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FOUNDATIONS OF BEHAVIORAL NEUROSCIENCE
9TH EDITION
Prepared by Grant McLaren, Department of Psychology, Edinboro University of Pennsylvania
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Chapter 16
Autistic, Attention-Deficit, Stress, and Substance
Abuse Disorders
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Autistic Disorder
Description
Possible Causes
Attention-Deficit/Hyperactivity Disorder
Description
Possible Causes
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Stress Disorders
Physiology of the Stress Response
Health Effects of Long-Term Stress
Effects of Stress on the Brain
Posttraumatic Stress Disorder
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Substance Abuse Disorders
What is Addiction?
Commonly Abused Drugs
Heredity and Drug Abuse
Therapy for Drug Abuse
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Autistic, Attention-Deficit, Stress, and
Substance Abuse Disorders
Learning Objectives
1.
Describe the symptoms and possible causes of autism.
2.
Describe the symptoms and possible causes of attention-deficit/
hyperactivity disorder.
3.
Describe the physiological responses to stress and their effects on
health.
4.
Discuss some of the long-term effects of stress, including
posttraumatic stress disorder.
5.
Discuss the interactions between stress, the immune system, and
infectious diseases
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Autistic, Attention-Deficit, Stress, and
Substance Abuse Disorders
Learning Objectives
6.
Review the general characteristics and consequences of addiction.
7.
Discuss the neural mechanisms responsible for craving and
relapse.
8.
Describe the behavioral and pharmacological effects of opiates,
cocaine, amphetamine, and nicotine.
9.
Describe the behavioral and pharmacological effects of alcohol and
cannabis.
10.
Describe research on the role that heredity plays in addiction in
humans.
11.
Discuss methods of therapy for drug abuse.
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Autistic Disorder
Description
autistic disorder
A chronic disorder whose symptoms include failure to
develop normal social relations with other people,
impaired development of communicative ability, lack of
imaginative ability, and repetitive, stereotyped
movements.
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Autistic Disorder
Description
The symptoms of autistic disorder (often simply referred to as
autism) include a failure to develop normal social relations with
other people, impaired development of communicative ability, and
the presence of repetitive, stereotyped behavior.
Most people with autistic disorder display cognitive impairments.
The syndrome was named and characterized by Kanner (1943),
who chose the term (auto, “self,”-ism, “condition”) to refer to the
child’s apparent self-absorption.
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Autistic Disorder
Description
According to a review by Silverman et al. (2010), the incidence of
autistic disorder is 0.6–1.0 percent in the population.
The disorder is four times more common in males than in females.
However, if only cases of autism with mental retardation are
considered, the ratio falls to 2:1, and if only cases of highfunctioning autism are considered (those with average or aboveaverage intelligence and reasonably good communicative ability),
the ratio rises to approximately 7:1 (Fombonne, 2005).
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Autistic Disorder
Description
These data suggest that the social impairments are much more
common in males but the cognitive and communicative
impairments are more evenly shared by males and females.
The reported incidence of autism has increased in the past two
decades, but evidence indicates that the apparent increase is a
result of heightened awareness of the disorder and broadening of
the diagnostic criteria.
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Autistic Disorder
Description
By the way, studies have failed to find evidence that autism is
linked to childhood immunization.
In fact, the investigator who originally claimed to have obtained
evidence for a linkage between immunization and autism was
found guilty of dishonesty by the UK General Medical Council, and
the article that first made this claim was retracted by the journal
that published it, The Lancet (Dwyer, 2010).
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Autistic Disorder
Description
Autistic disorder is one of several pervasive developmental
disorders that have similar symptoms.
Asperger’s syndrome, the mildest form of autistic spectrum
disorder, is generally less severe than autistic disorder, and its
symptoms do not include a delay in language development or the
presence of important cognitive deficits.
The primary symptoms of Asperger’s syndrome are deficient or
absent social interactions and repetitive and stereotyped
behaviors along with obsessional interest in narrow subjects.
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Autistic Disorder
Description
Rett’s disorder is a genetic neurological syndrome seen in girls
that accompanies an arrest of normal brain development that
occurs during infancy.
Children with childhood disintegrative disorder show normal
intellectual and social development and then, sometime between
the ages of two and ten years, show a severe regression into
autism.
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Autistic Disorder
Description
According to the diagnostic manual of the American Psychiatric
Association (DSM-IV), a diagnosis of autistic disorder requires the
presence of three categories of symptoms: impaired social
interactions, absent or deficient communicative abilities, and the
presence of stereotyped behaviors.
Social impairments are the first symptoms to emerge. Infants with
autistic disorder do not seem to care whether they are held, or
they may arch their backs when picked up, as if they do not want
to be held.
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Autistic Disorder
Description
They do not look or smile at their caregivers.
If they are ill, hurt, or tired, they will not look to someone else for
comfort.
As they get older, they do not enter into social relationships with
other children and avoid eye contact with them.
They have difficulty predicting other people’s behavior or
understanding their motivations.
In severe cases, autistic people do not even seem to recognize
the existence of other people.
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Autistic Disorder
Description
The language development of people with autism is abnormal or
even nonexistent.
They often echo what is said to them, and they may refer to
themselves as others do—in the second or third person.
Autistic people generally show abnormal interests and behaviors.
For example, they may show stereotyped movements, such as
flapping their hand back and forth or rocking back and forth.
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Autistic Disorder
Possible Causes
Researchers and mental health professionals are convinced that
autism is caused by biological factors and that parents should be
given help and sympathy, not blame.
Careful studies have shown that the parents of autistic children
are just as warm, sociable, and responsive as other parents (Cox
et al., 1975).
In addition, parents with one autistic child often raise one or more
normal children. If the parents were at fault, we should expect all
of their offspring to be autistic.
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Autistic Disorder
Heritability
Evidence indicates that autism is strongly heritable.
The best evidence for genetic factors comes from twin studies.
These studies indicate that the concordance rate for autism in
monozygotic twins is approximately 70 percent, while the rate in
dizygotic twins studied so far is approximately 5 percent.
The concordance rate for the more broadly defined autistic
spectrum disorders (ASD), is 90 percent for monozygotic twins
and 10 percent for dizygotic twins (Sebat et al., 2007).
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Autistic Disorder
Brain Pathology
Evidence suggests that approximately 20 percent of all cases of
autism have definable biological causes, such as rubella (German
measles) during pregnancy; prenatal thalidomide; encephalitis
caused by the herpes virus; and tuberous sclerosis, a genetic
disorder that causes the formation of benign tumors in many
organs, including the brain.
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Autistic Disorder
Brain Pathology
Evidence indicates significant abnormalities in the development of
the brains of autistic children.
Courchesne et al. (2005, 2007) note that although the autistic
brain is, on average, slightly smaller at birth, it begins to grow
abnormally quickly, and by 2–3 years of age it is about 10 percent
larger than a normal brain.
Following this early spurt, the growth of the autistic brain slows
down, so by adolescence it is only about 1–2 percent larger than
normal.
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Autistic Disorder
Brain Pathology
The regions that appear to be most involved in the functions that
are impaired in autism show the greatest growth early in life and
the slowest growth between early childhood and adolescence.
For example, the frontal cortex and temporal cortex of the autistic
brain grow quickly during the first two years of life but then show
little or no increase in size during the next four years, whereas
these two regions grow by 20 percent and 17 percent,
respectively, in normal brains.
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Autistic Disorder
Brain Pathology
Functional imaging during presentation of various animations
showed normal activation of early levels of the visual association
cortex (the extrastriate cortex), but activation of the superior
temporal sulcus (STS) and the medial prefrontal cortex was much
lower in members of the autism group. (See Figure 16.1.)
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Autistic Disorder
Brain Pathology
The lack of interest in or understanding of other people is reflected
in the response of the autistic brain to the sight of the human face.
As we saw in Chapter 6, the fusiform face area (FFA), located on
a region of visual association cortex on the base of the brain, is
involved in the recognition of individual faces.
A functional imaging study by Schultz (2005) found little or no
activity in the fusiform face area of autistic adults looking at
pictures of human faces. (See Figure 16.2.)
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Autistic Disorder
Brain Pathology
Oxytocin, a peptide that serves as a hormone and
neuromodulator, facilitates pair bonding and increases trust and
closeness to others. Modahl et al. (1998) reported that autistic
children had lower levels of this peptide.
Studies suggest that oxytocin can improve sociability of people
with ASD.
Guastella et al. (2010a) found that administration of oxytocin
increased the performance of adolescent males with ASD on a
test of emotional recognition.
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Attention-Deficit/Hyperactivity Disorder
attention-deficit/hyperactivity disorder (ADHD)
A disorder characterized by uninhibited responses, lack
of sustained attention, and hyperactivity; first shows itself in
childhood.
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Attention-Deficit/Hyperactivity Disorder
Description
ADHD is the most common behavior disorder that shows itself in
childhood.
It is usually first discovered in the classroom, where children are
expected to sit quietly and pay attention to the teacher or work
steadily on a project
They have difficulty withholding a response, act without reflecting,
often show reckless and impetuous behavior, and let interfering
activities intrude into ongoing tasks.
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Attention-Deficit/Hyperactivity Disorder
Description
According to the DSM-IV, the diagnosis of ADHD requires the
presence of six or more of nine symptoms of inattention and six or
more of nine symptoms of hyperactivity and impulsivity that have
persisted for at least six months.
Symptoms of inattention include such things as “often had
difficulty sustaining attention in tasks of play activities” or “is often
easily distracted by extraneous stimuli.”
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Attention-Deficit/Hyperactivity Disorder
Description
ADHD can be very disruptive of a child’s education and that of
other children in the same classroom.
It is seen in 4–5 percent of grade school children. Boys are about
ten times more likely than girls to receive a diagnosis of ADHD,
but in adulthood the ratio is approximately 2 to 1, which suggests
that many girls with this disorder fail to be diagnosed.
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Attention-Deficit/Hyperactivity Disorder
Description
Because the symptoms can vary—some children’s symptoms are
primarily those of inattention, some are those of hyperactivity, and
some show mixed symptoms—most investigators believe that this
disorder has more than one cause.
Diagnosis is often difficult, because the symptoms are not well
defined. ADHD is often associated with aggression, conduct
disorder, learning disabilities, depression, anxiety, and low selfesteem.
The most common treatment for ADHD is administration of
methylphenidate (Ritalin), a drug that inhibits the reuptake of
dopamine.
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Attention-Deficit/Hyperactivity Disorder
Possible Causes
There is strong evidence from both family studies and twin studies
for hereditary factors that play a role in determining a person’s
likelihood of developing ADHD.
The estimated heritability of ADHD ranges from 75 to 91 percent
(Thapar, O’Donovan, and Owen, 2005).
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Attention-Deficit/Hyperactivity Disorder
Possible Causes
The symptoms of ADHD resemble those produced by damage to
the prefrontal cortex: distractibility, forgetfulness, impulsivity, poor
planning, and hyperactivity (Aron, Robbins, and Poldrack, 2004).
The prefrontal cortex uses working memory to guide thoughts and
behavior, regulate attention, monitor the effects of our actions, and
organize plans for future actions (Arnsten, 2006).
Damage or abnormalities in the neural circuits that perform these
functions give rise to the symptoms of ADHD.
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Attention-Deficit/Hyperactivity Disorder
Possible Causes
Many studies have shown that the effect of dopamine levels in the
prefrontal cortex on the functions of this region follow an inverted
U-shaped curve. (See Figure 16.3.)
Graphs of many behavioral functions have an inverted U shape.
For example, moderate levels of motivation increase performance
on most tasks, but very low levels fail to induce a person to
perform, and very high levels tend to make people nervous and
interfere with their performance.
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Stress Disorders
Walter Cannon, a prominent twentieth-century physiologist,
introduced the term stress to refer to the physiological reaction
caused by the perception of aversive or threatening situations.
The physiological responses that accompany the negative
emotions prepare us to threaten rivals or fight them or to run away
from dangerous situations.
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Stress Disorders
stress
A general, imprecise term that can refer either to a
stress response or to a stressor (stressful situation).
fight-or-flight response
A species-typical response preparatory to fighting or
fleeing; thought to be responsible for some of the
deleterious effects of stressful situations on health.
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Stress Disorders
Physiology of the Stress Response
Emotions consist of behavioral, autonomic, and endocrine
responses.
The latter two components, the autonomic and endocrine
responses, are the ones that can have adverse effects on health.
Because threatening situations generally call for vigorous activity,
the autonomic and endocrine responses that accompany them are
catabolic; that is, they help to mobilize the body’s energy
resources.
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Stress Disorders
Physiology of the Stress Response
The sympathetic branch of the autonomic nervous system is
active, and the adrenal glands secrete epinephrine,
norepinephrine, and steroid stress hormones.
Epinephrine affects glucose metabolism, causing the nutrients
stored in muscles to become available to provide energy for
strenuous exercise.
Along with norepinephrine, the hormone also increases blood flow
to the muscles by increasing the output of the heart.
In doing so, it also increases blood pressure.
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Stress Disorders
Physiology of the Stress Response
Besides serving as a stress hormone, norepinephrine is (as you
know) secreted in the brain as a neurotransmitter.
Some of the behavioral and physiological responses produced by
aversive stimuli appear to be mediated by noradrenergic neurons.
Presumably, this stress-induced release is controlled by a
pathway from the central nucleus of the amygdala to the locus
coeruleus, the nucleus of the brain stem that contains NEsecreting neurons.
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Stress Disorders
Physiology of the Stress Response
glucocorticoid
One of a group of hormones of the adrenal cortex that
are important in protein and carbohydrate metabolism,
secreted especially in times of stress.
The other stress-related hormone is cortisol, a steroid secreted by
the adrenal cortex.
Cortisol is called a glucocorticoid because it has profound effects
on glucose metabolism.
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Stress Disorders
Physiology of the Stress Response
In addition, glucocorticoids help to break down protein and convert
it to glucose, help to make fats available for energy, increase
blood flow, and stimulate behavioral responsiveness, presumably
by affecting the brain.
Glucocorticoids have other physiological effects, too, some of
which are only poorly understood.
Almost every cell in the body contains glucocorticoid receptors,
which means that few of them are unaffected by these hormones.
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Stress Disorders
Physiology of the Stress Response
The secretion of glucocorticoids is controlled by neurons in the
paraventricular nucleus of the hypothalamus (PVN).
corticotropin-releasing hormone (CRH)
A hypothalamic hormone that stimulates the anterior
pituitary gland to secrete ACTH (adrenocorticotropic
hormone).
adrenocorticotropic hormone (ACTH)
A hormone released by the anterior pituitary gland in
response to CRH; stimulates the adrenal cortex to produce
glucocorticoids.
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Stress Disorders
Health Effects of Long-Term Stress
The short-term effects of glucocorticoids are essential, the longterm effects are damaging.
These effects include increased blood pressure, damage to
muscle tissue, steroid diabetes, infertility, inhibition of growth,
inhibition of the inflammatory responses, and suppression of the
immune system.
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Stress Disorders
Health Effects of Long-Term Stress
Inhibition of growth in children who are subjected to prolonged
stress prevents them from attaining their full height.
Inhibition of the inflammatory response makes it more difficult for
the body to heal itself after an injury, and suppression of the
immune system makes an individual vulnerable to infections.
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Stress Disorders
Health Effects of Long-Term Stress
The adverse effects of stress on healing were demonstrated in a
study by Kiecolt-Glaser et al. (1995), who performed punch biopsy
wounds in the subjects’ forearms, a harmless procedure that is
used often in medical research.
The subjects were people who were providing long-term care for
relatives with Alzheimer’s disease—a situation that is known to
cause stress—and control subjects of the same approximate age
and family income.
The investigators found that healing of the wounds took
significantly longer in the caregivers (48.7 days versus 39.3 days).
(See Figure 16.5)
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Stress Disorders
Effects of Stress on the Brain
Research with animals has shown that long-term exposure to
glucocorticoids destroys neurons located in field CA1 of the
hippocampal formation.
Perhaps, then, the stressful stimuli to which people are subjected
throughout their lives increase the likelihood of memory problems
as they grow older.
In fact, Lupien et al. (1996) found that elderly people with elevated
blood levels of glucocorticoids learned a maze more slowly than
did those with normal levels.
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Stress Disorders
Effects of Stress on the Brain
Salm et al. (2004) found that brief episodes of prenatal stress can
affect brain development and produce changes that last the
animal’s lifetime.
Once a day during the last week of gestation, they removed
pregnant rats from their cage and gave them an injection of a
small amount of sterile saline—a procedure that lasted less than 5
minutes.
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Stress Disorders
Effects of Stress on the Brain
This stress altered the development of their amygdalas.
The investigators found that the volume of the lateral nucleus of
the amygdala, measured in adulthood, was increased by
approximately 30 percent in the animals that sustained prenatal
stress. (See Figure 16.6.)
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Stress Disorders
Effects of Stress on the Brain
Uno et al. (1989) found that if long-term stress is intense enough,
it can even cause brain damage in young primates. The
investigators studied a colony of vervet monkeys housed in a
primate center in Kenya.
They found that some monkeys died, apparently from stress.
Vervet monkeys have a hierarchical society, and monkeys near
the bottom of the hierarchy are picked on by the others; thus, they
are almost continuously subjected to stress.
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Stress Disorders
Effects of Stress on the Brain
The deceased monkeys had gastric ulcers and enlarged adrenal
glands, which are signs of chronic stress.
And as Figure 16.7 shows, neurons in the CA1 field of the
hippocampal formation were completely destroyed. (See Figure
16.7.)
Severe stress appears to cause brain damage in humans as well;
Jensen, Genefke, and Hyldebrandt (1982) found evidence of brain
degeneration in CT scans of people who had been subjected to
torture.
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Stress Disorders
Effects of Stress on the Brain
More mild forms of stress early in life also appear to affect brain
development.
van Harmelen et al. (2010) found that episodes of emotional
maltreatment during childhood was associated with an average
7.2 percent reduction in the volume of the dorsomedial prefrontal
cortex. (See Figure 16.8.)
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Stress Disorders
Posttraumatic Stress Disorder
The aftermath of tragic and traumatic events such as those that
accompany wars and natural disasters often includes
psychological symptoms that persist long after the stressful events
are over.
posttraumatic stress disorder (PTSD)
A psychological disorder caused by exposure to a
situation of extreme danger and stress; symptoms
include recurrent dreams or recollections; can interfere
with social activities and cause a feeling of
hopelessness.
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Stress Disorders
Posttraumatic Stress Disorder
The likelihood of developing PTSD is increased if the traumatic
event involved danger or violence from other people, such as
assault, rape, or wartime experiences (Yehuda and LeDoux,
2007).
The symptoms produced by such exposure include recurrent
dreams or recollections of the event, feelings that the traumatic
event is recurring (“flashback” episodes), and intense
psychological distress.
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Stress Disorders
Posttraumatic Stress Disorder
Evidence from twin studies suggest that genetic factors play a role
in a person’s susceptibility to develop PTSD.
In fact, genetic factors influence not only the likelihood of
developing PTSD after being exposed to traumatic events, but
also the likelihood that the person will be involved in such an
event (Stein et al., 2002)
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Stress Disorders
Posttraumatic Stress Disorder
A few studies have identified several specific genes as possible
risk factors for developing PTSD.
These genes include those responsible for the production of
dopamine D2 receptors, dopamine transporters, and 5-HT
transporters (Nugent, Amstadter, and Koenen, 2008).
The risk for PTSD appears to depend on both genetic and
environmental factors.
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Stress Disorders
Posttraumatic Stress Disorder
Kolassa et al. (2010) studied 424 survivors of the genocide in the
Rwanda.
They found that the likelihood of developing PTSD increased with
the number of traumatic events the person had experienced. (See
Figure 16.9.)
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Stress Disorders
Posttraumatic Stress Disorder
Several studies have found evidence that the amygdala is
responsible for emotional reactions in people with PTSD and that
the prefrontal cortex plays a role in these reactions in people
without PTSD by inhibiting the activity of the amygdala (Rauch,
Shin, and Phelps, 2006).
For example, a functional imaging study by Shin et al. (2005)
found that when shown pictures of faces with fearful expressions,
people with PTSD show greater activation of the amygdala and
smaller activation of the prefrontal cortex than did people without
PTSD.
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Stress Disorders
Posttraumatic Stress Disorder
The most common treatments for PTSD are cognitive behavior
therapy, group therapy, and SNRIs.
Boggio et al. (2010) report on the results of a clinical trial of
transcranial magnetic stimulation (TMS) of the dorsolateral
prefrontal cortex on 30 patients with PTSD.
They found that 10 sessions of stimulation of the left or right
dlPFC significantly reduced the symptoms of PTSD, and that the
beneficial effects were still seen 3 months later.
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Stress Disorders
Stress and Infectious Diseases
Long-term stress can be harmful to one’s health and can even
result in brain damage.
The most important cause of these effects is elevated levels of
glucocorticoids, but the high blood pressure caused by
epinephrine and norepinephrine also plays a contributing role.
In addition, the stress response can impair the functions of the
immune system, which protects us from assault from viruses,
microbes, fungi, and other types of parasites.
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Stress Disorders
Stress and Infectious Diseases
antigen
A protein present on a microorganism that permits the
immune system to recognize the microorganism as an
invader.
antibody
A protein produced by a cell of the immune system that
recognizes antigens present on invading
microorganisms.
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Stress Disorders
Stress and Infectious Diseases
Stone, Reed, and Neale (1987) attempted to determine whether
stressful events in people’s daily lives might predispose them to
upper respiratory infection.
If a person is exposed to a microorganism that might cause such
a disease, the symptoms do not occur for several days; that is,
there is an incubation period between exposure and signs of the
actual illness.
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Stress Disorders
Stress and Infectious Diseases
The results were as predicted: During the three-to-five-day period
just before showing symptoms of an upper respiratory infection,
people experienced an increased number of undesirable events
and a decreased number of desirable events in their lives. (See
Figure 16.10.)
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Substance Abuse Disorders
Drug addiction poses a serious problem to our species. Consider
the disastrous effects caused by the abuse of one of our oldest
drugs, alcohol: automobile accidents, fetal alcohol syndrome,
cirrhosis of the liver, Korsakoff's syndrome, increased rate of heart
disease, and increased rate of intracerebral hemorrhage.
Smoking (addiction to nicotine) greatly increases the chances of
dying of lung cancer, heart attack, and stroke; and women who
smoke give birth to smaller, less healthy babies.
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Substance Abuse Disorders
Cocaine addiction can cause psychotic behavior, brain damage,
and death from overdose; and competition for lucrative and illegal
markets terrorizes neighborhoods, subverts political and judicial
systems, and causes many violent deaths.
The use of “designer drugs” exposes users to unknown dangers
of untested and often contaminated products, as several people
discovered when they acquired Parkinson's disease after taking a
synthetic opiate that was tainted with a neurotoxin.
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Substance Abuse Disorders
What is 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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Substance Abuse Disorders
What is 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.
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Substance Abuse Disorders
What is Addiction?
A Little Background
The most universal recreational drug, and perhaps the first one
that our ancestors discovered, is ethyl alcohol.
Yeast spores are present everywhere, and these microorganisms
can feed on sugar solutions and produce alcohol as a by-product.
Undoubtedly, people in many different parts of the world
discovered the pleasurable effects of drinking liquids that had
been left alone for a while, such as the juice that had accumulated
in the bottom of a container of fruit.
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Substance Abuse Disorders
What is Addiction?
Positive Reinforcement
Drugs that lead to dependency must first reinforce people’s
behavior.
If, in a particular situation, a behavior is regularly followed by an
appetitive stimulus (one that the organism will tend to approach),
then that behavior will become more frequent in that situation.
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Substance Abuse Disorders
What is Addiction?
Positive Reinforcement Role in Addiction
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.
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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Substance Abuse Disorders
What is Addiction?
Positive Reinforcement Role in Addiction
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.
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Substance Abuse Disorders
What is Addiction?
Neural Mechanisms
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).
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What is Addiction?
Neural Mechanisms
This effect is not the only effect of reinforcing stimuli, and even
aversive stimuli can trigger the release of dopamine (Salamone,
1992).
But even though 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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What is 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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What is 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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What is Addiction?
Neural Mechanisms
As we saw in Chapter 13, this process, normally mediated by
glutamatergic NMDA receptors, is the neural basis of many forms
of learning.
A single injection of an addictive drug produces synaptic
strengthening in the VTA that lasts for about five days. If an animal
receives cocaine for about two weeks, the changes in the VTA
persist.
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What is Addiction?
Neural Mechanisms
As a result of the changes in the VTA, increased activation is seen
in a variety of regions that receive dopaminergic input from the
VTA, including the ventral striatum, which includes the NAC, and
the dorsal striatum, which includes the caudate nucleus and
putamen.
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What is Addiction?
Neural Mechanisms
Synaptic changes that are responsible for the compulsive
behaviors that characterize addiction occur only after continued
use of an addictive drug.
The most important of these changes appears to occur in the
dorsal striatum.
We saw in Chapter 12 that the basal ganglia (which includes the
dorsal striatum) play a critical role in instrumental conditioning,
and the process of addiction involves just that.
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What is Addiction?
Negative Reinforcement
A behavior that turns off (or reduces) an aversive stimulus will be
reinforced.
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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What is Addiction?
Negative Reinforcement
tolerance
The fact that increasingly large doses of drugs must be
taken to achieve a particular effect; caused by
compensatory mechanisms that oppose the effect of the
drug.
withdrawal symptoms
The appearance of symptoms opposite to those
produced by a drug when the drug is suddenly no
longer taken; caused by the presence of compensatory
mechanisms.
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What is 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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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.
Once the animal has stopped responding, the experimenter
administers a “free” injection of the drug.
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Craving and Relapse
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
16.11.)
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Substance Abuse Disorders
Craving and Relapse
Volkow et al. (2002) 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).
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Craving and Relapse
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 16.12)
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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 ten cigarettes per day. (See Figure 16.13.)
These results suggest that abnormalities in the prefrontal cortex
may be a common factor in schizophrenia and substance abuse
disorders.
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Craving and Relapse
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 longterm 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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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).
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Craving and Relapse
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.
These results suggest that abnormalities in the prefrontal cortex
may be a common factor in schizophrenia and substance abuse
disorders.
Whether preexisting abnormalities increase the risk of these
disorders or whether the disorders cause the abnormalities has
not yet been determined.
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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 ten cigarettes per day. (See Figure 16.13.)
These results suggest that abnormalities in the prefrontal cortex
may be a common factor in schizophrenia and substance abuse
disorders.
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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.
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Commonly Abused Drugs
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.”
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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.
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Commonly Abused Drugs
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.
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Opiates
Opiate receptors in the periaqueductal gray matter are primarily
responsible for the analgesia, those in the preoptic area are
responsible for the hypothermia, those in the mesencephalic
reticular formation are responsible for the sedation, and those in
the ventral tegmental area (VTA) and the nucleus accumbens
(NAC) are responsible for the reinforcing effects of opiates.
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Commonly Abused Drugs
Opiates
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 VTA (Devine and Wise, 1994) or the NAC
(Goeders, Lane, and Smith, 1984).
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Commonly Abused Drugs
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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Commonly Abused Drugs
Stimulant Drugs: Cocaine and Amphetamine
Methamphetamine is chemically related to amphetamine, but is
considerably more potent.
Because the effects of cocaine and methamphetamine are so
potent and so rapid, they are probably the most effective
reinforcers of all available drugs.
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Commonly Abused Drugs
Stimulant Drugs: Cocaine and Amphetamine
As we have seen, the mesolimbic dopamine system plays an
essential role in all forms of reinforcement.
If drugs that block dopamine receptors are injected into the NAC,
cocaine loses much of its reinforcing effect (McGregor and
Roberts, 1993; Caine et al., 1995).
In addition, destruction of dopaminergic terminals in the NAC with
a local injection of 6-HD interferes with the reinforcing effects of
both cocaine and amphetamine (Caine and Koob, 1994).
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Commonly Abused Drugs
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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Commonly Abused Drugs
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 so-called “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.
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Nicotine
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.
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 smoking-related diseases.
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Commonly Abused Drugs
Nicotine
Investigators estimate that in just a few years, tobacco will be the
largest single health problem worldwide, with over 6.4 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).
In the United States alone, tobacco addiction kills more than
430,000 people each year (Chou and Narasimhan, 2005).
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Commonly Abused Drugs
Nicotine
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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Commonly Abused Drugs
Nicotine
Ours is not the only species willing to self-administer nicotine; so
will laboratory animals.
Nicotine stimulates nicotinic acetylcholine receptors, of course.
It also increases the activity of dopaminergic neurons of the
mesolimbic system and causes dopamine to be released in the
NAC (Damsma, Day, and Fibiger, 1989).
Figure 16.15 shows the effects of two injections of nicotine or
saline on the extracellular dopamine level of the NAC, measured
by microdialysis. (See Figure 16.15.)
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Commonly Abused Drugs
Nicotine
Nicotine stimulates nicotinic acetylcholine receptors, of course.
It also increases the activity of dopaminergic neurons of the
mesolimbic system and causes dopamine to be released in the
NAC (Damsma, Day, and Fibiger, 1989).
Figure 16.15 shows the effects of two injections of nicotine or
saline on the extracellular dopamine level of the NAC, measured
by microdialysis. (See Figure 16.15.)
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Commonly Abused Drugs
Nicotine
Naqvi and his colleagues reported (Naqvi et al. 2007; Naqvi and
Bechara, 2009), a patient sustained a stroke that damaged his
insula.
In fact, so did several other patients with insular damage. Naqvi
and his colleagues identified 19 cigarette smokers with damage to
the insula and 50 smokers with brain damage that spared this
region.
Nineteen of the patients had damage to the insula, and twelve of
them “quit smoking easily, immediately, without relapse, and
without persistence of the urge to smoke” (p. 531).
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Nicotine
One patient with insula damage quit smoking but still reported
feeling an urge to smoke.
Figure 16.16 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
16.16.)
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Commonly Abused Drugs
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 16.17.)
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Commonly Abused Drugs
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.
In studies with laboratory animals the anxiolytic effects manifest
themselves as a release from the punishing effects of aversive
stimuli.
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Commonly Abused Drugs
Alcohol
Alcohol produces both positive and negative reinforcement.
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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Commonly Abused Drugs
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.
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Commonly Abused Drugs
Alcohol
Alcohol has two major sites of action in the nervous system,
acting as an indirect antagonist at NMDA receptors and an indirect
agonist at GABAA receptors (Chandler, Harris, and Crews, 1998).
That is, alcohol enhances the action of GABA at GABAA receptors
and interferes with the transmission of glutamate at NMDA
receptors.
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Commonly Abused Drugs
Alcohol
The anxiolytic effects of a GABAA agonist are apparently
responsible for the negatively reinforcing effects of alcohol.
The sedative effect of alcohol also appears to be exerted at the
GABAA receptor.
Figure 16.18 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 16.18.)
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Commonly Abused Drugs
Alcohol
Although the effects of heroin withdrawal have been exaggerated,
those produced by 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 an intravenous
injection of a benzodiazepine.
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Commonly Abused Drugs
Alcohol
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 drugs that block opiate receptors
also block the reinforcing effects of alcohol in a variety of species,
including rats, monkeys, and humans.
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Alcohol
In addition, endogenous opioids may play a role in craving in
abstinent alcoholics.
Heinz et al. (2005) found that 1 to 3 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 16.19.)
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Commonly Abused Drugs
Cannabis
Another drug that people regularly self-administer—almost
exclusively by smoking—is THC, the active ingredient in
marijuana.
THC, like other drugs with abuse potential, has a stimulating effect
on dopaminergic neurons.
A microdialysis study by Chen et al. (1990) found that low doses
of THC increased the release of dopamine in the NAC. (See
Figure 16.20.)
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Commonly Abused Drugs
Cannabis
The primary reinforcing component of marijuana, THC, is one of
approximately 70 different chemicals produced only by the
cannabis plant.
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
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.
Evidence indicates that the drug does so by disrupting the normal
functions of the hippocampus, which plays such an important role
in memory. (Kunos and Batkai, 2001).
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Heredity and Drug Abuse
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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Heredity and Drug Abuse
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 of a trait in a
particular population (that can be attributed to genetic variability).
The average value of h2 for addiction ranged from approximately
0.4 for hallucinogenic drugs to just over 0.7 for cocaine.
As you will see in Figure 16.21 , the authors included addiction to
gambling, which is not a drug. (See Figure 16.21.)
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Heredity and Drug Abuse
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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Heredity and Drug Abuse
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 alcohol dehydrogenase, an enzyme involved in
metabolism of alcohol, plays a role in susceptibility to alcoholism.
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Substance Abuse Disorders
Therapy for Drug Abuse
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.
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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Therapy for Drug Abuse
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.
Buprenorphine blocks the effects of opiates and itself produces
only a weak opiate effect.
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Therapy for Drug Abuse
As we saw in Chapters 14 and 15, deep brain stimulation (DBS)
has been shown to have therapeutic effects on the symptoms of
Parkinson’s disease, depression, anxiety disorders, and
obsessive-compulsive 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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Therapy for Drug Abuse
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 and
transdermal patches that release nicotine through the skin have
been marketed.
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Therapy for Drug Abuse
Both methods maintain a sufficiently high level of nicotine in the
brain to decrease a person’s craving for nicotine.
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.
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Therapy for Drug Abuse
Another drug, bupropion, is an antidepressant drug that serves as
a catecholamine reuptake inhibitor.
Bupropion has been approved for use in several countries for
treating nicotine addiction.
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
-opioid receptor.
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Therapy for Drug Abuse
Figure 16.22 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.
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 for the smokers who received
bupropion and placebo. (See Figure 16.22.)
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Therapy for Drug Abuse
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.
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Therapy for Drug Abuse
A study by O’Brien, Volpicelli, and Volpicelli (1996) reported the
results of two long-term programs using naltrexone along with
more traditional behavioral treatments.
Both programs found that administration of naltrexone significantly
increased the likelihood of success.
As Figure 16.23 shows, naltrexone increased the number of
participants who managed to abstain from alcohol. (See Figure
16.23.)
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Therapy for Drug Abuse
One more drug has shown promise for treatment of alcoholism.
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.
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).
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