craving and Relapse
• Once the animal has stopped responding, the experimenter administers a “free” injection
of the drug (drug reinstatement procedure) or presents a stimulus that has been
associated with the drug (cue reinstatement procedure).
• In response to these stimuli, the animals begin responding at the lever once more
(Kalivas, Peters, and Knackstedt, 2006).
• Presumably, this kind of relapse (reinstatement of a previously extinguished response) is
a good model for the craving that motivates drug-seeking behavior in a former addict.
(See Figure 18.3.)
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Figure 18.3, page 621
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Common Features of Addiction
Craving and Relapse
• Volkow et al. (1992) found that the activity of the medial prefrontal cortex of cocaine
abusers was lower than that of normal subjects during abstinence.
• In addition, when addicts are performing tasks that normally activate the prefrontal cortex,
their medial prefrontal cortex is less activated than that of healthy control subjects, and
they perform more poorly on the tasks (Bolla et al., 2004; Garavan and Stout, 2005).
• In fact, Bolla and her colleagues found that the amount of activation of the medial
prefrontal cortex was inversely related to the amount of cocaine that cocaine abusers
normally took each week: The lower the brain activity, the more cocaine the person took.
(See Figure 18.4.)
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Figure 18.4, page 622
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Common Features of Addiction
Craving and Relapse
• People with a long history of drug abuse not only show the same deficits on tasks that
involve the prefrontal cortex as do people with lesions of this region, they also show
structural abnormalities of this region.
• For example, Franklin et al. (2002) reported an average decreases of 5–11 percent in the
gray matter of various regions of the prefrontal cortex of chronic cocaine abusers.
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Common Features of Addiction
Craving and Relapse
• Thompson et al. (2004) found decreases in the gray matter volume of the cingulate cortex
and limbic cortex of methamphetamine users, and Ersche et al. (2011) found similar
decreases in the brains of cocaine users.
• De Ruiter et al. (2011) found evidence of loss of behavioral control caused by decreased
activation of the dorsomedial PFC in both heavy smokers and pathological gamblers,
which supports the assertion of some investigators that pathological gambling should be
regarded as a form of addiction (Thomas et al., 2011).
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Common Features of Addiction
Craving and Relapse
• Zhang et al. (2011) found decreased gray matter in the prefrontal cortex that was
proportional to the amount of people’s lifetime tobacco use.
• Of course, the results of these studies do not permit us to determine whether
abnormalities in the prefrontal cortex predispose people to become addicted or whether
drug taking causes these abnormalities (or both).
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Common Features of Addiction
Craving and Relapse
• As we saw in Chapter 16, the negative and cognitive symptoms of schizophrenia appear
to be a result of hypofrontality—decreased activity of the prefrontal cortex.
• These symptoms are very similar to those that accompany long-term drug abuse.
• In fact, studies have shown a high level of comorbidity of schizophrenia and substance
abuse. (Comorbidity refers to the simultaneous presence of two or more disorders in the
same person.)
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Common Features of Addiction
Craving and Relapse
• For example, up to half of all people with schizophrenia have a substance abuse disorder
(alcohol or illicit drugs), and 70 to 90 percent are nicotine dependent (Brady and Sinha,
2005).
• In fact, in the United States, smokers with psychiatric disorders—who constitute
approximately 7 percent of the population—consume 34 percent of all cigarettes. (Dani
and Harris, 2005).
• Mathalon et al. (2003) found that prefrontal gray matter volumes were 10.1 percent lower
in alcoholic patients, 9.0 percent lower in schizophrenic patients, and 15.6 percent lower
in patients with both disorders. (See Figure 18.5.)
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Figure 18.5, page 623
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Common Features of Addiction
Craving and Relapse
• Weiser et al. (2004) administered a smoking questionnaire to a random sample of
adolescent military recruits each year.
• Over a 4- to 16-year follow-up period, they found that compared with nonsmokers, the
prevalence of hospitalization for schizophrenia was 2.3 times higher in recruits who
smoked at least 10 cigarettes per day. (See Figure 18.6.)
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Figure 18.6, page 623
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Common Features of Addiction
Craving and Relapse
• These results suggest that abnormalities in the prefrontal cortex may be a common factor
in schizophrenia and substance abuse disorders.
• Again, I must note that research has not yet determined whether preexisting
abnormalities increase the risk of these disorders or whether the disorders cause the
abnormalities.
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Common Features of Addiction
Craving and Relapse
• As we have just seen, the presence of drug-related stimuli can trigger craving and drugseeking behavior.
• In addition, clinicians have long observed that stressful situations can cause former drug
addicts to relapse.
• These effects have been observed in rats that had previously learned to self-administer
cocaine or heroin.
• For example, Covington and Miczek (2001) paired naïve rats with rats that had been
trained to become dominant.
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Common Features of Addiction
Craving and Relapse
• After being defeated by the dominant rats, the socially stressed rats became more
sensitive to the effects of cocaine and showed bingeing—self-administration of larger
amounts of the drug.
• Kosten, Miserendino, and Kehoe (2000) showed that stress that occurs early in life can
have long-lasting effects.
• They stressed infant rats by isolating them from their mothers and littermates for one hour
per day for eight days.
• When these rats were given the opportunity in adulthood to inject themselves with
cocaine, they readily acquired the habit and took more of the drugs than did control rats
that had not been stressed. (See Figure 18.7.)
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Figure 18.7, page 623
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Common Features of Addiction
Craving and Relapse
• An important link between stressful experiences and drug craving is provided by
corticotropin releasing hormone, or CRH. (This peptide is also referred to as corticotropin
releasing factor, or CRF.)
• As we saw in Chapter 17, CRH plays an important role in development of adverse effects
on health produced by stress and on the development of anxiety disorders.
• Just as administration of a drug or of stimuli previously associated with drug-taking
behavior can cause relapse, so can stressful experiences (Shalev, Erb, and Shaham,
2010).
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Common Features of Addiction
Craving and Relapse
• For example, administration of CRH can reinstate drug-taking behavior, and
administration of a drug that blocks CRH receptors can reduce the likelihood of relapse
from drugs or drug cues.
• CRH receptors in the VTA appear to be particularly important.
• Infusion of CRH into the VTA causes relapse, and infusion of a CRH receptor antagonist
prevents reinstatement of drug-taking by a stressful stimulus (Wang et al., 2007).
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Common Features of Addiction
Section Summary
• Addictive drugs are those whose reinforcing effects are so potent that some people who
are exposed to them are unable to go for very long without taking the drugs and whose
lives become organized around taking them.
• Fortunately, most people who are exposed to drugs do not become addicted to them.
• Originally, most addictive drugs came from plants, which used them as a defense against
insects or other animals that otherwise would eat them, but chemists have synthesized
many other drugs that have even more potent effects.
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Common Features of Addiction
Section Summary
• If a person regularly takes some addictive drugs (most notably, the opiates), the effects of
the drug show tolerance, and the person must take increasing doses to achieve the same
effect.
• If the person then stops taking the drug, withdrawal effects, opposite to the primary
effects of the drug, will occur.
• However, withdrawal effects are not the cause of addiction; the abuse potential of a drug
is related to its ability to reinforce drug-taking behavior.
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Common Features of Addiction
Section Summary
• Positive reinforcement occurs when a behavior is regularly followed by an appetitive
stimulus—one that an organism will approach.
• Addictive drugs produce positive reinforcement; they reinforce drug-taking behavior.
• Laboratory animals will learn to make responses that result in the delivery of these drugs.
• The faster a drug produces its effects, the more quickly dependence will be established.
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Common Features of Addiction
Section Summary
• All addictive drugs that produce positive reinforcement stimulate the release of dopamine
in the NAC, a structure that plays an important role in reinforcement.
• Neural changes that begin in the VTA and NAC eventually involve the dorsal striatum,
which plays a critical role in instrumental conditioning.
• The activity of inhibitory circuits in the prefrontal cortex promote resistance to addiction.
• The susceptibility of adolescents to the addictive potential of drugs may be associated
with the relative immaturity of the prefrontal cortex.
• Orexin and MCH play a role in the establishment of addiction.
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Section Summary
• Negative reinforcement occurs when a behavior is followed by the reduction or
termination of an aversive stimulus.
• If, because of a person’s social situation or personality characteristics, he or she feels
unhappy or anxious, a drug that reduces these feelings can reinforce drug -taking
behavior by means of negative reinforcement.
• Also, the reduction of unpleasant withdrawal symptoms by a dose of the drug undoubtedly
plays a role in maintaining drug addictions, but it is not the sole cause of craving.
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Commonly Abused Drugs
• People have been known to abuse an enormous variety of drugs, including alcohol,
barbiturates, opiates, tobacco, amphetamine, cocaine, cannabis, hallucinogens such as
LSD, PCP, volatile solvents such as glues or even gasoline, ether, and nitrous oxide.
• Obviously, I cannot hope to discuss all these drugs in any depth and keep the chapter to
a reasonable length, so I will restrict my discussion to the most important of them in terms
of popularity and potential for addiction.
• Some drugs, such as caffeine, are both popular and addictive, but because they do not
normally cause intoxication, impair health, or interfere with productivity, I will not discuss
them here.
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Opiates
• Opium, derived from a sticky resin produced by the opium poppy, has been eaten and
smoked for centuries.
• Opiate addiction has several high personal and social costs.
• First, because heroin—the most commonly abused opiate—is an illegal drug in most
countries, an addict becomes, by definition, a criminal.
• Second, because of tolerance, a person must take increasing amounts of the drug to
achieve a “high.”
• The habit thus becomes more and more expensive.
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Opiates
• Third, an opiate addict often uses unsanitary needles; at present, a substantial
percentage of people who inject illicit drugs have been exposed in this way to hepatitis or
the AIDS virus.
• Fourth, if the addict is a pregnant woman, her infant will also become dependent on the
drug, which easily crosses the placental barrier.
• The infant must be given opiates right after being born and then weaned off the drug with
gradually decreasing doses.
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Opiates
• Fifth, the uncertainty about the strength of a given batch of heroin makes it possible for a
user to receive an unusually large dose of the drug, with possibly fatal consequences.
• And some of the substances used to dilute heroin are themselves toxic.
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Neural Basis of Reinforcing Effects
• As we saw earlier, laboratory animals will self-administer opiates. When an opiate is
administered systemically, it stimulates opiate receptors located on neurons in various
parts of the brain and produces a variety of effects, including analgesia, hypothermia
(lowering of body temperature), sedation, and reinforcement.
• Opiate receptors in the periaqueductal gray matter are primarily responsible for the
analgesia, those in the preoptic area are responsible for the hypothermia, and those in
the mesencephalic reticular formation are responsible for the sedation.
• As we shall see, opiate receptors in the ventral tegmental area and the NAC appear to
play a role in the reinforcing effects of opiates.
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Neural Basis of Reinforcing Effects
• As we saw in Chapter 4, there are three major types of opiate receptors:  (mu), 
(delta), and  (kappa).
• Evidence suggests that m receptors and  receptors are responsible for reinforcement
and analgesia and that stimulation of k receptors produces aversive effects.
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Neural Basis of Reinforcing Effects
• Evidence for the role of m receptors comes from a study by Matthes et al. (1996), who
performed a targeted mutation against the gene responsible for production of the m opiate
receptor in mice.
• These animals, when they grew up, were completely insensitive to the reinforcing or
analgesic effects of morphine, and they showed no signs of withdrawal symptoms after
having been given increasing doses of morphine for six days. (See Figure 18.8.)
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Figure 18.8, page 626
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Neural Basis of Reinforcing Effects
• As we saw earlier, reinforcing stimuli cause the release of dopamine in the NAC.
Injections of opiates are no exception to this general rule; Wise et al. (1995) found that
the level of dopamine in the NAC increased by 150 to 300 percent while a rat was
pressing a lever that delivered intravenous injections of heroin.
• Rats will also press a lever that delivers injections of an opiate directly into the ventral
tegmental area (Devine and Wise, 1994) or the NAC (Goeders, Lane, and Smith, 1984).
• In other words, injections of opiates into both ends of the mesolimbic dopaminergic
system are reinforcing.
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Neural Basis of Reinforcing Effects
• The release of endogenous opioids may even play a role in the reinforcing effects of
some addictive drugs.
• Studies have shown that administration of naloxone (a drug that blocks opiate receptors)
reduces the reinforcing effects of alcohol in both humans and laboratory animals.
• Naloxone
• a drug that blocks  opiate receptors; antagonizes the reinforcing and sedative
effects of opiates
• Because the use of opiate blockers has recently been approved as a treatment for
alcoholism, I will discuss relevant research later in this chapter.
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Neural Basis of Tolerance and Withdrawal
• Several studies have investigated the neural systems that are responsible for the
development of tolerance and subsequent withdrawal effects of opiates.
• Maldonado et al. (1992) made rats physically dependent on morphine and then injected
naloxone into various regions of the brain to determine whether the sudden blocking of
opiate receptors would stimulate symptoms of withdrawal.
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Neural Basis of Tolerance and Withdrawal
• This technique—administering an addictive drug for a prolonged interval and then
blocking its effects with an antagonist—is referred to as antagonist-precipitated
withdrawal.
• Antagonist-Precipitated Withdrawal
• sudden withdrawal from long-term administration of a drug caused by cessation of the
drug and administration of an antagonistic drug
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Neural Basis of Tolerance and Withdrawal
• The investigators found that the most sensitive site was the locus coeruleus, followed by
the periaqueductal gray matter.
• Injection of naloxone into the amygdala produced a weak withdrawal syndrome.
• Using a similar technique (first infusing morphine into various regions of the brain and
then precipitating withdrawal by giving the animals an intraperitoneal injection of
naloxone), Bozarth (1994) confirmed the role of the locus coeruleus and the
periaqueductal gray matter in the production of withdrawal symptoms.
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Neural Basis of Tolerance and Withdrawal
• A single dose of an opiate decreases the firing rate of neurons in the locus coeruleus, but
if the drug is administered chronically, the firing rate will return to normal.
• Then, if an opiate antagonist is administered (to precipitate withdrawal symptoms), the
firing rate of these neurons increases dramatically, which increases the release of
norepinephrine in the regions that receive projections from this nucleus (Koob, 1996;
Nestler, 1996).
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Neural Basis of Tolerance and Withdrawal
• In addition, lesions of the locus coeruleus reduce the severity of antagonist-precipitated
withdrawal symptoms (Maldonado and Koob, 1993).
• A microdialysis study by Aghajanian, Kogan, and Moghaddam (1994) found that
antagonist-precipitated withdrawal caused an increase in the level of glutamate, the major
excitatory neurotransmitter, in the locus coeruleus.
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Stimulant Drugs: Cocaine and Amphetamine
• Cocaine and amphetamine have similar behavioral effects, because both act as potent
dopamine agonists. However, their sites of action are different.
• Cocaine binds with and deactivates the dopamine transporter proteins, thus blocking the
reuptake of dopamine after it is released by the terminal buttons.
• Amphetamine also inhibits the reuptake of dopamine, but its most important effect is to
directly stimulate the release of dopamine from terminal buttons.
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Stimulant Drugs: Cocaine and Amphetamine
• Methamphetamine is chemically related to amphetamine, but is considerably more potent.
• Freebase cocaine (“crack”), a particularly potent form of the drug, is smoked and thus
enters the blood supply of the lungs and reaches the brain very quickly.
• Because its effects are so potent and so rapid, it is probably the most effective reinforcer
of all available drugs.
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Stimulant Drugs: Cocaine and Amphetamine
• When people take cocaine, they become euphoric, active, and talkative.
• They say that they feel powerful and alert. Some of them become addicted to the drug,
and obtaining it becomes an obsession to which they devote more and more time and
money.
• Laboratory animals, which will quickly learn to self-administer cocaine intravenously, also
act excited and show intense exploratory activity.
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Stimulant Drugs: Cocaine and Amphetamine
• After receiving the drug for a day or two, rats start showing stereotyped movements, such
as grooming, head bobbing, and persistent locomotion (Geary, 1987).
• If rats or monkeys are given continuous access to a lever that permits them to selfadminister cocaine, they often self-inject so much cocaine that they die.
• In fact, Bozarth and Wise (1985) found that rats that self-administered cocaine were
almost three times more likely to die than were rats that self-administered heroin.
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Stimulant Drugs: Cocaine and Amphetamine
• As we have seen, the mesolimbic dopamine system plays an essential role in all forms of
reinforcement, except perhaps for the reinforcement that is mediated by stimulation of
opiate receptors.
• Many studies have shown that intravenous injections of cocaine and amphetamine
increase the concentration of dopamine in the NAC, as measured by microdialysis.
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Stimulant Drugs: Cocaine and Amphetamine
• For example, Figure 18.9 shows data collected by Di Ciano et al. (1995) in a study with
rats that learned to press a lever that delivered intravenous injections of cocaine or
amphetamine.
• The colored bars at the base of the graphs indicate the animals’ responses, and the line
graphs indicate the level of dopamine in the NAC. (See Figure 18.9.)
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Figure 18.9, page 627
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Stimulant Drugs: Cocaine and Amphetamine
• One of the alarming effects of cocaine and amphetamine seen in people who abuse these
drugs regularly is psychotic behavior: hallucinations, delusions of persecution, mood
disturbances, and repetitive behaviors.
• These symptoms so closely resemble those of paranoid schizophrenia that even a trained
mental health professional cannot distinguish them unless he or she knows about the
person’s history of drug abuse.
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Stimulant Drugs: Cocaine and Amphetamine
• However, these effects apparently disappear once people stop taking the drug.
• As we saw in Chapter 16, the fact that these symptoms are provoked by dopamine
agonists and reduced by drugs that block dopamine receptors suggests that overactivity
of dopaminergic synapses is responsible for the positive symptoms of schizophrenia.
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Stimulant Drugs: Cocaine and Amphetamine
• Some evidence suggests that the use of stimulant drugs may have adverse long-term
effects on the brain.
• For example, a PET study by McCann et al. (1998) discovered that prior abusers of
methamphetamine showed a decrease in the numbers of dopamine transporters in the
caudate nucleus and putamen, despite the fact that they had abstained from the drug for
approximately three years.
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Stimulant Drugs: Cocaine and Amphetamine
• The decreased number of dopamine transporters suggests that the number of
dopaminergic terminals in these regions is diminished.
• As the authors note, these people might have an increased risk of Parkinson’s disease
as they get older. (See Figure 18.10.)
• Studies with laboratory animals have also found that methamphetamine can damage
terminals of serotonergic axons and trigger death of neurons through apoptosis in the
cerebral cortex, striatum, and hippocampus (Cadet, Jayanthi, and Deng, 2003).
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Figure 18.10, page 628
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Nicotine
• Nicotine might seem rather tame in comparison to opiates, cocaine, and amphetamine.
• Nevertheless, nicotine is an addictive drug, and it accounts for more deaths than the socalled “hard” drugs.
• The combination of nicotine and other substances in tobacco smoke is carcinogenic and
leads to cancer of the lungs, mouth, throat, and esophagus.
• Approximately one-third of the adult population of the world smokes, and smoking is one
of the few causes of death that is rising in developing countries.
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Nicotine
• The World Health Organization estimates that 50 percent of the people who begin to
smoke as adolescents and continue smoking throughout their lives will die from smokingrelated diseases.
• Investigators estimate that in just a few years, tobacco will be the largest single health
problem worldwide, with over 6 million deaths per year (Mathers and Loncar, 2006).
• In fact, tobacco use is the leading cause of preventable death in developed countries
(Dani and Harris, 2005).
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Nicotine
• In the United States alone, tobacco addiction kills more than 430,000 people each year
(Chou and Narasimhan, 2005).
• Smoking by pregnant women also has negative effects on the health of their fetuses—
apparently worse than those of cocaine (Slotkin 1998).
• Unfortunately, approximately 25 percent of pregnant women in the United States expose
their fetuses to nicotine.
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Nicotine
• Ours is not the only species willing to self-administer nicotine; so will laboratory animals
(Donny et al., 1995).
• Nicotine stimulates nicotinic acetylcholine receptors, of course.
• It also increases the activity of dopaminergic neurons of the mesolimbic system (Mereu et
al., 1987) and causes dopamine to be released in the NAC (Damsma, Day, and Fibiger,
1989).
• Figure 18.11 shows the effects of two injections of nicotine or saline on the extracellular
dopamine level of the NAC, measured by microdialysis. (See Figure 18.11.)
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Figure 18.11, page 629
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Nicotine
• Injection of a nicotinic agonist directly into the ventral tegmental area will reinforce a
conditioned place preference (Museo and Wise, 1994).
• Conversely, injection of a nicotinic antagonist into the VTA will block the ability of nicotine
to cause the release of dopamine in the nucleus accumbens and reduce the reinforcing
effect of intravenous injections of nicotine (Corrigall, Coen, and Adamson, 1994; Gotti et
al., 2010).
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Nicotine
• But although nicotinic receptors are found in both the VTA and the NAC, Corrigall and his
colleagues found that injections of a nicotinic antagonist in the NAC has no effect on
reinforcement.
• Consistent with these findings, Nisell, Nomikos, and Svensson (1994) found that infusion
of a nicotinic antagonist into the VTA will prevent an intravenous injection of nicotine from
triggering the release of dopamine in the NAC.
• Infusion of the antagonist into the NAC will not have this effect.
• Thus, the reinforcing effect of nicotine appears to be caused by activation of nicotinic
receptors in the ventral tegmental area.
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Nicotine
• Studies have found that the endogenous cannabinoids play a role in the reinforcing
effects of nicotine.
• Rimonabant, a drug that blocks cannabinoid CB1 receptors, reduces nicotine selfadministration and nicotine-seeking behavior in rats (Cohen, Kodas, and Griebel, 2005),
apparently by reducing the release of dopamine in the NAC (De Vries and Schoffelmeer,
2005).
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Nicotine
• By blocking CB1 receptors, rimonabant decreases the reinforcing effects of nicotine.
• As we saw in Chapter 12, rimonabant was used for anti-obesity therapy for a short time,
but was withdrawn from the market because of dangerous side effects.
• Clinical trials have found that rimonabant appears to help prevent relapse in people who
are trying to quit smoking, but it is not approved for this purpose, either.
• However, the effects of the drug in humans and laboratory animals suggest that craving
for nicotine, like the craving for food, is enhanced by the release of endocannabinoids in
the brain.
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Nicotine
• The nicotinic ACh receptor exists in three states.
• When a burst of ACh is released by an acetylcholinergic terminal button, the receptors
open briefly, permitting the entry of calcium. (Most nicotinic receptors serve as
heteroreceptors on terminal buttons that release another neurotransmitter.
• The entry of calcium stimulates the release of that neurotransmitter.)
• Within a few milliseconds, the enzyme AChE has destroyed the acetylcholine, and the
receptors either close again or enter a desensitized state, during which they bind with, but
do not react to, ACh.
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Nicotine
• Normally, few nicotinic receptors enter the desensitized state.
• However, when a person smokes, the level of nicotine in the brain rises slowly and stays
steady for a prolonged period because nicotine, unlike ACh, is not destroyed by AChE.
• At first, nicotinic receptors are activated, but the sustained low levels of the drug convert
many nicotinic receptors to the desensitized state.
• Thus, nicotine has dual effects on nicotinic receptors: activation and then desensitization.
• In addition, probably in response to desensitization, the number of nicotinic receptors
increases (Dani and De Biasi, 2001).
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Nicotine
• As Naqvi et al. (2007) report, Mr. N. sustained a stroke that damaged his insula. In fact,
several other patients with insular damage had the same experience.
• Naqvi and his colleagues identified nineteen cigarette smokers with damage to the insula
and fifty smokers with brain damage that spared this region.
• Of the nineteen patients who had damage to the insula, twelve “quit smoking easily,
immediately, without relapse, and without persistence of the urge to smoke” (Naqvi et al.,
2007, p. 531).
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Nicotine
• One patient with insula damage quit smoking but still reported feeling an urge to smoke.
• Figure 18.12 shows computer-generated images of brain damage that showed a
statistically significant correlation with disruption of smoking.
• As you can see, the insula, which is colored red, showed the highest association with
cessation of smoking. (See Figure 18.12.)
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Figure 18.12, page 630
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Nicotine
• Other studies have corroborated the report by Naqvi and his colleagues (Hefzy, Silver,
and Silver, 2011).
• In addition, Forget et al. (2010) found that infusion of an inhibitory drug into the insula of
rats reduced the reinforcing effects of nicotine. (See Figure 18.13.)
• I mentioned earlier that Zhang et al. (2011) found decreased gray matter in the frontal
cortex of smokers, which may be at least partly responsible for the difficulty that smokers
have in breaking their habit.
• These investigators also found that the insula was larger in smokers, which is consistent
with the apparent role of the insula in nicotine addiction.
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Figure 18.13, page 630
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Nicotine
• Researches have discovered a pathway in the brain that inhibits the reinforcing effects of
nicotine.
• Neurons in the medial habenula, a region of the midbrain, contain a special type of
nicotinic ACh receptor that includes an 5 subunit.
• The neurons that contain these receptors send their axons to the interpeduncular
nucleus, located in the midline of the midbrain, caudal to the medial habenula.
• This pathway appears to be part of an system that inhibits the reinforcing effects of
nicotine.
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Nicotine
• The medial habenula-interpeduncular nucleus circuit appears to protect the animals (and
presumably, our own species) against intake of large quantities of nicotine.
• A normal mouse will increase its response rate when the amount of nicotine contained in
each injection increases—up to a point, that is.
• Eventually, larger injections will suppress the animal’s response rate so that it will not
receive too much nicotine.
• But if 5 ACh receptors in the habenula are deactivated, this inhibitory effect does not
occur. (See Figure 18.14.)
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Figure 18.14, page 631
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Alcohol
• Alcohol has enormous costs to society.
• A large percentage of deaths and injuries caused by motor vehicle accidents are related
to alcohol use, and alcohol contributes to violence and aggression.
• Chronic alcoholics often lose their jobs, their homes, and their families; many die of
cirrhosis of the liver, exposure, or diseases caused by poor living conditions and abuse of
their bodies.
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Alcohol
• As we saw in Chapter 15, women who drink during pregnancy run the risk of giving birth
to babies with fetal alcohol syndrome, which includes malformation of the head and the
brain and accompanying mental retardation.
• In fact, alcohol consumption by pregnant women is one of the leading causes of mental
retardation in the Western world today.
• Therefore, understanding the physiological and behavioral effects of this drug is an
important issue.
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Alcohol
• Alcohol has the most serious effects on fetal development during the brain growth spurt
period, which occurs during the last trimester of pregnancy and for several years after
birth.
• Ikonomidou et al. (2000) found that exposure of the immature rat brain triggered
widespread cell death through apoptosis.
• The investigators exposed immature rats to alcohol at different times during the period of
brain growth and found that different regions were vulnerable to the effects of the alcohol
at different times.
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Alcohol
• Alcohol has two primary sites of action: It serves as an indirect agonist at GABA A
receptors and as an indirect antagonist at NMDA receptors.
• Apparently, both of these actions trigger apoptosis. Ikonomidou and her colleagues found
that administration of a GABA A agonist (phenobarbital, a barbiturate) or an NMDA
antagonist (MK-801) to seven-day-old rats caused brain damage by means of apoptosis.
(See Figure 18.15.)
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Figure 18.15, page 632
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Alcohol
• At low doses, alcohol produces mild euphoria and has an anxiolytic effect—that is, it
reduces the discomfort of anxiety.
• At higher doses, it produces incoordination and sedation.
• Alcohol produces both positive and negative reinforcement.
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Alcohol
• The positive reinforcement manifests itself as mild euphoria.
• As we saw earlier, negative reinforcement is caused by the termination of an aversive
stimulus.
•
If a person feels anxious and uncomfortable, then an anxiolytic drug that relieves this
discomfort provides at least a temporary escape from an unpleasant situation.
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Alcohol
• The negative reinforcement provided by the anxiolytic effect of alcohol is probably not
enough to explain the drug’s addictive potential.
• Other drugs, such as the benzodiazepines (tranquilizers such as Valium), are even more
potent anxiolytics than alcohol, yet such drugs are abused less often.
• It is probably the unique combination of stimulating and anxiolytic effects—of positive and
negative reinforcement—that makes alcohol so difficult for some people to resist.
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Alcohol
• Alcohol, like other addictive drugs, increases the activity of the dopaminergic neurons of
the mesolimbic system and increases the release of dopamine in the NAC as measured
by microdialysis (Gessa et al., 1985; Imperato and Di Chiara, 1986).
• The release of dopamine appears to be related to the positive reinforcement that alcohol
can produce.
• An injection of a dopamine antagonist directly into the NAC decreases alcohol intake in
rats (Samson et al., 1993), as does the injection of a drug into the ventral tegmental area
that decreases the activity of the dopaminergic neurons there (Hodge et al., 1993).
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Alcohol
• As I just mentioned, alcohol has two major sites of action in the nervous system, acting as
an indirect antagonist at NMDA receptors and an indirect agonist at GABA A receptors
(Chandler, Harris, and Crews, 1998).
• That is, alcohol enhances the action of GABA at GABA A receptors and interferes with the
transmission of glutamate at NMDA receptors.
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Alcohol
• As we saw in Chapter 13, NMDA receptors are involved in long-term potentiation, a
phenomenon that plays an important role in learning.
• Therefore, it will not surprise you to learn that alcohol, which antagonizes the action of
glutamate at NMDA receptors, disrupts long-term potentiation and interferes with the
spatial receptive fields of place cells in the hippocampus (Givens and McMahon, 1995;
Matthews, Simson, and Best, 1996).
• Presumably, this effect at least partly accounts for the deleterious effects of alcohol on
memory and other cognitive functions.
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Alcohol
• Withdrawal from long-term alcohol intake (like that of heroin, cocaine, amphetamine, and
nicotine) decreases the activity of mesolimbic neurons and their release of dopamine in
the NAC (Diana et al., 1993).
• If an indirect antagonist for NMDA receptors is then administered, dopamine secretion in
the NAC recovers.
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Alcohol
• The evidence suggests the following sequence of events: Some of the acute effects of a
single dose of alcohol are caused by the antagonistic effect of the drug on NMDA
receptors.
• Long-term suppression of NMDA receptors causes upregulation—a compensatory
increase in the sensitivity of the receptors.
• Then, when alcohol intake suddenly ceases, the increased activity of NMDA receptors
inhibits the activity of ventral tegmental neurons and the release of dopamine in the NAC.
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Alcohol
• Although the effects of heroin withdrawal have been exaggerated, those produced by
barbiturate or alcohol withdrawal are serious and can even be fatal.
• The increased sensitivity of NMDA receptors as they rebound from the suppressive effect
of alcohol can trigger seizures and convulsions.
• Convulsions caused by alcohol withdrawal are considered to be a medical emergency,
and are usually treated with benzodiazepines.
• Confirming the cause of these reactions, Liljequist (1991) found that seizures caused by
alcohol withdrawal could be prevented by giving mice a drug that blocks NMDA receptors.
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Alcohol
• The second site of action of alcohol is the GABA A receptor.
• Alcohol binds with one of the many binding sites on this receptor and increases the
effectiveness of GABA in opening the chloride channel and producing inhibitory
postsynaptic potentials.
• Proctor et al. (1992) recorded the activity of single neurons in the cerebral cortex of slices
of rat brains.
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Alcohol
• They found that the presence of alcohol significantly increased the postsynaptic response
produced by the action of GABA at the GABA A receptor.
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Alcohol
• The sedative effect of alcohol also appears to be exerted at the GABA A receptor.
• Suzdak et al. (1986) discovered a drug (Ro15-4513) that reverses alcohol intoxication by
blocking the alcohol binding site on this receptor.
• Figure 18.16 shows two rats that received injections of enough alcohol to make them
pass out.
• The one facing us also received an injection of the alcohol antagonist and appears
completely sober. (See Figure 18.16.)
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Figure 18.16, page 633
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Alcohol
• This wonder drug has not been put on the market, nor is it likely to be.
• Although the behavioral effects of alcohol are mediated by their action on GABA A
receptors and NMDA receptors, high doses of alcohol have other, potentially fatal effects
on all cells of the body, including destabilization of cell membranes.
• Thus, people taking some of the alcohol antagonist could then go on to drink themselves
to death without becoming drunk in the process.
• Drug companies naturally fear possible liability suits stemming from such occurrences.
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Alcohol
• I mentioned earlier that opiate receptors appear to be involved in a reinforcement
mechanism that does not directly involve dopaminergic neurons.
• The reinforcing effect of alcohol is at least partly caused by its ability to trigger the release
of the endogenous opioids.
• Several studies have shown that the opiate receptor blockers such as naloxone or
naltrexone block the reinforcing effects of alcohol in a variety of species, including rats,
monkeys, and humans (Altschuler, Phillips, and Feinhandler, 1980; Davidson, Swift, and
Fitz, 1996; Reid, 1996).
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Alcohol
• In addition, endogenous opioids may play a role in craving in abstinent alcoholics.
• Heinz et al. (2005) found that one to three weeks of abstinence increased the number of
 opiate receptors in the NAC.
• The greater the number of receptors, the more intense the craving was.
• Presumably, the increased number of  receptors increased the effects of endogenous
opiates on the brain and served as a contributing factor to the craving for alcohol. (See
Figure 18.17.)
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Figure 18.17, page 634
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Cannabis
• Another drug that people regularly self-administer—almost exclusively by smoking—is
THC, the active ingredient in marijuana.
• As you learned in Chapter 4, the site of action of the endogenous cannabinoids in the
brain is the CB1 receptor.
• The endogenous ligands for the CB1 receptor, anandamide and 2-AG, are lipids.
• Administration of a drug that blocks CB1 receptors abolishes the “high” produced by
smoking marijuana (Huestis et al., 2001).
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Cannabis
• THC, like other drugs with abuse potential, has a stimulating effect on dopaminergic
neurons.
• Chen et al. (1990) injected rats with low doses of THC and measured the release of
dopamine in the NAC by means of microdialysis.
• Sure enough, they found that the injections caused the release of dopamine. (See Figure
18.18.)
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Figure 18.18, page 634
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Cannabis
• Chen et al. (1993) found that local injections of small amounts of THC into the ventral
tegmental area had no effect on the release of dopamine in the NAC.
• However, injection of THC into the NAC did cause dopamine release there.
• Thus, the drug appears to act directly on dopaminergic terminal buttons—presumably on
presynaptic heteroreceptors, where it increases the release of dopamine.
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Cannabis
• A variety of laboratory animals, including mice, rats, and monkeys, will self-administer
drugs that stimulate CB1 receptors, including THC (Maldonado and Rodriguez de
Fonseca, 2002).
• A targeted mutation that blocks the production of CB1 receptors abolishes the reinforcing
effect not only of cannabinoids, but also of morphine and heroin (Cossu et al., 2001).
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• This mutation also decreases the reinforcing effects of alcohol and the acquisition of selfadministration of cocaine (Houchi et al., 2005; Soria et al., 2005).
• In addition, as we saw in the previous section, rimonabant—a drug that blocks CB 1
receptors—decreases the reinforcing effects of nicotine.
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Cannabis
• The primary reinforcing component of marijuana, THC, is one of approximately seventy
different chemicals produced only by the cannabis plant.
• Another chemical, cannabidiol (CBD), plays an entirely different role.
• Unlike THC, which produces anxiety and psychotic-like behavior in large doses, CBD had
antianxiety and antipsychotic effects.
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Cannabis
• THC is a partial agonist of cannabinoid receptors, whereas CBD is an antagonist.
• Also unlike THC, CBD does not produce psychotropic effects: It is not reinforcing, and it
does not produce a “high.”
• In recent years, levels of THC in marijuana have increased greatly, while levels of CBD
have decreased.
• During the past decade, the numbers of people who seek treatment for dependence on
cannabis has also increased (Morgan et al., 2010).
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Cannabis
• Morgan and her colleagues recruited ninety-four people who used marijuana regularly for
a study on the effects of THC and CBD.
• The investigators measured the concentration of THC and CBD in a sample of their
marijuana and in a sample of their urine.
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Cannabis
• They found that people smoking their customary marijuana with low levels of CBD and
high levels of THC paid more attention to photographs of cannabis-related stimuli and
said that they liked them better than those smoking their customary marijuana with higher
levels of CBD.
• Both groups gave high ratings to food-related photographs, so CBD had no effect on their
interest in food. (See Figure 18.19.)
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Figure 18.19, page 635
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• As we saw in Chapter 4, the hippocampus contains a large concentration of THC
receptors. Marijuana is known to affect people’s memory.
• Specifically, it impairs their ability to keep track of a particular topic; they frequently lose
the thread of a conversation if they are momentarily distracted.
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• Evidence indicates that the drug does so by disrupting the normal functions of the
hippocampus, which plays such an important role in memory.
• Pyramidal cells in the CA1 region of the hippocampus release endogenous cannabinoids,
which provide a retrograde signal that inhibits GABAergic neurons that normally inhibit
them.
• In this way, the release of endogenous cannabinoids facilitates the activity of CA1
pyramidal cells and facilitates long-term potentiation (Kunos and Batkai, 2001).
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Cannabis
• We might expect that facilitating long-term potentiation in the hippocampus would
enhance its memory functions.
• However, the reverse is true; Hampson and Deadwyler (2000) found that the effects of
cannabinoids on a spatial memory task were similar to those produced by hippocampal
lesions.
• Thus, excessive activation of CB1 receptors in field CA1 appears to interfere with normal
functioning of the hippocampal formation.
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Cannabis
• Two articles (Moore et al., 2007; Le Bec et al., 2009; Minozzi et al., 2010) report a
disturbing finding: The incidence of psychotic disorders such as schizophrenia is
increased in cannabis users—especially those who have used cannabis frequently.
• Of course, a correlational study cannot prove the existence of a cause-and-effect
relationship.
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Cannabis
• It is possible that people who are more likely to develop psychotic symptoms are also
more likely to use cannabis.
• However, statistical adjustments suggest that a cause-and-effect relationship between
cannabis use and psychosis cannot be ruled out.
• Moore et al. (2007) conclude “that there is now sufficient evidence to warn young people
that using cannabis could increase their risk of developing a psychotic illness later in life”
(p. 319).
• This issue certainly deserves further study.
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Section Summary
• Opiates produce analgesia, hypothermia, sedation, and reinforcement.
• Opiate receptors in the periaqueductal gray matter are responsible for the analgesia,
those in the preoptic area for the hypothermia, those in the mesencephalic reticular
formation for the sedation, and those in the ventral tegmental area and NAC at least
partly for the reinforcement.
• A targeted mutation in mice indicates that  opiate receptors are responsible for
analgesia, reinforcement, and withdrawal symptoms.
• The release of the endogenous opioids may play a role in the reinforcing effects of natural
stimuli or even other addictive drugs such as alcohol.
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Section Summary
• The symptoms that are produced by antagonist-precipitated withdrawal from opiates can
be elicited by injecting naloxone into the periaqueductal gray matter and the locus
coeruleus, which implicates these structures in these symptoms.
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Section Summary
• Cocaine inhibits the reuptake of dopamine by terminal buttons, and amphetamine causes
the dopamine transporters in terminal buttons to run in reverse, releasing dopamine from
terminal buttons.
• Besides producing alertness, activation, and positive reinforcement, cocaine and
amphetamine can produce psychotic symptoms that resemble those of paranoid
schizophrenia.
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Section Summary
• The reinforcing effects of cocaine and amphetamine are mediated by an increase in
dopamine in the NAC.
• Chronic methamphetamine abuse is associated with reduced numbers of dopaminergic
axons and terminals in the striatum (revealed as a decrease in the numbers of dopamine
transporters located there).
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Section Summary
• The status of nicotine as a strongly addictive drug (for both humans and laboratory
animals) was long ignored, primarily because it does not cause intoxication and because
the ready availability of cigarettes and other tobacco products does not make it necessary
for addicts to engage in illegal activities.
• However, the craving for nicotine is extremely motivating.
• Nicotine stimulates the release of mesolimbic dopaminergic neurons, and injection of
nicotine into the ventral tegmental area is reinforcing.
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Section Summary
• Cannabinoid CB1 receptors are involved in the reinforcing effect of nicotine as well.
• Nicotine from smoking excites nicotinic acetylcholine receptors but also desensitizes
them, which leads to unpleasant withdrawal effects.
• The activation of nicotinic receptors on presynaptic terminal buttons in the ventral
tegmental area also produced long-term potentiation.
• Damage to the insula is associated with cessation of smoking, which suggests that this
region plays a role in the maintenance of cigarette addiction.
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Section Summary
• Suppression of its activity with inhibitory drugs reduces nicotine intake in laboratory
animals.
• Nicotine stimulation of the release of GABA in the lateral hypothalamus decreases the
activity of MCH neurons and reduces food intake, which explains why cessation of
smoking often leads to weight gain.
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Section Summary
• Infusion of an orexin antagonist in the insula suppresses nicotine intake.
• Activity of a circuit from the medial habenula to the interpeduncular nucleus does the
same.
• This effect depends on the presence of neurons with 5 ACh receptors in the habenula.
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Section Summary
• Exposure to alcohol during the period of rapid brain development has devastating effects
and is the leading cause of mental retardation.
• This exposure causes neural destruction through apoptosis.
• Alcohol and barbiturates have similar effects. Alcohol has positively reinforcing effects
and, through its anxiolytic action, has negatively reinforcing effects as well.
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Section Summary
• It serves as an indirect antagonist at NMDA receptors and an indirect agonist at GABA A
receptors. It stimulates the release of dopamine in the NAC.
• Withdrawal from long-term alcohol abuse can lead to seizures, an effect that seems to be
caused by compensatory upregulation of NMDA receptors.
• Release of the endogenous opioids also plays a role in the reinforcing effects of alcohol.
• Increases in the numbers of  opiate receptors during abstinence from alcohol may
intensify craving.
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Section Summary
• The active ingredient in cannabis, THC, stimulates receptors whose natural ligand is
anandamide. THC, like other addictive drugs, stimulates the release of dopamine in the
NAC.
• The presence of cannabidiol (CBD) in marijuana has a protective effect against
dependence on cannabis.
• The CB1 receptor is responsible for the physiological and behavioral effects of THC and
the endogenous cannabinoids.
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Section Summary
• A targeted mutation against the CB 1 receptor reduces the reinforcing effect of alcohol,
cocaine, and the opiates as well as that of the cannabinoids.
• Blocking CB1 receptors also decreases the reinforcing effects of nicotine.
• Cannabinoids produce memory deficits by acting on inhibitory GABAergic neurons in the
CA1 field of the hippocampus.
• Two disturbing reports indicate that cannabis use is associated with the incidence of
schizophrenia.
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• Not everyone is equally likely to become addicted to a drug.
• Many people manage to drink alcohol moderately, and most users of potent drugs such
as cocaine and heroin use them “recreationally” without becoming dependent on them.
• Evidence indicates that both genetic and environmental factors play a role in determining
a person’s likelihood of consuming drugs and of becoming dependent on them.
• In addition, there are both general factors (likelihood of taking and becoming addicted to
any of a number of drugs) and specific factors (likelihood of taking and becoming addicted
to a particular drug).
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• Tsuang et al. (1998) studied 3372 male twin pairs to estimate the genetic contributions to
drug abuse.
• They found strong general genetic and environmental factors: Abusing any category of
drug was associated with abusing drugs in all other categories: sedatives, stimulants,
opiates, marijuana, and psychedelics.
• Abuse of marijuana was especially influenced by family environmental factors.
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• Abuse of every category except psychedelics was influenced by genetic factors peculiar
to that category. Abuse of heroin had a particularly strong unique genetic factor.
• Another study of male twin pairs (Kendler et al., 2003) found a strong common genetic
factor for the use of all categories of drugs and found in addition that shared
environmental factors had a stronger effect on use than on abuse.
• In other words, environment plays a strong role in influencing a person to try a drug and
perhaps continue to use it recreationally, but genetics plays a stronger role in determining
whether the person become addicted.
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• Goldman, Oroszi, and Ducci (2005) reviewed twin studies that attempted to measure the
heritability of various classes of addictive disorders.
• Heritability (h2) is the percentage of variability in a particular population that can be
attributed to genetic variability.
• The average value of h 2 ranged from approximately 0.4 for hallucinogenic drugs to just
over 0.7 for cocaine. As you will see in Figure 18.20, the authors included addiction to
gambling. (See Figure 18.20.)
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Figure 18.20, page 637
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• The genetic basis of addiction to alcohol has received more attention than addiction to
other drugs.
• Alcohol consumption is not distributed equally across the population; in the United States;
10 percent of the people drink 50 percent of the alcohol (Heckler, 1983) .
• Many twin studies and adoption studies confirm that the primary reason for this disparity
is genetic.
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• A susceptibility to alcoholism could conceivably be caused by differences in the ability to
digest or metabolize alcohol or by differences in the structure or biochemistry of the brain.
• There is evidence that variability in the gene responsible for the production of alcohol
dehydrogenase, an enzyme involved in metabolism of alcohol, plays a role in
susceptibility to alcoholism.
• A particular variant of this gene, which is especially prevalent in eastern Asia, is
responsible for a reaction to alcohol intake that most people find aversive and that
discourages further drinking (Goldman, Oroszi, and Ducci, 2005).
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• However, most investigators believe that differences in brain physiology—for example,
those that control sensitivity to the reinforcing effects of drugs or sensitivity to various
environmental stressors—are more likely to play a role.
• For example, increased sensitivity to environmental stressors might encourage the use of
alcohol as a means to reduce the stress-related anxiety.
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• Investigators have also focused on the possibility that susceptibility to addiction may
involve differences in functions of specific neurotransmitter systems.
• As we saw earlier, nicotinic ACh receptors that contain the 5 subunit, found on neurons
in the medial habenula, play a role in inhibiting the reinforcing effects of nicotine.
• Genetic studies found that a particular allele of the gene responsible for the production of
this receptor is associated with increased susceptibility to nicotine addiction and
consequent development of lung cancer (Bierut, 2008).
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• A study by Kuryatov, Berrettini, and Lindstrom (2011) found that the presence of this allele
reduces the sensitivity of the 5 ACh receptors, and hence reduces the inhibitory effect of
large doses of nicotine.
• The result would be increased susceptibility to the addictive effects of nicotine.
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• Renthal et al. (2009) performed a genome-wide analysis of the effects of cocaine on
genetic material in the mouse DNA.
• They found that cocaine turned on hundreds of genes, many of which were already
known to be involved in the behavioral effects of the drug.
• One of their most interesting discoveries was that cocaine turns on the genes that
produce sirtuins, proteins that play important regulatory roles in cells.
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• They also found that a sirtuin agonist increased the reinforcing effects of cocaine and that
a sirtuin antagonist decreased it.
• As other investigators have noted, their approach holds promise for discovering the
molecular biology of addictive drugs and identifying potential treatments for people who
abuse them.
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Section Summary
• Most people who are exposed to addictive drugs—even drugs with a high abuse
potential—do not become addicts.
• Evidence suggests that the likelihood of addiction, especially to alcohol and nicotine, is
strongly affected by heredity.
• Drug taking and addiction are affected by general hereditary and environmental factors
that apply to all drugs and specific factors that apply to particular drugs.
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Section Summary
• A better understanding of the physiological basis of reinforcement and punishment will
help us to understand the effects of heredity on susceptibility to addiction.
• Some individual genes have been shown to affect abuse of particular drugs.
• For example, variations in the genes for alcohol dehydrogenase play a role in
susceptibility to alcoholism, variations in the gene for the 5 ACh receptor affect the
likelihood of nicotine addiction, and the genes that produce sirtuins modify
responsiveness to the addictive potential of cocaine.
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• There are many reasons for engaging in research on the physiology of drug abuse,
including an academic interest in the nature of reinforcement and the pharmacology of
psychoactive drugs.
• But most researchers entertain the hope that the results of their research will contribute to
the development of ways to treat and—better yet—prevent drug abuse in members of our
own species.
• As you well know, the incidence of drug abuse is far too high; obviously, research has not
yet solved the problem. However, real progress is being made.
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• The most common treatment for opiate addiction is methadone maintenance. Methadone
is a potent opiate, just like morphine or heroin.
• If it were available in a form suitable for injection, it would be abused. (In fact, methadone
clinics must control their stock of methadone carefully to prevent it from being stolen and
sold to opiate abusers.)
• Methadone maintenance programs administer the drug to their patients in the form of a
liquid, which they must drink in the presence of the personnel supervising this procedure.
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• Because the oral route of administration increases the opiate level in the brain slowly, the
drug does not produce a high, the way an injection of heroin will.
• In addition, because methadone is long-lasting, the patient’s opiate receptors remain
occupied for a long time, which means that an injection of heroin has little effect.
• Of course, a very large dose of heroin will still produce a “rush,” so the method is not
foolproof.
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• A newer drug, buprenorphine, shows promise of being an even better therapeutic agent
for opiate addiction than methadone (Vocci, Acri, and Elkashef, 2005).
• Buprenorphine is a partial agonist for the  opiate receptor. (You will recall from Chapter
16 that a partial agonist is a drug that has a high affinity for a particular receptor but
activates that receptor less than the normal ligand does.
• This action reduces the effects of a receptor ligand in regions of high concentration and
increases it in regions of low concentration, as shown in Figure 16.14.)
• Buprenorphine blocks the effects of opiates and itself produces only a weak opiate effect.
Unlike methadone, it has little value on the illicit drug market.
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• A randomized placebo-controlled trial compared the effectiveness of buprenorphine and
buprenorphine plus naloxone in recovering opiate addicts (Fudala et al., 2003).
• People in the two drug-treatment groups reported less craving than those in the control
group.
• The proportion of people who continued to be abstinent was 17.8 percent for people
treated with buprenorphine, 20.7 percent for people treated with the combination of the
two drugs, and only 5.8 percent for people receiving a placebo. (See Figure 18.21.)
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Figure 18.21, page 639
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• After one month, all subjects were given buprenorphine plus naloxone for eleven months.
• The percentage of people who abstained (indicated by the absence of opiates in urine
samples) ranged from 35.2 to 67.4 percent at various times during the 11-month period.
• A major advantage of buprenorphine, besides its efficacy, is the fact that it can be used in
office-based treatment.
• The addition of a small dose of naloxone ensures that the combination drug has no abuse
potential—and will, in fact, cause withdrawal symptoms if it is taken by an addict who is
currently taking an opiate.
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• As we saw, opiate receptor blockers such as naloxone and naltrexone interfere with the
action of opiates.
• Emergency rooms always have one of these drugs available to rescue patients who have
taken an overdose of heroin, and many lives have been saved by these means.
• But although an opiate antagonist will block the effects of heroin, the research reviewed
earlier in this chapter suggests that it should increase the craving for heroin.
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• As we saw earlier, the reinforcing effects of cocaine and amphetamine are primarily a
result of the sharply increased levels of dopamine that these drugs produce in the NAC.
• Drugs that block dopamine receptors certainly block the reinforcing effects of cocaine and
amphetamine, but they also produce dysphoria and anhedonia.
• People will not tolerate the unpleasant feelings these drugs produce, so they are not
useful treatments for cocaine and amphetamine abuse.
• Drugs that stimulate dopamine receptors can reduce a person’s dependence on cocaine
or amphetamine, but these drugs are just as addictive as the drugs they replace and have
the same deleterious effects on health.
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• An interesting approach to cocaine addiction was suggested by a study by Carrera et al.
(1995), who conjugated cocaine to a foreign protein and managed to stimulate rats’
immune systems to develop antibodies to cocaine.
• The antibodies bound with molecules of cocaine and prevented them from crossing the
blood–brain barrier.
• As a consequence, these “cocaine-immunized” rats were less sensitive to the activating
effects of cocaine, and brain levels of cocaine in these animals were lower after an
injection of cocaine.
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• Since this study was carried out, animal studies with vaccines against cocaine, heroin,
methamphetamine, and nicotine have been carried out, and several human clinical trials
with vaccines for cocaine and nicotine have taken place (Cerny and Cerny, 2009; Carroll
et al., 2011; Hicks et al., 2011; Stowe et al., 2011).
• The results of these animal studies and human trials are promising, and more extensive
human trials are in progress.
• Theoretically, at least, treatment of addictions with immunotherapy should interfere only
with the action of an abused drug and not with the normal operations of people ’s
reinforcement mechanisms.
• Thus, the treatment should not decrease their ability to experience normal pleasure.
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• Yet another approach to addiction is being investigated. As we saw in Chapters 13, 16,
and 17, deep brain stimulation (DBS) has been shown to have therapeutic effects on the
symptoms of Parkinson’s disease, depression, anxiety disorders, and obsessivecompulsive disorder.
• A review by Luigjes et al. (2011) reported that seven animal studies have investigated the
effectiveness of stimulation of the NAC, subthalamic nucleus (STN), dorsal striatum,
habenula, medial PFC, and hypothalamus.
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• Eleven studies with human subjects have targeted the NAC or the STN. So far, the
authors report, the NAC appears to be the most promising target.
• For example, Mantione et al. (2010) stimulated the NAC of a forty-seven-year-old male
smoker. The investigators reported that the man effortlessly stopped smoking and lost
weight (he was obese).
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• Deep brain stimulation is not a procedure to take lightly. It involves brain surgery, which
runs a risk of complications such as hemorrhage and infection.
• Of course, addictions include significant health risks, including death from infections or
lung cancer, so each case requires an analysis of the potential risks and benefits.
• In any event, the use of DBS is currently experimental, and we must consider the strong
possibility that such a dramatic procedure will produce placebo effects.
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• Yes, surgical procedures are susceptible to placebo effects.
• A less invasive procedure, transcranial magnetic stimulation, is also being investigated as
a treatment for addictions.
• For example, Amiaz et al. (2009) applied TMS over the left dorsolateral PFC of nicotine
addicts.
• The treatment reduced tobacco use (verified by urinalysis), but the therapeutic effects
eventually diminished over time.
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• A treatment similar to methadone maintenance has been used successfully as an adjunct
to treatment for nicotine addiction.
• For several years, chewing gum containing nicotine has been available by prescription,
and more recently, transdermal patches that release nicotine through the skin have been
marketed.
• Both methods maintain a sufficiently high level of nicotine in the brain to decrease a
person’s craving for nicotine.
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• Once the habit of smoking has subsided, the dose of nicotine can be decreased to wean
the person from the drug.
• Carefully controlled studies have shown that nicotine maintenance therapy, and not
administration of a placebo, is useful in treatment for nicotine dependence ( Raupach and
van Schayck, 2011).
• However, nicotine maintenance therapy is most effective if it is part of a counseling
program.
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• One of the limitations of treating a smoking addiction with nicotine maintenance is that
this procedure does not provide an important non-nicotine component of smoking: the
sensations produced by the action of cigarette smoke on the airways.
• As we saw earlier in this chapter, stimuli associated with the administration of addictive
drugs play an important role in sustaining an addictive habit.
• Smokers who rate the pleasurability of puffs of normal and denicotinized cigarettes within
seven seconds, which is less time than it takes for nicotine to leave the lungs, enter the
blood, and reach the brain, reported that puffing denicotinized cigarettes produced equally
strong feelings of euphoria and satisfaction and reductions in the urge to smoke.
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• Furthermore, blocking the sensations of cigarette smoke on the airways by first inhaling a
local anesthetic diminishes smoking satisfaction.
• Denicotinized cigarettes are not a completely adequate substitute for normal cigarettes,
because nicotine itself, not just the other components of smoke, makes an important
contribution to the sensations felt in the airways.
• In fact, trimethaphan, a drug that blocks nicotinic receptors but does not cross the bloodbrain barrier, decreases the sensory effects of smoking and reduces satisfaction.
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• Because trimethaphan does not interfere with the effects of nicotine on the brain, this
finding indicates that the central effects of nicotine are not sufficient by themselves to
maintain an addiction to nicotine.
• Instead, the combination of an immediate cue from the sensory effects of components of
cigarette smoke on the airways and a more delayed, and more continuous, effect of
nicotine on the brain serves to make smoking so addictive (Naqvi and Bechara, 2005;
Rose, 2006).
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• As we saw earlier in this chapter, studies with laboratory animals have found that the
endogenous cannabinoids are involved in the reinforcing effects of nicotine as well as
those of marijuana.
• A recent clinical trial reported that rimonabant, a drug that blocks CB 1 receptors, was
effective in helping smokers to quit their habit (Henningfield et al., 2005).
• One significant benefit of the drug was a decrease in the weight gain that typically
accompanies cessation of smoking and often discourages smokers who are trying to quit.
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• As we saw in Chapter 12, the endocannabinoids stimulate eating, apparently by
increasing the release of MCH and orexin.
• Blocking CB1 receptors abolishes this effect and helps to counteract the effects of
withdrawal from nicotine on these neurons.
• But the problem with rimonabant is that some clinical trials have found that the drug can
cause anxiety and depression, which provoked the withdrawal of its approval as an
antiobesity medication.
• At the present time, approval of rimonabant to treat nicotine addiction seems unlikely.
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• Another drug, varenicline, has been approved for therapeutic use to treat nicotine
addiction.
• Varenicline was developed especially as a treatment for nicotine addiction.
• The drug serves a partial agonist for the nicotinic receptor, just as buprenorphine serves
as a partial agonist for the  opiate receptor.
• As a partial nicotinic agonist, varenicline maintains a moderate level of activation of
nicotinic receptors but prevents high levels of nicotine from providing excessive levels of
stimulation.
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• Figure 18.22 shows the effects of treatment with varenicline and bupropion on rates of
continuous abstinence rates of smokers enrolled in a randomized, double-blind, placebo
control study (Nides et al., 2006).
• By the end of the 52-week treatment program, 14.4 percent of the smokers treated with
varenicline were still abstinent, compared with 6.3 percent and 4.9 percent of the smokers
who received bupropion and placebo, respectively. (See Figure 18.22.)
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Figure 18.22, page 640
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• As I mentioned earlier, several studies have shown that opiate antagonists decrease the
reinforcing value of alcohol in a variety of species, including our own.
• This finding suggests that the reinforcing effect of alcohol—at least in part—is produced
by the secretion of endogenous opioids and the activation of opiate receptors in the brain.
• A study by Davidson, Swift, and Fitz (1996) clearly illustrates this effect.
• The investigators arranged a double-blind, placebo-controlled study with sixteen collegeage men and women to investigate the effects of naltrexone on social drinkers.
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• None of the participants were alcohol abusers, and pregnancy tests ensured that the
women were not pregnant.
• They gathered around a table in a local restaurant/bar for three two-hour drinking
sessions, two weeks apart.
• For several days before the meeting, they swallowed capsules that contained either
naltrexone or an inert placebo.
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• The results showed that naltrexone increased the latency to take the first sip and to take
a second drink and that the blood alcohol levels of the naltrexone-treated participants
were lower at the end of the session.
• In general, the people who had taken naltrexone found that their drinks did not taste very
good—in fact, some of them asked for a different drink after taking the first sip.
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• These results are consistent with reports of the effectiveness of naltrexone as an adjunct
to programs designed to treat alcohol abuse.
• For example, O’Brien, Volpicelli, and Volpicelli (1996) reported the results of two longterm programs using naltrexone along with more traditional behavioral treatments.
• Both programs found that administration of naltrexone significantly increased the
likelihood of success.
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• As Figure 18.23 shows, naltrexone decreased the participants’ craving for alcohol and
increased the number of participants who managed to abstain from alcohol. (See Figure
18.23.)
• Currently, many treatment programs are using a sustained-release form of naltrexone to
help treat alcoholism, and results with the drug have been encouraging (Gastfriend,
2011).
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Figure 18.23, page 641
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• One more drug has shown promise for treatment of alcoholism.
• As we saw earlier in this chapter, alcohol serves as an indirect agonist at the GABA A
receptor and an indirect antagonist at the NMDA receptor.
• Acamprosate, an NMDA-receptor antagonist that has been used in Europe to treat
seizure disorders, was tested for its ability to stop seizure induced by withdrawal from
alcohol.
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• The researchers discovered that the drug had an unexpected benefit: Alcoholic patients
who received the drug were less likely to start drinking again (Wickelgren, 1998).
• Several double-blind studies have confirmed the therapeutic benefits of acamprosate, but
the these benefits appear to be modest (Rösner et al., 2010).
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Section Summary
• Although drug abuse is difficult to treat, researchers have developed several useful
therapies.
• Methadone maintenance replaces addiction to heroin by addiction to an opiate that does
not produce euphoric effects when administered orally.
• Buprenorphine, a partial agonist for the  opiate receptor, reduces craving for opiates.
• Because it is not of interest to opiate addicts (especially when it is combined with
naltrexone), it can be administered by a physician at an office visit.
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Section Summary
• The development of antibodies to cocaine and nicotine in humans and to several other
drugs in rats holds out the possibility that people may someday be immunized against
addictive drugs, preventing the entry of the drugs into the brain.
• Deep brain stimulation of the NAC and STN and TMS of the prefrontal cortex show
promise as a treatment for addiction.
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Section Summary
• Nicotine-containing gum and transdermal patches help smokers to combat their addiction.
• However, sensations from the airways produced by the presence of cigarette smoke play
an important role in addiction, and oral and transdermal administration do not provide
these sensations.
• Rimonabant, a CB1 receptor antagonist, aids in smoking cessation and reduces the
likelihood of weight gain, but may produce adverse emotional effects.
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Section Summary
• Bupropion, an antidepressant drug, has also been shown to help smokers stop their habit.
• Varenicline, a partial agonist for the nicotinic receptor, may be even more effective.
• The most effective pharmacological adjunct to treatment for alcoholism appears to be
naltrexone, an opiate receptor blocker that reduces the drug’s reinforcing effects.
• Acamprosate, an NMDA-receptor antagonist, appears to facilitate treatment of alcoholism.
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