Science Brain and Behavior contiuned 20

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HOW DOES THE BRAIN DEVELOP AND ADAPT? ! 211
happen if a third eye were transplanted in the embryonic frog head. This eye would
probably send connections to one of the tecta, which would now have to accommodate
to the new input.
This accommodation is exactly what happened, as shown in Figure 6-24. The third
eye sent connections to one of the tecta, in competition with the ungrafted eye sending
axons there. This competition resulted in the formation of one neural column for
each eye.We can only imagine what this frog made of the world with its three eyes.
To summarize, the details of neural connections are modified by experience. An
organism’s genetic blueprint is vague in regard to exactly which connections in the
brain go to exactly which neurons. Experience fine-tunes neural connectivity.
Critical Periods for Experience and
Brain Development
At particular times in the course of brain development, specific experiences are especially
important for development to be normal. In kittens, for example, the effect of suturing
one eye closed has the most disruptive effect on cortical organization between
Normal
Infant
Adolescent
Adult
Abnormal
L R L R L L R L R L
Figure 6-23
Ocular-Dominance Columns In the postnatal
development of the cat brain, axons enter the cortex
where they grow large terminal arborizations. In infancy,
the projections of both eyes overlap (L, left eye; R, right
eye). In adulthood, a nonoverlapping pattern of terminal
arborizations from each of the eyes, shown at the bottom
left, is normal. If one eyelid of a kitten is sewn shut during
a critical week of development, the terminations from that
eye retract and those from the open eye expand, as shown
at the right.
Right
optic
tectum
Left
optic
tectum
(A) (B)
Retina
Grafted
third eye
Figure 6-24
Three-Eyed Frog (A) A third eye was
grafted prenatally into this frog. (B) The
third eye forms connections with one
optic tectum—in this case, the right.
Because the connections of the third eye
are shared with the frog’s left eye, these
two eyes compete for synaptic space,
leading to the formation of alternating
bands of connections.
From Martha Constantine-Paton and Margaret I. Law, “Eye Specific Termination
Bands in Tecta of Three-Eyed Frogs,” Science, November 10, 1978, vol. 202,
pp. 639–641. ©1978 by the American Association for the Advancement of Science.
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30 and 60 days after birth. A time span during which brain development is most sensitive
to a specific experience is often called a critical period.
The absence of appropriate sensory experience during a critical period may result
in abnormal brain development, leading to abnormal behavior that endures even into
adulthood. Richard Tees offered an analogy to help explain the concept of critical periods.
He pictured the developing animal as a little train traveling past an environmental
setting, perhaps the Rocky Mountains. All the windows are closed at the
beginning of the journey (prenatal development), but, at particular stages of the trip,
the windows in certain cars open, exposing the occupants (different parts of the brain)
to the outside world. Some windows open to expose the brain to specific sounds, others
to certain smells, others to particular sights, and so on.
This exposure affects the brain’s development and, in the absence of any exposure
through an open window, that development is severely disturbed. As the journey continues,
the windows become harder to open until, finally, they are permanently closed.
This closure does not mean that the brain can no longer change, but changes become
much harder to induce.
Now, imagine two different trains, one headed through the Rocky Mountains and
another, the Orient Express, traveling across eastern Europe. The “views” from the windows
are very different, and the effects on the brain are correspondingly different. In
other words, not only is the brain altered by the experiences that it has during a critical
period, but the particular kinds of experiences encountered matter, too.
An extensively studied behavior that relates to the concept of critical periods is
imprinting, a critical period during which an animal learns to restrict its social preferences
to a specific class of objects, usually the members of its own species. In birds,
such as chickens or waterfowl, the critical period for imprinting is often shortly after
hatching. Normally, the first moving object that a young hatchling sees is a parent or
sibling, and so the hatchling’s brain appropriately imprints to its own species.
This appropriate imprinting is not inevitable, however. Konrad Lorenz (1970)
demonstrated that, if the first animal or object that baby goslings encounter is a person,
the goslings imprint to that person as though he or she were their mother. Figure 6-25
shows a flock of goslings that imprinted to Lorenz and followed him wherever he went.
This incorrect imprinting has long-term consequences for the hatchlings, which will
often direct their subsequent sexual behavior inappropriately toward humans. A Barbary
dove that had become imprinted to Lorenz
directed its courtship toward his hand and even
tried to copulate with the hand if it were held in a
certain orientation.
Interestingly, birds inappropriately imprint
not just to humans but to inanimate objects, especially
moving objects. Chickens have been induced
to imprint to a milk bottle sitting on the
back of a toy train moving around a track. But
the brain is not entirely clueless when it comes to
selecting a target to which to imprint. Given a
choice, young chicks will imprint on a real chicken
over any other stimulus.
Its rapid acquisition and permanent behavioral
consequences suggest that, during imprinting,
the brain makes a rapid change of some kind,
probably a structural change, given the permanence
of the new behavior. Gabriel Horn and his
colleagues at Cambridge University (1985) tried
212 ! CHAPTER 6
Critical period. Developmental
“window” during which some event has a
long-lasting influence on the brain; often
referred to as a sensitive period.
Imprinting. Process that predisposes an
animal to form an attachment to objects
or animals at a critical period in
development.
Figure 6-25
Strength of Imprinting Ethologist
Konrad Lorenz followed by goslings that
imprinted on him. Because he was the
first “object” that the geese encountered
after hatching, he became their
“mother.”
Thomas D. McAvoy/Time Magazine
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to identify what changes in the brains of chicks during imprinting. The results of Horn’s
electron microscopic studies show that the synapses in a specific region of the forebrain,
the IMHV, enlarge with imprinting. Imprinting, then, seems to be a good model for
studying brain plasticity during development, in part because the changes are rapid, related
to specific experience, and localized in the brain.
Abnormal Experience and Brain Development
If complex experiences can stimulate brain growth and influence later behavior, severely
restricted experiences seem likely to retard both brain growth and behavior. To
study the effects of such restrictions, Donald Hebb and his colleagues placed young
Scottish terriers in the dark with as little stimulation as possible and compared their
behavior with that of dogs raised in a normal environment.
When the dogs raised in the barren environment were later removed from that environment,
their behavior was very unusual. They showed virtually no reaction to people
or other dogs, and they appeared to have lost the sensation of pain. Even sticking
pins in them produced no response.When given a dog version of the Hebb-Williams
intelligence test for rats, these dogs performed very poorly and were unable to learn
some tasks that dogs raised in more stimulating settings could learn easily.
The results of subsequent studies have shown that depriving young animals specifically
of visual input or even of maternal contact has devastating consequences for their
behavioral development and, presumably, for the development of the brain. For instance,
Austin Riesen and his colleagues (Riesen, 1982) extensively studied animals raised in
the dark and found that, even though the animals’ eyes still work, they may be functionally
blind after early visual deprivation. The absence of visual stimulation results in the
atrophy of dendrites on cortical neurons, which is essentially the opposite of the results
observed in the brains of animals raised in complex and stimulating environments.
Not only does the absence of specific sensory inputs adversely affect brain development,
so do more-complex abnormal experiences. In the 1950s,Harry Harlow began
the first systematic laboratory studies of analogous deprivation in laboratory animals.
Harlow showed that infant monkeys raised without maternal (or paternal) contact
have grossly abnormal intellectual and social behaviors in adulthood.
Harlow separated baby monkeys from their mothers shortly after birth and raised
them in individual cages. Perhaps the most stunning effect was that, in adulthood,
these animals were totally unable to establish normal relations with other animals.Unfortunately,
Harlow did not analyze the brains of the deprived monkeys.We would predict
atrophy of cortical neurons, especially in the frontal-lobe regions known to be
related to normal social behavior.
The importance of the environment in brain development cannot be overemphasized.
Children exposed to barren environments or to abuse or neglect will be at a serious
disadvantage later in life. Proof can be seen in the retarded intellectual development
of children raised in dreadful circumstances, as described in “Romanian Orphans” on
page 214. Although it is often argued that children can succeed in school and in life if
they really want to, it is clear that abnormal developmental experiences can alter the
brain irrevocably. As a society, we cannot be complacent about the environments to
which our children are exposed.
Exposure to stress is another type of early experience that appears to have a major
effect on a child’s later behavior. Stress can actually alter the expression of certain genes
such as those related to the transport of serotonin back across the presynaptic membrane.
Such alteration in serotonin activity can severely alter how the brain responds
to stressful experiences later in life.
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Stress early in life may predispose people to develop various behavioral disorders,
including depression (Sodhi & Sanders-Bush, 2004). Early stress can also leave a lasting
imprint on brain structure: the amygdala is enlarged and the hippocampus is reduced
in size (Salm et al., 2004). Such changes have been associated with the development of
depressive and anxiety disorders (see Chapters 7 and 11).
Hormones and Brain Development
The determination of sex is largely genetic. In mammals, the Y chromosome present in
males controls the process by which an undifferentiated primitive gonad develops into
testes, as illustrated in Figure 6-9. The testes subsequently secrete testosterone, which
stimulates the development of male reproductive organs and, in puberty, the appearance
ofmale secondary sexual characteristics such as facial hair and the deepening of the voice.
Gonadal hormones also influence the development of neurons. Testosterone is released
in males during a brief period in the course of prenatal brain development, and
it subsequently acts to alter the brain, much as it alters the sex organs. This process is
called masculinization.
214 ! CHAPTER 6
Romanian Orphans
Focus on Disorders
In the 1970s, the Communist regime governing Romania
outlawed all forms of birth control and abortion. The natural
result was thousands of unwanted pregnancies. More
than 100,000 unwanted children were placed in orphanages
where the conditions were appalling.
The children were housed and clothed but had virtually
no environmental stimulation. In most instances, they were
confined to cots. There were few, if any, playthings and virtually
no personal interaction with caregivers. Bathing often
consisted of being hosed down with cold water. After the
Communist government fell and the outside world was able
to intervene, hundreds of these children were rescued and
placed in adoptive homes throughout the world, especially
in the United States, Canada, and the United Kingdom.
Several studies of the fate of these severely deprived
children document their poor physical state on arrival in
their new homes. They were malnourished; they had chronic
respiratory and intestinal infections; and they were severely
developmentally impaired. A British study by Michael Rutter
and his colleagues (Rutter, 1998) found them to be two
standard deviations below age-matched children for weight,
height, and head circumference. Assessments with the use of
scales of motor and cognitive development showed most of
the children to be in the retarded range.
The improvement in these children in the first 2 years
after placement in their adoptive homes was nothing short of
The conditions depicted in this photograph are those found in the
warehousing of Romanian orphans in the 1970s and 1980s.
Findings from studies on this population have shown that the lack
of stimulation hampered normal brain development.
Johnson/Gamma-Liaison
Masculinization. Process by which
exposure to androgens (male hormones)
alters the brain, rendering it “malelike.”
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Just as testosterone does not affect all body organs, it does not affect all regions of
the brain. It does, however, affect many brain regions and in many different ways. For
instance, it affects the number of neurons formed in certain brain areas, reduces the
number of neurons that die, increases cell growth, increases or reduces dendritic
branching, increases or reduces synaptic growth, and regulates the activity of synapses.
Although we have emphasized the role of testosterone in brain development, estrogen
also likely influences postnatal brain development. Goldstein and colleagues found
sex differences in the volume of cortical regions that are known to have differential levels
of receptors for testosterone and estrogen, respectively, as diagrammed in Figure
6-26 (Goldstein et al., 2001). Clearly, hormones alter brain development:
a male brain and a female brain are not the same.
Testosterone’s effects on brain development were once believed
to be unimportant, because this hormone was thought
to primarily influence regions of the brain related to sexual
behavior but not regions of “higher” functions.We now know
that this belief is false. Testosterone changes the structure of
cells in many regions of the cortex, with diverse behavioral
consequences that include influences on cognitive processes.
HOW DOES THE BRAIN DEVELOP AND ADAPT? ! 215
spectacular. Average height and weight became nearly normal,
although head circumference remained below normal.
(Head circumference can be taken as a very rough measure
of brain size.)
Many of the children were now in the normal range of
motor and cognitive development. A significant number,
however, were still considered retarded. Why were there individual
differences in recovery from the past deprivation?
The key factor in predicting recovery was age at adoption.
Those children adopted before 6 months of age did
significantly better than those adopted later. In a Canadian
study by Elenor Ames (1997), Romanian orphans who were
adopted before 4 months of age had an average Stanford-Binet
IQ of 98 when tested at 41/2 years of age. In comparison, agematched
Canadian controls had an average IQ of 109. Findings
from brain-imaging studies showed the Romanian children
adopted at an older age to have smaller-than-normal brains.
Although there are no formal studies of large groups of
these children as they approached adolescence, anecdotal
reports of individual children who were adopted at an older
age indicate continuing problems in adolescence. Some of
these youngsters confronted significant learning disabilities
in school, suffered from hyperactivity, and did not develop
normal patterns of social interaction.
The inescapable conclusion emerging from the Romanian
orphanage experience is that the human brain may be
able to recover from a brief period of extreme deprivation in
early infancy, but periods longer than 6 months produce significant
abnormalities in brain development that cannot be
overcome completely. This conclusion is supported by the
case study of an American girl named Genie, who experienced
severe social and experiential deprivation as well as
chronic malnutrition at the hands of her psychotic father (see
Curtis, 1978). She was discovered at the age of 13, after
spending much of her life in a closed room, during which
time she was punished for making any noise. After her rescue,
she, too, showed rapid growth and cognitive development,
although her language development remained severely
retarded.
To summarize, studies of the Romanian orphans, of
orphans from other highly impoverished settings, and of
cases such as that of Genie make it clear that the developing
brain requires stimulation for normal development. Although
the brain may be able to catch up after a short period
of deprivation, more than a few months of severe deprivation
results in a smaller-than-normal brain and associated
behavioral abnormalities, especially in cognitive and social
skills.
Figure 6-26
Sex Differences in Brain Volume
Cerebral areas related to sex differences
in the distribution of estrogen (blue)
and androgen (pink) receptors in the
developing brain correspond to areas of
relatively larger cerebral volumes in
adult women and men. After Goldstein
et al., 2001.
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Consider the example described earlier in Experiment 6-1. Jocelyn Bachevalier
trained infant male and female monkeys in the concurrent-discrimination task, in
which the subject has to learn which of two objects in a series of object pairs conceals
a food reward. In addition, Bachevalier trained the animals in another task, known as
object-reversal learning. The task is to learn that one particular object always conceals
a food reward, whereas another object never does. After this pattern has been learned,
the reward contingencies are reversed so that the particular object that has always been
rewarded is now never rewarded, whereas the formerly unrewarded object now conceals
the reward. When this new pattern has been learned, the contingencies are reversed
again, and so on, for five reversals.
Bachevalier found that 21/2-month-old male monkeys were superior to female
monkeys on the object-reversal task, but females did better on the concurrent task.Apparently,
the different brain areas required for these two tasks mature at different rates
in male and female monkeys. Bachevalier later tested additional male monkeys whose
testes had been removed at birth and so were no longer exposed to testosterone. These
animals performed like females on the tasks, implying that testosterone was influencing
the rate of brain development in areas related to certain cognitive behaviors.
Bachevalier and her colleague Bill Overman (Overman et al., 1996) then repeated
the experiment, this time using as their subjects children from 15 to 30 months old.
The results were the same: boys were superior at the object-reversal task and girls were
superior at the concurrent task. There were no such male–female differences in performance
among older children (32–55 months of age). Presumably, by this older age,
the brain regions required for each task had matured in both boys and girls. At the earlier
age, however, gonadal hormones seemed to be influencing the rate of maturation
in certain regions of the brain, just as they had in the baby monkeys.
Although the biggest effects of gonadal hormones may be during early development,
their role is by no means finished in infancy. Gonadal hormones (including both
testosterone and estrogen, which is produced in large quantities by the ovaries in females)
continue to influence the structure of the brain throughout an animal’s life. In
fact, removal of the ovaries in middle-aged laboratory rats leads to marked growth of
dendrites and the production of more glial cells in the cortex. This finding of widespread
neural change in the cortex associated with loss of estrogen has implications for
the treatment of postmenopausal women.
Gonadal hormones also affect how the brain responds to events in the environment.
For instance, among rats housed in complex environments, males show more
dendritic growth in neurons of the visual cortex than do females (see Juraska, 1990).
In contrast, females housed in this setting show more dendritic growth in the hippocampus
than do males. Apparently, the same experience can affect the male and female
brain differently owing to the mediating influence of gonadal hormones.
This finding means that, as females and males develop, their brains continue to become
more and more different from each other, much like coming to a fork in a road.
Once having chosen to go down one path, your direction of travel is forever changed
as the roads diverge and become increasingly farther apart.
To summarize, gonadal hormones alter the basic development of neurons, shape
the nature of experience-dependent changes in the brain, and influence the structure
of neurons throughout our lifetimes. These neural effects of sex hormones need to be
considered by those who believe that behavioral differences between males and females
are solely the result of environmental experiences.
In part, it is true that environmental factors exert a major influence. But one reason
that they do may be that male and female brains are different to start with, and even the
same events, when experienced by structurally different brains, may lead to different
effects on the brain. In our view, the important task is not to deny the presence of sex
216 ! CHAPTER 6
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differences in brain organization and function, but rather to understand the degree to
which those neurological differences contribute to observed differences in behavior.
Another key question related to hormonal influences on brain development is
whether there might be sex differences in brain organization that are independent of hormonal
action. In other words, are differences in the action of sex-chromosome genes unrelated
to sex hormones? Although little is known about such genetic effects in humans,
the results of recent studies in birds make it clear that genetic effects on brain cells may indeed
contribute to sex differentiation. See “Hormones and the Range of a Behavior.”
Injury and Brain Development
If the brain is damaged in the course of development, is it irrevocably altered? In the
1930s, Donald Hebb studied children with major birth-related injuries to the frontal
lobes and found that such children had severe and permanent behavioral abnormalities
in adulthood.He concluded that severe brain damage early in life can alter the subsequent
development of the rest of the brain, leading to chronic behavioral disorders.
To what extent have other studies confirmed Hebb’s conclusion? There are few
anatomical studies of humans with early brain injuries, but we can make some general
predictions from the study of laboratory animals. In general, early brain injuries do
produce abnormal brains, especially at certain critical periods in development.
HOW DOES THE BRAIN DEVELOP AND ADAPT? ! 217
Hormones and the Range of a Behavior
Focus on New Research
Songbirds such as finches have an especially
interesting brain dimorphism (two different
forms) related to singing. Males sing
and females do not. This behavioral sex difference
is directly related to a neural birdsong
circuit that is present in males but not
in females.
Robert Agate and his colleagues (2003)
studied the brain of a rare strain of zebra
finch, a gynandromorph that exhibits physical
characteristics of both sexes, as shown
in the accompanying photograph. Genetic
analysis shows that cells on one half of
the brain and body are genetically female
and cells on the other half are genetically
male.
Because both sides of the bird body and brain were exposed
to the same hormones in the bloodstream during prenatal
development, the effect of male and female genes on
the birdsong circuit can be examined to determine how the
genes and hormones might interact. Two hypotheses
result:
1. If the sex difference in the birdsong circuit
were totally related to the presence
of hormones prenatally, then both sides of
the brain should be equally masculine or
feminine.
2. If the genetic sex of the cells were important
to sexual differentiation, then the two
sides of the brain would be different. In
this case, the normal role of the hormone
might be to enhance the genetic effect
rather than to produce the sex difference.
Agate’s results confirm the second hypothesis:
the neural song circuit was masculine on the male
side of the brain. Such a structural difference could be explained
only by a genetic difference in the brain that was at
least partly independent of the effects of the hormones.
This zebra finch is a rare
gynandromph, as can be seen
by the female plumage on one
side of the body and the male
pllumage on the other side.
Robert Agate
For more information on the role
hormones play in brain development
and cognitive functioning, visit the
Chapter 6 Web links on the Brain and
Behavior Web site (www.worth
publishers.com/kolb).
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For humans, the worst time appears to be in the last
half of the intrauterine period and the first couple of
months after birth. Rats that suffer injuries at a comparable
time have significantly smaller brains than normal, and
their cortical neurons show a generalized atrophy relative
to normal brains, as illustrated in Figure 6-27. Behaviorally,
these animals appear cognitively retarded, deficient
in a wide range of skills.
The effect of injury to the developing brain is not always
devastating, however. For example, researchers have
known for more than 100 years that children with brain
injuries in the first couple of years after birth almost never
have the severe language disturbances common to adults
with equivalent injuries. Animal studies help explain why.
Whereas damage to the rat brain in the developmental
period comparable to the last few months of gestation
in humans produces widespread cortical atrophy, damage at a time in the development
of the rat brain that is roughly comparable to age 6 months to 2 years in humans actually
produces more dendritic development in rats, as seen on the right in Figure 6-27.
Furthermore, these animals show dramatic recovery of functions, implying that the
brain has a capacity during development to compensate for injury.
Drugs and Brain Development
The U.S. National Institute on Drug Abuse (NIDA) estimates that about 25 percent of
all live births in the United States today are exposed to nicotine in utero. Similar statistics
on alcohol consumption by pregnant mothers are not available, but the effects of alcohol
consumption in the etiology of fetal alcohol effects are well documented, as detailed in
Chapter 7.
NIDA also estimates that 5.5 percent of all expectant mothers, approximately
221,000 pregnant women each year in the United States, use an illicit drug at least once
in the course of their pregnancies.And what about caffeine? More than likely most children
were exposed to caffeine (from coffee, tea, cola drinks, and chocolate) in utero.
The precise effects of drug intake on brain development are poorly understood,
but the overall conclusion from current knowledge is that children with prenatal exposure
to a variety of psychoactive drugs have an increased likelihood of later drug use
(Malanga & Kosofsky, 2003). Many experts suggest that, although, again, poorly studied,
childhood disorders such as learning disabilities and hyperactivity may be related
to prenatal exposure to drugs such as nicotine or caffeine or both.Malanga and Kosofsky
note poignantly that “society at large does not yet fully appreciate the impact that
prenatal drug exposure can have on the lives of its children.”
Other Kinds of Abnormal Brain Development
The nervous system need not be damaged by external forces to develop abnormally.
For instance, many genetic abnormalities are believed to result in abnormalities in the
development and, ultimately, the structure of the brain. Spina bifida, a condition in
which the genetic blueprint goes awry and the neural tube does not close completely,
leads to an incompletely formed spinal cord. After birth, children with spina bifida
usually have serious motor problems because of this spinal-cord abnormality.
Imagine what would happen if some genetic abnormality caused the front end of
the neural tube not to close properly. Because the front end of the neural tube forms
218 ! CHAPTER 6
Cortical neuron
in adult
Frontal-cortex
injury
Damage on day 1 Damage on day 10
Figure 6-27
Time-Dependent Effects
In the rat, damage to the
frontal cortex on the day
of birth leads to the
development of cortical
neurons with simple
dendritic fields and a
sparse growth of spines in
the adult (left). In contrast,
damage to the frontal
cortex at 10 days of age
leads to the development
of cortical neurons with
expanded dendritic fields
and denser spines than
normal in adults (right).
Adapted from “Possible
Anatomical Basis of Recovery of
Function After Neonatal Frontal
Lesions in Rats,” by B. Kolb and
R. Gibb, 1993, Behavioral
Neuroscience, 107, p. 808.
Visit the Brain and Behavior Web site
(www.worthpublishers.com/kolb)
and go to the Chapter 6 Web links to learn
more about abnormal brain development.
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the brain, this failure would result in gross abnormalities in brain development. Such
a condition exists and is known as anencephaly. Infants affected by this condition die
soon after birth.
Abnormal brain development can be much subtler than anencephaly. For example,
if cells do not migrate to their correct locations and these mispositioned cells do
not subsequently die, they can disrupt brain function and may lead to disorders ranging
from seizures to schizophrenia. In a variety of conditions, neurons fail to differentiate
normally. In certain cases, the neurons fail to produce long dendrites or spines. As
a result, connectivity in the brain is abnormal, leading to mental retardation.
The opposite condition also is possible: neurons continue to make dendrites and
form connections with other cells to the point at which these neurons become extraordinarily
large. The functional consequences of all the newly formed connections
can be devastating. Excitatory synapses in the wrong location effectively short-circuit
a neuron’s function.
A curious consequence of abnormal brain development is that behavioral effects
may emerge only as the brain matures and the maturing regions begin to play a greater
role in behavior. This consequence is especially true of frontal-lobe injuries. The frontal
lobes continue to develop into early adulthood, and
often not until adolescence do the effects of frontal-lobe
abnormalities begin to be noticed.
Schizophrenia is a disease characterized by its slow
development, usually not becoming obvious until late
adolescence. As detailed in Chaper 15, the schizophrenic
brain has many abnormalities, some of which are in the
frontal lobes. “Schizophrenia” on page 220 relates the
progress and possible origin of the disease.
Mental Retardation
Mental retardation, or developmental disability, refers to
impairment in cognitive functioning that accompanies
abnormal brain development. Impairment may range
in severity from mild, allowing an almost normal life
style, to severe, requiring constant care. As summarized
in Table 6-4, mental retardation can result from chronic
malnutrition, genetic abnormalities such as Down’s syndrome,
hormonal abnormalities, brain injury, or neurological
disease. Different causes produce different abnormalities in brain
organization, but the critical similarity across all types of retardation is
that the brain is not normal.
A study by Dominique Purpura (1974) is one of the few systematic investigations
of the brains of developmentally disabled children. Purpura
used Golgi stain to examine the neurons of children who had died from accident
or disease unrelated to the nervous system.When he examined the
brains of children with various forms of retardation, he found that dendrite
growth was stunted and the spines were very sparse relative to dendrites
from children of normal intelligence, as illustrated in Figure 6-28.
The simpler structure of these neurons is probably indicative of a
marked reduction in the number of connections in the brain, which presumably
caused the developmental disability. Variation in both the nature
and the extent of neuronal abnormality in different children would
lead to different behavioral syndromes.
HOW DOES THE BRAIN DEVELOP AND ADAPT? ! 219
Anencephaly. Failure of the forebrain to
develop.
Causes of Mental Retardation
Cause Example mechanism Example condition
Phenylketonuria (PKU)
Down syndrome
Fetal alcohol syndrome
Rubella (also called
German measles)
Retardation
Cerebral palsy
Kwashiorkor
Children in Romanian
orphanages
Error of metabolism
Chromosomal
abnormality
Exposure to a toxin
Infection
Anoxia (oxygen
deprivation)
Abnormal brain
development
Sensory deprivation
Genetic abnormality
Abnormal embryonic
development
Prenatal disease
Birth trauma
Malnutrition
Environmental
abnormality
Table 6-4
Retarded
child
Normal
child
Figure 6-28
Neural Contrast
Representative dendritic
branches from cortical neurons
in a child of normal intelligence
(left) and a developmentally
disabled child (right), whose
neurons are smaller and have
far fewer spines. Adapted from
“Dendritic Spine ‘Dysgenesis’ and
Mental Retardation,” by D. P.
Purpura, 1974, Science, 186, p. 1127
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220 ! CHAPTER 6
Schizophrenia
Focus on Disorders
When Mrs. T. was 16 years old, she began to experience
her first symptom of schizophrenia: a profound
feeling that people were staring at her. These bouts
of self-consciousness soon forced her to end her
public piano performances. Her self-consciousness
led to withdrawal, then to fearful delusions that
others were speaking about her behind her back,
and finally to suspicions that they were plotting to
harm her. At first Mrs. T.’s illness was intermittent,
and the return of her intelligence, warmth, and ambition
between episodes allowed her to complete
several years of college, to marry, and to rear three
children. She had to enter a hospital for the first time
at age 28, after the birth of her third child, when she
began to hallucinate.
Now, at 45, Mrs. T. is never entirely well. She has
seen dinosaurs on the street and live animals in her refrigerator.
While hallucinating, she speaks and writes
in an incoherent, but almost poetic way. At other
times, she is more lucid, but even then the voices she
hears sometimes lead her to do dangerous things,
such as driving very fast down the highway in the middle
of the night, dressed only in a nightgown. . . . At
other times and without any apparent stimulus, Mrs.
T. has bizarre visual hallucinations. For example, she
saw cherubs in the grocery store. These experiences
leave her preoccupied, confused, and frightened, unable
to perform such everyday tasks as cooking or
playing the piano. (Gershon & Rieder, 1992, p. 127)
It has always been easier to identify schizophrenic behavior
than to define what schizophrenia is. Perhaps the one
universally accepted criterion for its diagnosis is the absence
of other neurological disturbances or affective (mood) disorders
that could cause a person to lose touch with reality—a
definition by default. Some textbooks emphasize bizarre hallucinations
and disturbances of thought, much like those displayed
by Mrs. T. However,the symptoms of schizophrenia
are heterogeneous, suggesting that the biological abnormalities
vary from person to person.
In 1913, Emil Kraepelin first proposed that schizophrenia
follows a progressively deteriorating course with a dismal
final outcome. This opinion was dominant throughout
most of the twentieth century. Today, a consensus is emerging
that Kraepelin’s view is probably incorrect. Most patients
appear to stay at a fairly stable level after the first few years
HOW DO ANY OF US DEVELOP A NORMAL BRAIN?
When we consider the complexity of the brain, the less-than-precise process of brain
development, and the number of factors that can influence it, we are left marveling at
how so many of us end up with brains that pass for normal. After all, we must all have
In Review .
The brain is especially plastic during its development and can therefore be molded by experience
into different forms, at least at the microscopic level. Not only is the brain plastic
in response to external events, it may be changed as well by internal events, including
the effects of hormones, injury, abnormal genes and drugs. The sensitivity of the brain to
experience varies with time. At critical periods in development, specific parts of the brain
are particularly sensitive to experience and environment. If experiences are abnormal,
then the brain’s development is abnormal, possibly leading to such disorders as schizophrenia
or various degrees of developmental disability.
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HOW DOES THE BRAIN DEVELOP AND ADAPT? ! 221
of displaying schizophrenic symptoms, with little evidence
of a decline in neuropsychological functioning. The symptoms
come and go, much as for Mrs. T., but the severity is
relatively constant after the first few episodes.
Numerous studies have investigated the brains of schizophrenia
patients, both in autopsies and in MRI and CT scans.
Although the results vary, most neuroscientists agree that the
brains of people who develop schizophrenia are lighter in
weight than normal and have enlarged ventricles. Research
findings also suggest that schizophrenic brains have smaller
frontal lobes (or at least a reduction in the number of neurons
in the prefrontal cortex) and thinner parahippocampal gyri.
One of the most interesting discoveries is that of Joyce
Kovelman and Arnold Scheibel (1984), who found abnormalities
in the orientation of neurons in the hippocampi of schizophrenics.
Rather than the consistently parallel orientation of
neurons in this region characteristic of normal brains, the
schizophrenic brains have a more haphazard organization, as
shown in the accompanying drawing.
Evidence is increasing that the abnormalities observed
in schizophrenic brains are associated with disturbances
of brain development. William Bunney and his colleagues
(1997) suggested that at least a subgroup of schizophrenia sufferers
experience either environmental insults or some type of
abnormal gene activity in the fourth to sixth month of fetal development.
These events are thought to result in abnormal
cortical development, particularly in the frontal lobes. Later in
adolescence, as the frontal lobes approach maturity, the person
begins to experience symptoms deriving from this abnormal
prenatal development.
Examples from the hippocampus of pyramidal-cell orientation in (A) a normal brain and (B) a
schizophrenic brain, where the orientations of these pyramidal neurons are highly disorganized. (Adapted
from “A Neurohistologic Correlate of Schizophrenia” by J. A. Kovelman and A. B. Scheibel, 1984, Biological Psychiatry, 19, p. 1613.)
Hippocampus
Organized (normal) pyramidal neurons
(A)
Disorganized (schizophrenic) pyramidal neurons
(B)
had neurons that migrated to wrong locations, made incorrect connections, and were
exposed to viruses or other harmful substances. If the brain were as fragile as it might
seem, to end up with a normal brain would be almost impossible.
Apparently, animals have evolved a substantial capacity to repair minor abnormalities
in brain development. Most people have developed in the range that we
call “normal” because the human brain’s plasticity and regenerative powers overcome
minor developmental deviations. Recall that one stage in brain development
consists of cell death and synaptic pruning. By initially overproducing neurons
and synapses, the brain has the capacity to correct any errors that might have arisen
accidentally.
These same plastic properties of the brain later allow us to cope with the ravages
of aging. Neurons are dying throughout our lifetimes and, by age 50, we ought to be
able to see significant effects of all of this cell loss, especially considering the cumulative
results of exposure to environmental toxins, drugs, closed head injuries, and so on.
But this is not what happens. Although teenagers may not believe it, very few 50-yearolds
are demented. By most criteria, the 50-year-old who has been intellectually active
throughout adulthood is likely to be much wiser than the 18-year-old whose brain has
lost relatively few neurons.
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Clearly, we must have some mechanism to compensate for loss and minor injury
to our brain cells. This capacity for plasticity and change, for learning and adapting, is
a most important characteristic of the human brain during development and throughout
life.We return to learning and memory in Chapter 13.
SUMMARY
What are the stages of neural development? Human brain maturation is a long process,
lasting well into the 20s. Neurons, the units of brain function, develop a phenotype,
migrate, and, as their processes elaborate, establish connections with other neurons even
before birth. The developing brain produces many more neurons and connections than
it needs and then prunes back in toddlerhood and again in adolescence to a stable adult
level maintained by some neurogenesis throughout the life span.
How does behavior develop? Throughout the world, across the cultural spectrum, from
newborn to child to adolescent and through adulthood, we develop through similar behavioral
stages. As infants develop physically, motor behaviors emerge in a predictable
sequence from gross, poorly directed movements toward objects to controlled pincer
grasps to pick up objects as small as pencils by about 11 months. Cognitive behaviors
also develop through a series of testable stages of logic and problem solving. Researchers
such as Jean Piaget have identified and characterized four or more distinct stages of cognitive
development, each of which can be identified by special behavioral tests.
How do behavioral and neural maturation relate to one another? Behaviors emerge as
the neural systems that produce them develop. Cognitive behavior follows a similar developmental
sequence from the rudimentary to the complex. The hierarchical relation
between brain structure and function can be inferred by matching the median developmental
timetables of neurodevelopment with observed behavior. Motor behaviors
emerge in synchrony with the maturation of motor circuits in the cerebral cortex, basal
ganglia, and cerebellum, as well as in the connections from these areas to the spinal
cord. Similar correlations between emerging behaviors and neuronal development can
be seen in the maturation of cognitive behavior, as circuits in the frontal and temporal
lobes mature in early adulthood.
What factors influence neural maturation and plasticity? The brain is most plastic
during its development, and the structure of neurons and their connections can be
molded by various factors throughout development. The brain’s sensitivity to factors
such as external events, quality of environment, drugs, gonadal hormones, and injury,
varies over time: at critical periods in the course of development, different brain regions
are particularly sensitive to different events.
How sensitive is the developing brain to injury? Perturbations of the brain in the
course of development from, say, anoxia, trauma, or toxins can significantly alter brain
development and result in severe behavioral abnormalities including retardation and
cerebral palsy. The brain does have a substantial capacity to repair or correct minor abnormalities,
however, allowing most people to develop normal behavioral repertoires
and to maintain brain function throughout life.
KEY TERMS
amblyopia, p. 210
anencephaly, p. 219
apoptosis, p. 200
cell-adhesion molecule
(CAM), p. 199
chemoaffinity hypothesis,
p. 210
critical period, p. 212
filopod, p. 199
glioblast, p. 194
growth cone, p. 199
growth spurt, p. 206
imprinting, p. 212
masculinization, p. 214
netrin, p. 199
222 ! CHAPTER 6
neuroscience interact ive
Many resources are available for
expanding your learning online:
www.worthpublishers.com/kolb
Try the Chapter 6 quizzes and
flashcards to test your mastery of the
chapter material. You’ll also be able to
link to other sites that will reinforce
what you’ve learned.
www.embryo.soad.umich.edu
Link here to see a remarkable collection
of human embryos through magnetic
resonance microscopy.
www.nads.org
Investigate current research about
Down’s syndrome at the National
Association for Down’s Syndrome.
www.ucpa.org
Learn more about cerebral palsy at the
home page of United Cerebral Palsy.
On your Foundations CD-ROM, you
can visit the module on Neural
Communication for an important
review on the neural structure.
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HOW DOES THE BRAIN DEVELOP AND ADAPT? ! 223
REVIEW QUESTIONS
1. Describe the gross development of the nervous system. Summarize and explain
the steps in brain development.
2. What roles do neurochemicals, genetics, and experience play in development?
3. How does behavioral development relate to neural development?
4. How does experience affect brain development?
FOR FURTHER THOUGHT
1. Experience plays an important role in brain development. How might
interaction between sex and environment account for the broad spectrum of
sexual identity in adulthood?
2. How can the principles of behavioral neurodevelopment help to explain why
each brain is unique?
RECOMMENDED READING
Edelman,G.M. (1987).Neural Darwinism: The theory of neuronal group selection. New York:
Basic Books. Edelman applies the Darwinian concept of survival of the fittest to the nervous
system’s shedding of neurons in the course of development and throughout a person’s
lifetime.Although not universally accepted, the ideas in the book are amusing to read.
Greenough,W. T., & Chang, F. F. (1988). Plasticity of synapse structure and pattern in the
cerebral cortex. In A. Peters and E. G. Jones (Eds.), Cerebral cortex: Vol. 7. Development
and maturation of the cerebral cortex (pp. 391–440). New York: Plenum. Greenough is
one of the world leaders in the study of experience-dependent change in the nervous
system. This chapter not only provides a nice historical review, but also lays out seminal
ideas on the developmental plasticity of the nervous system.
Hebb, D. O. (1949). The organization of behavior. New York:Wiley. Although 1949 may
seem like a long time ago for a book to be still relevant today, Hebb’s book may be the
most important single volume on brain and behavior. It was the first serious attempt to
outline a neuropsychological theory of how the brain could produce behavior and,
especially, thought. Development is an important theme in the book because Hebb
believed that experience plays an essential role in developing the cognitive and neural
structures necessary for adulthood. This book is mandatory reading for any student
going on to graduate school in behavioral neuroscience.
Meany,M. J. (2001).Maternal care, gene expression, and the transmission of individual
differences in stress reactivity across generations.Annual Review of Neuroscience, 24,
1161–1192.Meany is a leading researcher on the role of maternal behavior in brain and
behavioral development. This review brings together a wide range of findings showing
how the effects of experience can cross generations through alterations in gene expression.
Michel, G. F., & Moore, C. L. (1995).Developmental psychobiology. Cambridge, MA: MIT
Press. Most neural development books are thin on behavioral development, but this
book strikes a nice balance in its analysis of both brain and behavioral development.
Purves, D., & Lichtman, J.W. (1985). Principles of neural development. Sunderland, MA:
Sinauer. Although not primarily about the development of the cortex, the book
provides sufficient background to enable a thorough understanding of the principles
that guide nervous system development.
neural Darwinism, p. 200
neural plate, p. 196
neural stem cell, p. 194
neural tube, p. 190
neuroblast, p. 194
neurotrophic factor, p. 195
progenitor (precursor)
cell, p. 194
radial glial cell, p. 197
tropic molecule, p. 199
ventricular zone, p. 194
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Focus on New Research: The Neural Basis of
Drug Cravings
The Domoic Acid Mystery
Principles of Psychoparmacology
Drug Routes into the Nervous System
Individual Differences in Response to
Psychoactive Drugs
Drug Action at Synapses: Agonists and Antagonists
An Acetylcholine Synapse: Examples of Drug Action
Classification of Psychoactive Drugs
Antianxiety Agents and Sedative Hypnotics
Focus on Disorders: Fetal Alcohol Syndrome
Antipsychotic Agents
Antidepressants
Focus on Disorders: Major Depression
Narcotic Analgesics
Stimulants
Drugs, Experience, Context,
and Genes
Tolerance
Sensitization
Addiction and Dependence
Explaining Drug Abuse
Behavior on Drugs
Why Doesn’t Everyone Abuse Drugs?
Can Drugs Cause Brain Damage?
Focus on Disorders: Drug-Induced Psychosis
Hormones
Hierarchical Control of Hormones
Homeostatic Hormones
Gonadal Hormones
Stress Hormones
Ending a Stress Response
224 !
C H A P T E R7
How Do Drugs and Hormones
Influence the Brain and Behavior?
Left: Dr. Dennis Kunkel/Phototake. Middle: Edward Holub/Corbis.
Right: Pascal Goetgheluck/Photo Researchers, Inc.
CH07.qxd 1/28/05 10:16 AM Page 224

Paul Phillips and his colleagues (2003) examined
whether the cues that signal a cocaine reward to cocaineaddicted
rats can produce a release of DA from dopamine
terminals in the nucleus accumbens and whether such release
is related to drug-seeking behavior. The rats learned
that, when a light flashed, they could press a bar to activate
an indwelling cannula and receive an injection of cocaine.
Thus, the light was the cue.
The experimenters implanted into the rats’ nucleus accumbens
a carbon-fiber microelectrode that chemically reacts
with DA to produce an electrical signal if DA levels
increase. They found that the light cue produced a brief DA
release in drug-addicted rats but not in control rats. In association
with the DA release, the rat addicts approached
the bar and pressed it to receive a cocaine injection.
Electrical stimulation of the VTA produced the same
brief release in the addicted rats and was followed by cocaine
seeking behavior as well. These results suggest that
learned associations to drug-related cues actually empower
those cues alone to activate DA release in the VTA and that
this release is associated with drug-seeking behavior. Thus,
the release of DA in the VTA, which is normally associated
with natural interest in food, sexual activity, or other rewarding
stimuli, may also be the neural corollary of behaviors
related to drug craving.
This poses a major difficulty in developing treatments
for addiction: that natural rewards and addiction are dependent
on the same neurons. The same brain events that
cue drug craving, including DA release in the nucleus
accumbens, are associated with many everyday stimuli,
including aversive, novel, and intense stimuli, and even
actions that result in monetary rewards (Zink, Pagnoni,
Martin-Skurski, Chappelow, & Berns, 2004). For this reason,
addictions are extremely difficult to treat. Attempts
range from counseling to therapy with drugs, from cognitive-
behavior therapy, remarkably, even to psychosurgery
in which the nucleus accumbens is destroyed by a
lesion.
Even when treatment is successful, a person may never
really be free from drug cravings. Nevertheless, understanding
the neural changes associated with the acquisition
of an addiction holds great promise for the development of
effective therapies.
The Neural Basis of Drug Cravings
Focus on New Research
E xposure to drug paraphernalia and other prominent
drug-related cues induce intense craving in addicts
and thereby influence drug taking. What is the neural basis
of this craving? Where in the brain does it take place? Can
craving be prevented or reversed? The answers may be
found in the brain’s mesolimbic dopamine system.
Mesolimbic dopamine (DA) neurons are located in the
medial part of the midbrain called the ventral tegmental
area (VTA), and the axons of these neurons project to a part
of the basal ganglia called the nucleus accumbens, as
shown in Figure 7-1. Several lines of evidence associate
the nucleus accumbens with addictive behavior. If rewarding
stimuli are presented to a rat, as many as 80% of
the neurons in the VTA discharge, and DA is released from
their synapses in the nucleus accumbens. The use of
probes in the nucleus accumbens that measure DA level
reveals that the neuronal discharge is associated with a
brief DA surge.
The injection of DA into the nucleus accumbens of rats
through a small cannula appears to be rewarding because
these rats will push a bar to receive the injection. They will
also push a bar to receive electrical stimulation of the VTA,
which also excites dopamine neurons to release DA into
the nucleus accumbens. Many addictive drugs likewise
increase DA release or potentiate its action in the nucleus
accumbens.
Figure 7-1
Mesolimbic Dopamine Pathways Axons of neurons in the
midbrain ventral tegmental area project to the nucleus
accumbens, frontal cortex, and hippocampus.
Frontal
cortex
Ventral
tegmental
area of midbrain
Hippocampus
(part of limbic
system)
Nucleus
accumbens of
basal ganglia
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Psychopharmacology is the study of how drugs affect the nervous system and
behavior. In this chapter, we group various drugs by their major behavioral effects.
You will learn that the effects of drugs depend on how they are taken, in
what quantities, and under what circumstances.
We begin by looking at the major ways that drugs are administered, what routes
they take to reach the central nervous system, and how they are eliminated from the
body. We consider how drugs act on neurons and why different people may respond
differently to the same dose of a drug. Many principles related to drugs also apply to
the action of hormones, the chapter’s final topic.
Before we examine how drugs produce their effects on the brain for good or for
ill, we must raise a caution: the sheer number of neurotransmitters, receptors, and possible
sites of drug action is astounding. Psychopharmacology research has made important
advances on some principles of drug action, but neuroscientists do not know
everything there is to know about any drug. To illustrate, consider some unexpected effects
produced by a drug long considered safe.
THE DOMOIC ACID MYSTERY
Japanese and Chinese fishermen discovered long ago that seaweed can be used as a
medicine. They may have observed that flies die after alighting on seaweed washed up
on the shore, and so they tried rubbing seaweed onto their skin as an insect repellent.
It worked. They also found that, when eaten, seaweed kills intestinal worms, and so
they used seaweed extracts to get rid of worms in children.
These folk remedies led scientists to analyze the chemical composition of the seaweed
Chondria armata. They identified two chemically similar insecticidal compounds
in it: domoic acid and kainic acid. Purified doses of these acids were given to large
numbers of children as a treatment for worms,with no reported side effects. Physicians
therefore concluded that these substances were nontoxic to humans. Unfortunately,
they were wrong.
On November 22, 1987, two people in Moncton, New Brunswick, Canada, were
hospitalized after suffering from gastroenteritis and mental confusion. Soon more reports
of the illness came from Quebec, and, by December 9, five people had died. In
all, more than 200 cases of this mysterious disorder were reported.
The severity of symptoms varied greatly, but the worst cases included marked confusion
and memory loss. For some who survived, memory impairment was permanent.
Autopsies revealed extensive cell loss in the hippocampus, in the amygdala and
surrounding cortex, and in the thalamus (Hynie & Todd, 1990).
The only experience common to the victims was that all had eaten mussels. To find
out whether the mussels were the source of the illness, scientists injected mussel extracts
into mice. Soon after, the mice started scratching behind one ear and then convulsed
and died. Apparently, these mussels did contain a toxin, but the curious scratching behavior
indicated that the toxin was unlike any other known shellfish poison.
Chemical analysis of the mussels showed that they contained high levels of domoic
acid. Investigators were surprised.How did the mussels become contaminated with domoic
acid, and why was it suddenly acting like a poison?
To answer the first question, the investigators traced the source of the mussels to
two Prince Edward Island cultured-mussel farms. Cultured-mussel farming began in
1975 and by the 1980s had grown into a large, successful industry, producing as much
as 3.2 million pounds of mussels annually. Mussel farmers release mussel sperm and
eggs into the water, where the resulting zygotes attach themselves to long ropes suspended
there. The mussels feed by siphoning from 2 to 6 liters of water per hour to extract
small sea organisms called phytoplankton.
226 ! CHAPTER 7
Psychopharmacology. Study of how
drugs affect the nervous system and
behavior.
Psychoactive drug. Substance that acts
to alter mood, thought, or behavior and is
used to manage neuropsychological
illness.
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More than 90 percent of the phytoplankton that the Prince Edward Island mussels
consumed were single-cell diatoms called Nitzschia pungens. When analyzed, the diatoms
were found to contain domoic acid. Because there had been no evidence of domoic
acid in diatoms before 1987, a search for the origins of the contamination began.
Apparently, a drought in 1987 produced a buildup of domoic acid–containing seaweed
in the streams and along the shoreline. By feeding on seaweed, the diatoms had accumulated
large quantities of domoic acid, which was then passed up the food chain to
the mussels as they fed on the diatoms.
But the discovery that domoic acid was the toxic agent in this episode only partly
solved the mystery. Remember that domoic acid had been thought harmless. It had
been widely used to rid children of worms. How had it now resulted in sickness, brain
damage, and death? And why were only some people affected? Surely, more than 200
people had eaten the contaminated mussels. In the following sections, where domoic
acid poisoning is used to illustrate some of the principles of drug action, you will find
the answers to these questions. In addition, you will learn how the domoic acid story
has led to other insights into brain function.
PRINCIPLES OF PSYCHOPHARMACOLOGY
Drugs are chemical compounds administered to bring about some desired change in
the body. Drugs are usually used to diagnose, treat, or prevent illness, to relieve pain
and suffering, or to improve some adverse physiological condition. In this chapter, we
focus on psychoactive drugs—substances that act to alter mood, thought, or behavior
and are used to manage neuropsychological illness.
Many psychoactive drugs are taken for nonmedical reasons or recreationally, by some
to the point that they become substances of abuse. Such drug taking impairs the user’s
functioning, promotes craving, and may produce addiction. Like domoic acid, some psychoactive
drugs can also act as toxins, producing sickness, brain damage, or death.
Drug Routes into the Nervous System
To be effective, a psychoactive drug has to reach its nervous system target. The way that
a drug enters and passes through the body to reach that target is called its route of
administration. Many drugs are administered orally because oral administration is a natural
and safe way to consume a substance. Drugs can
also be inhaled into the lungs, administered through rectal
suppositories, absorbed from patches applied to the
skin, or injected into the bloodstream, into a muscle, or
even into the brain.
Figure 7-2 illustrates the various routes of drug administration.
These different routes pose different barriers
between the drug and its target. Taking a drug by
mouth is easy and convenient, but not all drugs can pass
the barriers of the digestive-tract contents and walls.
Generally, there are fewer barriers between a drug and its
target if the drug is inhaled rather than swallowed.Drugs
that are administered as gases or aerosols penetrate the
cell linings of the respiratory tract easily and are absorbed
across these membranes into the bloodstream nearly as
quickly as they are inhaled. Presumably such drugs of
abuse as nicotine, cocaine, and marijuana, when administered
as a gas or smoke, are absorbed in a similar way.
HOW DO DRUGS AND HORMONES INFLUENCE THE BRAIN AND BEHAVIOR? ! 227
Diatoms, in a variety of shapes, form the
very base of the food chain. Nitzschia
pungens, the circular organisms in this
photograph, are ubiquitous in the ocean
and are frequently present in great
numbers in fresh water.
Taking drugs orally
is the safest,
easiest, and most
convenient way to
administer them.
Drugs that are weak
acids pass from the
stomach into the
bloodstream.
Drugs that are
weak bases pass
from the intestines
to the bloodstream.
Injecting a drug directly
into the brain allows it to
act quickly in low doses
because there are no
barriers.
Drugs inhaled into the
lungs encounter few
barriers en route to
the brain.
Drugs injected into
muscle encounter
more barriers than do
drugs inhaled.
Drugs injected into the
bloodstream encounter
the fewest barriers to
the brain but must be
hydrophilic.
Drugs contained in
adhesive patches are
absorbed through
the skin and into the
bloodstream.
Figure 7-2
Routes of Drug Administration
Philip Sze/Visuals Unlimited
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Our largest organ, the skin, has three layers of cells and is designed to be a protective
body coat. Some small-molecule drugs (e.g., nicotine) penetrate the skin’s barrier
almost as easily as they penetrate the cell lining of the respiratory tract, whereas largemolecule
drugs do not. There are still fewer obstacles if a drug is injected directly into
the blood. The fewest obstacles are encountered if a psychoactive drug is injected directly
into the brain.
Figure 7-2 also summarizes the characteristics of drugs that allow them to pass
through various barriers to reach their targets. Let us look more closely at the barriers
that a drug taken orally must pass to get to the brain. Oral administration is the most
complex route. To reach the bloodstream, an ingested drug must first be absorbed
through the lining of the stomach or small intestine. If the drug is liquid, it is absorbed
more readily. Drugs taken in solid form are not absorbed unless they can be dissolved
by the stomach’s gastric juices.
In either form, liquid or solid, absorption is affected by the physical and chemical
properties of the drug, as well as by the presence of other stomach or intestinal contents.
In general, if a drug is a weak acid, such as alcohol, it is readily absorbed across
the stomach lining. If it is a weak base, it cannot be absorbed until it passes through
the stomach and into the intestine—a process that may destroy it.
After it has been absorbed by the stomach or intestine, the drug must next enter
the bloodstream. This part of the journey requires additional properties. Because blood
has a high water concentration, a drug must be hydrophilic to be carried in the blood.
A hydrophobic substance will be blocked from entering the bloodstream. After it is in
the blood, a drug is then diluted by the approximately 6 liters of blood that circulate
through an adult’s body.
To reach its target, a drug must also travel from the blood into the extracellular
fluid, which requires that its molecules be small enough to pass through the pores of
capillaries, the tiny vessels that carry blood to the body’s cells. Even if the drug makes
this passage, it may encounter still other obstacles. For one thing, the sheer volume of
water in the body’s extracellular fluid (roughly 35 liters) will dilute the drug even further.
For another, the drug is at risk of being modified or destroyed by various metabolic
processes taking place in cells.
Considering the many obstacles that psychoactive drugs encounter on their journey
from mouth to brain, it is clear why inhaling a drug or injecting it into the bloodstream
has advantages. These alternative routes of administration bypass the obstacle
of the digestive tract. In fact, with each obstacle eliminated en route to the brain, the
dosage of a drug can be reduced by a factor of 10 without reducing its effects.
For example, 1 milligram (mg), equal to 1000 micrograms (lg), of amphetamine,
a psychomotor stimulant, produces a noticeable behavioral change when ingested
orally. If inhaled into the lungs or injected into the blood, thereby circumventing the
stomach, a dose of just one-tenth of a milligram (100 lg) produces the same results.
Similarly, if amphetamine is injected into the cerebrospinal fluid, thus bypassing both
the stomach and the blood, 10 lg is enough to produce an identical outcome, as is
merely 1 mcg if dilution in the cerebrospinal fluid also is skirted and the drug is injected
directly onto target neurons.
This math is well known to sellers and users of illicit drugs. Drugs that can be prepared
to be inhaled or injected intravenously are much cheaper per dose because the
amount required is so much smaller than that needed for an effective oral dose.
REVISITING THE BLOOD–BRAIN BARRIER
As you know, the passage of drugs across capillaries in the brain is made much more
difficult by the blood–brain barrier, which prevents the passage of most substances. The
brain has a rich capillary network. In fact, none of its neurons is farther than about 50
lm (one-millionth of a meter) away from a capillary.
228 ! CHAPTER 7
For more information on the routes of
drug administration, visit the Chapter 7
Web links on the Brain and Behavior
Web site (www.worthpublishers.
com/kolb).
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Figure 7-3 shows the structure of brain capillaries and why they are impermeable
to many substances. As you can see on the left side of Figure 7-3, like all capillaries,
brain capillaries are composed of a single layer of endothelial cells. In the walls of capillaries
in most parts of the body, endothelial cells are not fused together, and so substances
can pass through the clefts between the cells. In contrast, in the brain (at least
in most parts of it), endothelial cell walls are fused to form “tight junctions,” and so
molecules of most substances cannot squeeze between them.
Figure 7-3 also shows that the endothelial cells of brain capillaries are surrounded
by the end feet of astrocyte glial cells attached to the capillary wall, covering about 80
percent of it. The glial cells provide a route for the exchange of food and waste between
capillaries and the brain’s extracellular fluid and from there to other cells,
shown on the right in Figure 7-3. They may also play a role in maintaining the tight
junctions between endothelial cells and in making capillaries dilate to increase blood
flow to areas of the brain in which neurons are
very active.
You may wonder why endothelial cells form
tight junctions only in most parts of the brain,
not in all of it. Astrocytes attached to the capillaries
appear to be responsible for the tight junctions
formed by the endothelial cells. The cells of
capillary walls in a few brain regions lack tight
junctions, and so these regions, shown in Figure
7-4, lack a blood–brain barrier. One is the pituitary
gland of the hypothalamus. The pituitary is
a source of many hormones that are secreted
into the blood system, and their release is triggered
in part by other hormones carried to the
pituitary by the blood.
The absence of a blood–brain barrier in the
area postrema of the lower brainstem allows toxic
substances in the blood to trigger a vomiting
response. The pineal gland also lacks a blood–
brain barrier, enabling hormones to reach it and
modulate the day–night cycles that this structure
controls.
HOW DO DRUGS AND HORMONES INFLUENCE THE BRAIN AND BEHAVIOR? ! 229
Amino
acids
Astrocyte
feet
Capillaries in the body are
leaky and have few tight
junctions. Materials can move
in and out relatively easily.
Capillaries in the brain are not leaky,
have tight junctions, and are
covered with astrocyte feet. These
properties prevent materials from
moving in and out easily, and are
the basis of the blood–brain barrier.
Certain other
molecules
are carried across
the membrane by
active transport.
Small, uncharged
molecules are able
to pass through
the endothelial
membrane and
reach the brain.
Glucose Fats
CO2
CO2
+ –
Astrocyte feet
Capillary
Tight junction
Transporter
Large and electrically charged molecules
are unable to pass out of Endothelial cells the capillary.
O2
O2
Figure 7-3
Blood–Brain Barrier Capillaries in most
of the body allow for the passage of
substances between capillary cell
membranes, but those in the brain,
stimulated by the actions of astrocytes,
form the tight junctions of the
blood–brain barrier.
Figure 7-4
Barrier-Free Brain Sites The pituitary
gland is a target for many blood-borne
hormones, the pineal gland is a target
for hormones that affect circadian
rhythms, and the area postrema initiates
vomiting in response to noxious
substances.
Pineal gland: Allows entry
of chemicals that affect
day–night cycles.
Pituitary: Allows entry
of chemicals that
influence pituitary
hormones.
Area postrema:
Allows entry of toxic
substances that
induce vomiting.
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To carry out its work, the rest of the brain needs oxygen and glucose for fuel and
amino acids to build proteins, among other substances. These fuel molecules must routinely
travel from the blood to brain cells, just as carbon dioxide and other waste products
must routinely be excreted from brain cells into the blood.Molecules of these vital
substances cross the blood–brain barrier in two ways:
1. Small molecules such as oxygen and carbon dioxide, which are not ionized and so
are fat soluble, can pass right through the endothelial membrane.
2. Molecules of glucose, amino acids, and other food components can be carried across
the membrane by active-transport systems, such as sodium–potassium pumps—
proteins specialized for the transport of a particular substance.
When a substance has passed from the capillaries into the brain’s extracellular fluid, it
can move readily into neurons and glia.
The blood–brain barrier serves a number of purposes. Because the electrical activity
of neurons depends on certain extracellular concentrations of ions, it is important
that ionic substances not cross the blood–brain barrier and upset the brain’s electrical
activity. It is also important that neurochemicals from the rest of the body not pass into
the brain and disrupt the communication between neurons.
In addition, the blood–brain barrier protects the brain from the effects of many
circulating hormones and from various toxic and infectious substances. Injury or disease
can sometimes rupture the blood–brain barrier, letting pathogens through. For
the most part, however, the brain is very well protected from substances potentially
harmful to its functioning.
The blood–brain barrier has special relevance for understanding drug actions on
the nervous system. A drug can reach the brain only if its molecules are small and not
ionized, enabling them to pass through endothelial cell membranes, or if the drug has
a chemical structure that allows it to be carried across the membrane by an active-transport
system. Because very few drug molecules are small or have the correct chemical
structure, very few can gain access to the CNS. Because the blood–brain barrier works
so well, it is extremely difficult to find new drugs to use as treatments for brain diseases.
To summarize, drugs that can make the entire trip from the mouth to the brain
have some special chemical properties. The most effective ones are small molecules,
weak acids, water and fat soluble, potent in small amounts, and not easily degraded.
Domoic acid meets all these criteria. Because it is a weak acid, it is easily absorbed
through the stomach. It is potent in small amounts, and so it survives dilution in the
bloodstream and extracellular fluid. Finally, it is a small molecule similar in structure
to those of nutrients that are transported across the blood–brain barrier and so it, too,
is transported.
HOW THE BODY ELIMINATES DRUGS
After a drug has been administered, the body soon begins to break it down (catabolize)
and remove it.Drugs are catabolized throughout the body, broken down in the kidneys
and liver, as well as in the intestine by bile. They are excreted in urine, feces, sweat,
breast milk, and exhaled air.Drugs that are developed for therapeutic purposes are usually
designed not only to increase their chances of reaching their targets but also to enhance
their survival time in the body.
The body has trouble removing some ingested substances, making them potentially
dangerous, because they can build up in the body and become poisonous. For
instance, certain toxic metals, such as mercury, are not easily eliminated; when they accumulate,
they can produce severe neurological conditions.When researchers studied
the medical histories of patients with severe domoic acid poisoning, they found that all
230 ! CHAPTER 7
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had preexisting kidney problems. This finding suggests that the kidneys play an important
role in eliminating domoic acid. Because these patients’ kidneys did not function
normally, domoic acid reached toxic levels in their bodies.
Individual Differences in Response to
Psychoactive Drugs
The vast differences among individual responses to drugs are due to differences in age,
sex, body size, metabolic rate, and other factors that affect sensitivity to a particular
substance. For instance, larger people are generally less sensitive to a drug than smaller
people are, because their greater volume of body fluids dilutes drugs more.
Females are about twice as sensitive to drugs as males on average. This difference is
due in part to their relatively smaller body size, but it is also due to hormonal differences.
Old people may be twice as sensitive to drugs as young people are. The elderly
often have less-effective barriers to drug absorption as well as less-effective processes for
metabolizing and eliminating drugs from their bodies.
Individual differences in sensitivity to domoic acid were observed among people
who ate toxic mussels. Only 1 in 1000 became ill, and only some of those who were ill
suffered severe memory impairment, with even fewer dying. The three patients with
impaired memory were men aged 69, 71, and 84. All who died were men older than 68.
Apparently, domoic acid is either more readily absorbed or more poorly excreted or
both in older men. The results of subsequent studies of mice confirmed the greater sensitivity
of older animals to the toxic effects of domoic acid.
Drug Action at Synapses: Agonists
and Antagonists
Drugs take effect by initiating chemical reactions in the body or by influencing the
body’s ongoing chemical activities. As you know,many chemical reactions take place in
the nervous system’s neurons, especially at synapses. Most drugs that have psychoactive
effects do so by influencing these chemical reactions at synapses. So, to understand
how drugs work, we must explore the ways in which they modify synaptic actions.
Figure 7-5 summarizes the seven major steps in neurotransmission
at a synapse. Synthesis of the neurotransmitter can take place in the cell
body, the axon, or the terminal. The neurotransmitter is then held in
storage granules or in vesicles or in both until it is released from the terminal’s
presynaptic membrane.
The amount of transmitter released into the synapse is regulated in
relation to experience. When released, the transmitter acts on a receptor
embedded in the postsynaptic membrane. It is then either destroyed
or taken back up into the presynaptic terminal for reuse. The synapse
also has mechanisms for degrading excess neurotransmitter and removing
unneeded by-products from the synapse.
Each of these steps in neurotransmission includes a chemical reaction
that a drug can potentially influence in one of two ways: either by increasing
the effectiveness of neurotransmission or by diminishing it. Agonists
are drugs that increase the effectiveness of neurotransmission, whereas
antagonists decrease its effectiveness. Agonists and antagonists can work
in a variety of ways, but their end results are always the same. To illustrate,
consider the acetylcholine synapse between motor neurons and muscles.
HOW DO DRUGS AND HORMONES INFLUENCE THE BRAIN AND BEHAVIOR? ! 231
Agonist. Substance that enhances the
function of a synapse.
Antagonist. Substance that blocks the
function of a synapse.
Precursor
chemicals
Neurotransmitter
Receptor interaction
4
Storage
2
Inactivation
5
6
Degradation
7
Release
3
Synthesis
1
Reuptake
Figure 7-5
Points of Influence In principle, a
drug can modify seven major chemical
processes, any of which results in
reduced or enhanced synaptic
transmission.
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An Acetylcholine Synapse: Examples of
Drug Action
Figure 7-6 shows how selected drugs and toxins act as agonists or antagonists at the
acetylcholine synapse.Acetylcholine agonists excite muscles,making them rigid,whereas
acetylcholine antagonists inhibit muscles, rendering them flaccid. Some of these substances
may be new to you, but you have probably heard of others. Knowing their effects
at the synapse allows you to understand the behavioral effects that they produce.
Figure 7-6 shows two toxins that influence the release of ACh from the axon
terminal. Black widow spider venom is an agonist because it promotes the release
of acetylcholine to excess. A black widow spider bite contains enough toxin to
paralyze an insect but not enough to paralyze a person, but a victim may feel
some muscle weakness.
Botulin toxin, the poisonous agent in tainted foods such as canned
goods that have been improperly processed, acts as an antagonist
because it blocks the release of ACh. The effects of botulin toxin
can last from weeks to months.A severe case can result in the paralysis
of both movement and breathing and so cause death.
Despite being a poison, botulin toxin has medical uses. If injected
into a muscle, it can selectively paralyze that muscle. This selective
action makes it useful in blocking excessive and enduring muscular twitches or
contractions, including the contraction that makes movement difficult for people with
cerebral palsy.Under the trade name Botox, botulin toxin is also used cosmetically to paralyze
facial muscles that cause facial wrinkling.
Figure 7-6 also shows two drugs that act on receptors for acetylcholine. As you
learned in Chapter 5, nicotine’s molecular structure is similar enough to that of ACh
to allow nicotine to fit into the receptors’ binding sites where it acts as an agonist. Curare
acts as an antagonist by occupying cholinergic receptors and so preventing acetylcholine
from binding to them.
When curare binds to these receptors, it does not cause them to function; instead,
it blocks them. After having been introduced into the body, curare acts quickly, and it
is cleared from the body in a few minutes. Large doses, however, arrest movement and
breathing for a sufficient period of time to result in death.
Early European explorers of South America discovered that the Indians along the
Amazon River killed small animals by using arrowheads coated with curare prepared
from the seeds of a plant. The hunters themselves did not become poisoned when eating
the animals, because ingested curare cannot pass from the gut into the body.Many
curare-like drugs have been synthesized. Some are used to briefly paralyze large animals
so that they can be examined or tagged for identification. You have probably seen
this use of these drugs in wildlife programs on television. Skeletal muscles are more
sensitive to curare-like drugs than are respiratory muscles; so an appropriate dose will
paralyze an animal’s movement temporarily but still allow it to breathe.
The fifth drug action shown in Figure 7-6 is that of physostigmine, a drug that
inhibits cholinesterase, the enzyme that breaks down acetylcholine. Physostigmine therefore
acts as an agonist to increase the amount of ACh available in the synapse. Physostigmine
is obtained from an African bean and is used as a poison by native peoples in Africa.
Large doses can be toxic because they produce excessive excitation of the neuromuscular
synapse and so disrupt movement and breathing. In small doses, however,
physostigmine is used to treat myasthenia gravis, a condition of muscular weakness in
which muscle receptors are less than normally responsive to acetylcholine (recall
“Myasthenia Gravis” on page 132). The action of physostigmine is short lived, lasting
only a few minutes or, at most, a half hour. But another class of compounds called
232 ! CHAPTER 7
Black widow
spider venom
promotes
release of ACh.
Agonist
Botulin toxin
blocks release
of ACh.
Choline-rich diet increases
available acetylcholine
(ACh).
Physostigmine and
organophosphates block
the inactivation of ACh.
Nicotine stimulates
ACh receptors. Curare blocks
ACh receptors.
Antagonist
Antagonist
Acetylcholine
Acetylcholine
terminal
Agonist Agonist
Figure 7-6
Acetylcholine Agonists and
Antagonists Drugs affect ACh
transmission by affecting its synthesis,
release, or binding to the postsynaptic
receptor and by affecting its breakdown
or inactivation.
On your Foundations of Behavioral
Neuroscience CD, find the area on
synaptic transmission in the module on
neural communication. Review the
processes of excitatory synaptic function
and consider drugs that act as agonists,
such as those that affect acetylcholine.
(See the Preface for more information
about this CD.)
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organophosphates bind irreversibly to acetylcholinesterase
and consequently are extremely toxic.
Many insecticides and chemical weapons are organophosphates.
Insects use glutamate as a neurotransmitter
at the nerve–muscle junction but,
elsewhere in their nervous systems, they have
numerous nicotine receptors. Thus, organophosphates
poison insects by acting centrally, but they
poison chordates by acting peripherally as well.
Hundreds of other drugs can act on ACh neuromuscular
synapses, and thousands of additional
substances can act on other kinds of synapses. A
few that are neurotoxins are listed in Table 7-1.
Despite their varied effects, all these substances act
either as agonists or as antagonists. If you understand
the opposing actions of agonists and antagonists,
you will also understand how some drugs
can be used as antidotes for poisoning by other
drugs.
If a drug or toxin that is ingested affects neuromuscular
synapses, will it also affect acetylcholine
synapses in the brain? That depends on whether the substance can cross the
blood–brain barrier. Some of the drugs that act on ACh synapses at the muscles can also
act on ACh synapses in the brain. For example, physostigmine and nicotine can readily
pass the blood–brain barrier and affect the brain, whereas curare cannot. Thus, whether
a cholinergic agonist or antagonist has psychoactive action depends on the size and
structure of its molecules, which determine whether that substance can reach the brain.
CLASSIFICATION OF PSYCHOACTIVE DRUGS
Drugs with similar chemical structures can have quite different effects, whereas drugs
having different structures can have very similar effects. Hence classifications based on a
drug’s chemical structure have not been very successful. Classification schemes based on
In Review .
Drugs are substances used to treat physical or mental disorders. Psychoactive drugs, substances
that produce changes in behavior by acting on the nervous system, are one subject
of psychoparmacology, the study of how drugs affect the nervous system and behavior.
Drugs encounter various barriers on the journey between their entry into the body and
their action at a CNS target. Perhaps the most important obstacle is the blood–brain barrier,
which generally allows only substances needed for nourishing the brain to pass from
the capillaries into the CNS. Most drugs that have psychoactive effects do so by crossing
the blood–brain barrier and influencing chemical reactions at brain synapses. Drugs that
influence communication between neurons do so by acting either as agonists (increasing)
or as antagonists (decreasing) the effectiveness of neurotransmission. There are, however,
great individual differences in people’s responses to drugs due to differences in age, sex,
body size, and other factors that affect sensitivity to a particular substance. The body eliminates
drugs through feces, urine, sweat glands, the breath, and breast milk.
HOW DO DRUGS AND HORMONES INFLUENCE THE BRAIN AND BEHAVIOR? ! 233
Some Neurotoxins, Their Sources, and Their Actions
Substance Origin Action
Tetrodotoxin Puffer fish Blocks membrane permeability to
Na! ions
Magnesium Natural element Blocks Ca2! channels
Reserpine Tree Destroys storage granules
Colchicine Crocus plant Blocks microtubules
Caffeine Coffee bean Blocks adenosine receptors,
blocks Ca2! channels
Spider venom Black widow spider Stimulates ACh release
Botulin toxin Food poisoning Blocks ACh release
Curare Plant berry Blocks ACh receptors
Rabies virus Infected animal Blocks ACh receptors
Ibotenic acid Mushroom Similar to domoic acid/mimics
glutamate
Strychnine Plant Blocks glycine
Apamin Bees and wasps Blocks Ca2! channels
Table 7-1
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receptors in the brain also have been problematic, because a single drug can act on many
different receptors.The same problem arises with classification systems based on the neurotransmitter
that a drug affects, because many drugs act on many different transmitters.
The classification that we use, summarized in Table 7-2, is based on the most pronounced
behavioral or psychoactive effect that a drug produces. That breakdown divides
drugs into seven classes,with each class containing from a few to many thousands
of different chemicals in its subcategories.
Drugs that are used to treat neuropsychological illnesses are listed again in Table 7-3,
along with the dates that they were discovered and the names of their discoverers. You
may be surprised to know that their therapeutic actions were all originally discovered
by accident. Subsequently, scientists and pharmaceutical companies developed many
forms of each drug in an effort to increase its effectiveness and reduce its side effects. At
234 ! CHAPTER 7
Classification of Psychoactive Drugs
V. Narcotic analgesics
Morphine, codeine, heroin
VI. Psychomotor stimulants
Cocaine, amphetamine,
caffeine, nicotine
VII. Psychedelics and hallucinogens
Anticholinergics: atropine
Noradrenergics: mescaline
Serotonergics: LSD (lysergic
acid diethylamide), psilocybin
Tetrahydrocannabinol:
marijuana
I. Sedative hypnotics and antianxiety agents
Barbiturates (anesthetic agents), alcohol
Benzodiazepines: diazepam (Valium)
II. Antipsychotic agents
Phenothiazines: chlorpromazine
Butyrophenones: haloperidol
III. Antidepressants
Monoamine oxydase (MAO) inhibitors
Tricyclic antidepressants: imipramine (Tofranil)
Atypical antidepressants: fluoxetine (Prozac)
IV. Mood stabilizers
Lithium
Table 7-2
To learn more about the variety of
psychoactive drugs, visit the Chapter 7
Web links on the Brain and Behavior
Web site (www.worthpublishers.
com/kolb).
Barbiturate. Drug that produces
sedation and sleep.
Antianxiety agent. Drug that reduces
anxiety; minor tranquillizers such as
benzodiazepines and sedative-hypnotic
agents are of this type.
Tolerance. Lessening of response to a
drug over time.
Cross-tolerance. Response to a novel
drug is reduced because of tolerance
developed in response to a related drug.
Drugs Used for the Treatment of Mental Illness
Common
Illness Drug class Representative drug trade name Discoverer
Schizophrenia Phenothiazines Chlorpromazine Largactile
Thorazine
Haldol
Butyrophenone Haloperidol Paul Janssen (Belgium), 1957
Depression Monoamine oxidase (MAO) inhibitors Iproniazid Marsilid
Tricyclic antidepressants Imipramine Tofranil Roland Kuhn (Switzerland), 1957
Selective serotonin reuptake inhibitors Fluoxetine Prozac Eli Lilly Company, 1986
Bipolar disorder Lithium (metallic element) John Cade (Australia), 1949
Anxiety disorders Benzodiazepines Chlordiazepoxide Librium Leo Sternbach (Poland), 1940
Valium
Meprobamate Miltown
Equanil
Frank Berger and William Bradley
(Czechoslovakia), 1946
Nathan S. Kline and J. C. Saunders
(United States), 1956
Jean Delay and Pierre Deniker
(France), 1952
Table 7-3
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the same time, experimental researchers attempted to explain each drug’s action on the
nervous system—explanations that are as yet incomplete.We will consider the actions of
some of these drugs as we describe the classification system outlined in Table 7-2.
Antianxiety Agents and Sedative Hypnotics
The effects of antianxiety drugs and sedative hypnotics differ, depending on their dose.
At low doses they reduce anxiety, at medium doses they sedate, and at high doses they
produce anesthesia or coma. At very high doses they can kill (Figure 7-7).
Most common among this diverse group of drugs are alcohol, barbiturates, and
benzodiazepines. Alcohol is well known to most people because it is so widely consumed.
Its potentially devastating effects on developing fetuses are explored in “Fetal
Alcohol Syndrome,” on page 236. Barbiturates are sometimes prescribed as a sleeping
medication, but they are now mainly used to induce anesthesia before surgery. Benzodiazepines
are also known as minor tranquilizers or antianxiety agents. An example is
the widely prescribed drug Valium.
Benzodiazepines are often used by people who are having trouble coping with a
major life stress, such as a traumatic accident or a death in the family.Whereas both alcohol
and barbiturates can induce sleep, anesthesia, and coma at doses only slightly
higher than those that produce sedation, the dose of benzodiazepines that produces
sleep and anesthesia is substantially higher than that which is needed to relieve anxiety.
A characteristic feature of sedative hypnotics is that they cause weaker and weaker
responses in the user who takes repeated doses. A larger dose is then required to maintain
the drug’s initial effect. This lessening of response to a drug over time is called
tolerance. Cross-tolerance develops when the tolerance developed for one drug is carried
over to a different drug.
Cross-tolerance suggests that the two drugs are similar in their actions on the nervous
system. Alcohol, barbiturates, and benzodiazepines show cross-tolerance, suggesting
that they affect a common nervous system target. This common target is now
known to be the receptor sites for the major inhibitory neurotransmitter GABA. Neurons
that contain GABA are widely distributed in the nervous system and function to
inhibit the activity of other neurons (see Chapter 5).
One of the receptors affected by GABA is the GABAA receptor. As illustrated at the
left in Figure 7-8, this receptor contains a chloride channel. Excitation of the receptor
produces an influx of Cl– ions through its pore. Remember that an influx of Cl– ions
increases the concentration of negative charges inside the cell membrane, hyperpolarizing
it and making it less likely to initiate or
propagate an action potential. The inhibitory effect
of GABA, therefore, is to decrease a neuron’s
rate of firing.
The GABAA receptor is a target for sedative
hypnotics because it has not only a binding site
for GABA but two other binding sites as well.
One of these sites accepts alcohol and barbiturates
(the sedative-hypnotic site), whereas the
other accepts benzodiazepines (the antianxiety
site). Drugs binding to the sedative-hypnotic site
directly increase the influx of chloride ions and so
act like GABA. Consequently, the higher the dose
of these drugs, the greater their inhibitory effect
on neurons.
HOW DO DRUGS AND HORMONES INFLUENCE THE BRAIN AND BEHAVIOR? ! 235
Because of their
different actions, these
drugs should never be
taken together.
Combined doses can
cause coma or death.
GABA
Alcohol or
barbiturat e
Se dativehypnot
ic
site
Chlor ide
channel
Binding of sedativehypnotic
drugs (such as
alcohol or barbiturates) acts
like GABA, causing
increased chloride
conductance.
Cl–
GABA
B enzodiaz ep ine
Binding of antianxiety
drugs (benzodiazepines)
enhances binding effects of
GABA.
Antia nxie ty
site
Figure 7-8
Drug Effects at the GABAA Receptor
Sedative hypnotics, antianxiety agents,
and GABA each have different binding
sites.
Normal
Relief from anxiety
Disinhibition
Sedation
Sleep
General anesthesia
Coma
Death
Increasing dose of
sedative-hypnotic drug
Effect of drug
Figure 7-7
Effects of Sedatives This continuum
of behavioral sedation shows how
increasing doses of sedative-hypnotic
drugs can affect behavior.
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Fetal Alcohol Syndrome
Focus on Disorders
The term fetal alcohol syndrome (FAS) was coined in 1973
to describe a pattern of physical malformation and mental
retardation observed in some children born of alcoholic
mothers. Children with FAS may have abnormal facial features,
such as unusually wide spacing between the eyes.
They also have a range of brain abnormalities, from small
brains with abnormal gyri to abnormal clusters of cells and
misaligned cells in the cortex.
Related to these brain abnormalities are certain behavioral
symptoms that FAS children tend to have in common.
They display varying degrees of learning disabilities and lowered
intelligence test scores, as well as hyperactivity and
other social problems.
The identification of FAS stimulated widespread interest
in the effects of alcohol consumption by pregnant women.
The offspring of approximately 6 percent of alcoholic mothers
suffer from pronounced FAS. In major cities, the incidence of
FAS is about 1 in 700 births. Its incidence increases to as many
as 1 in 8 births on one Native American reservation in Canada.
FAS is not an all-or-none syndrome. Alcohol-induced
abnormalities can vary from hardly noticeable physical and
psychological effects to the full-blown FAS syndrome. The
severity of effects is thought to be related to when, how
much, and how frequently alcohol is consumed in the
course of pregnancy. Apparently, the effects are worse if alcohol
is consumed in the first 3 months of pregnancy, which,
unfortunately, may be a time when many women do not yet
realize that they are pregnant.
Severe FAS is also more likely to coincide with binge
drinking, which produces high blood-alcohol levels. Other
factors related to a more severe outcome are poor nutritional
health of the mother and the mother’s use of other drugs, including
the nicotine in cigarettes.
A major question raised by FAS is how much alcohol is
too much to drink during pregnancy. The answer to this question
is complex, because the effects of alcohol on a fetus depend
on so many factors. To be completely safe, it is best not
to drink at all in the months preceding pregnancy and during
it. This conclusion is supported by findings that as little
as one drink of alcohol per day during pregnancy can lead
to a decrease in intelligence test scores of children.
Fetal alcohol syndrome in both its full-blown and milder
forms has important lessons for us. Alcohol is a widely used
drug. When taken in moderation, it is thought to have some
health benefits; yet it does pose risks, although those risks
are completely preventable if alcohol is used appropriately.
A major problem is that women who are most at risk for
bearing FAS babies are poor and not well educated, with
alcohol-consumption problems that predate pregnancy and
little access to prenatal care. It is often difficult to inform
these women about the dangers that alcohol poses to a fetus
and to encourage them to abstain from drinking while they
are pregnant.
(Top) Effects of fetal alcohol syndrome are not merely physical;
many FAS children are severely retarded. (Bottom) The
convolutions characteristic of the brain of a normal child (left) are
grossly underdeveloped in the brain of a child who suffered from
fetal alcohol syndrome (right).
University of Washington, George Steinmetz
School of Medicine
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The effect of antianxiety drugs is different. Excitation of the antianxiety site enhances
the binding of GABA to its receptor site (Figure 7-8, center), which means that the availability
of GABA determines the potency of an antianxiety drug. Because GABA is very
quickly reabsorbed by the neurons that secrete it and by surrounding glial cells, GABA
concentrations are never excessive,making it hard to overdose on antianxiety drugs.
Scientists do not know what natural substances bind to the GABAA receptor binding
sites other than GABA. A. Leslie Morrow and her coworkers (1999) suggest that a
natural brain hormone, allopregnanolone, may bind to the sedative-hypnotic site. Allopregnanolone
is produced by the pituitary gland.An additional mechanism by which
alcohol may have its sedative effects is by facilitating the production of allopregnanolone,
which in turn activates the sedative-hypnotic site of the GABAA receptor,
thus producing sedation. An explanation of the less-potent effect of alcohol on human
males than on females is that females have higher levels of allopregnanolone, thus making
them more sensitive to the effects of alcohol.
Because of their different actions on the GABAA receptor, sedative-hypnotic and
antianxiety drugs should never be taken together (Figure 7-8, right). A sedative hypnotic
acts like GABA, but, unlike GABA, it is not quickly absorbed by surrounding cells.
Thus, by remaining at the binding site, its effects are enhanced by an antianxiety drug.
The cumulative action of the two drugs will therefore exceed the individual action of
either one. Even small combined doses of antianxiety and sedative-hypnotic drugs can
produce coma or death.
Drugs that act on GABA receptors may affect the development of the brain. Fetal
alcohol syndrome is an example of a developmental disorder due to effects of alcohol
that is ingested by a mother on the subsequent development and behavior of a fetus.
Antipsychotic Agents
The term psychosis is applied to neuropsychological conditions such as schizophrenia,
characterized by hallucinations (false sensory perceptions) or delusions (false beliefs).
The use of antipsychotic drugs, also called major tranquilizers or neuroleptics, has
greatly improved the functioning of schizophrenia patients and contributed to reducing
the number housed in institutions, as Figure 7-9 graphs. The success of antipsychotic
agents is an important therapeutic achievement because the incidence of schizophrenia
is high, about 1 in every 100 people.
Although major tranquilizers have been widely
used for 50 years, their therapeutic actions are still
not understood. They have an immediate effect in
reducing motor activity, and so they alleviate the
excessive agitation of some schizophrenia patients.
In fact, one of their negative side effects can be to
produce symptoms reminiscent of Parkinson’s disease,
in which control over movement is impaired.
After a short period of use they can reduce the
symptoms of schizophrenia. With prolonged use,
neuroleptics can cause dyskinesia, including rhythmical
movements of the mouth, hands, and other
body parts. The effects are usually reversible if the
person stops taking the drug.
At least part of the action of antipsychotic drugs
is to block the D2 receptor for dopamine.This action
led to the dopamine hypothesis of schizophrenia,
HOW DO DRUGS AND HORMONES INFLUENCE THE BRAIN AND BEHAVIOR? ! 237
On your Foundations CD, find the
area on synaptic transmission in the
module on neural communication.
Review the process of inhibitory synaptic
function and consider drugs that, like
GABA, act as antagonists in the CNS.
Fetal alcohol syndrome (FAS). Pattern
of physical malformation and mental
retardation observed in some children
born of alcoholic mothers.
Major tranquilizer (neuroleptic).
Drug that blocks the D2 receptor; used
mainly for treating schizophrenia.
Dopamine hypothesis of
schizophrenia. Proposal that
schizophrenic symptoms are due to
excess activity of the neurotransmitter
dopamine.
350
400
450
500
550
1946 1955 1960 1965 1970 2000
Year
Number of patients in mental institutions
(in thousands)
1950
Beginning of widespread
use of antipsychotic agents
Figure 7-9
Trends in Resident Care The dramatic
decrease in the number of resident
patients in state and municipal mental
hospitals in the United States began
after 1955, when psychoactive drugs
were introduced into widespread
therapeutic use. Adapted from A Primer of
Drug Action (p. 276), by R. M. Julien, 1995, New
York: W. H. Freeman and Company.
CH07.qxd 1/28/05 10:17 AM Page 237

which holds that some forms may be related to excessive DA activity,which antipsychotic
drugs control.Other support for the dopamine hypothesis comes from the schizophrenialike
symptoms of chronic users of amphetamine, a stimulant. As Figure 7-10 shows,
amphetamine is a DA agonist that fosters the release of DA from the presynaptic membrane
of DA synapses and blocks the reuptake of DA from the synaptic
cleft. If amphetamine causes schizophrenia-like symptoms by increasing
DA activity, perhaps naturally occurring schizophrenia is related to excessive
DA action, too.
Even though such drug effects lend support to the dopamine hypothesis
of schizophrenia, experimental studies have been unable to
find clear evidence of dopamine-related differences in the brains of
normal people and those of schizophrenia patients. The brains of patients
with schizophrenia do not contain a greater number of DA synapses,
release more DA from presynaptic membranes, or possess more
D2 receptors. Consequently, the cause of schizophrenia and the mechanism
by which antipsychotic agents work currently remain unclear.
Antidepressants
Major depression—a mood disorder characterized by prolonged feelings
of worthlessness and guilt, the disruption of normal eating habits,
sleep disturbances, a general slowing of behavior, and frequent thoughts of suicide—
is very common. At any given time, about 6 percent of the adult population suffers
from it, and, in the course of a lifetime, 30 percent may experience at least one episode
that lasts for months or longer. Depression affects twice as many women as men.
Most people recover from depression within a year of its onset, but, if the illness is left
untreated, the incidence of suicide is high, as discussed in “Major Depression” on page
240.Of all psychological disorders,major depression is one of the most treatable, and cognitive
and intrapersonal therapies are as effective as drug therapies (Comer, 2004). Three
different types of drugs have antidepressant effects: the monoamine oxidase (MAO)
inhibitors; the tricyclic antidepressants, so called because of their three-ringed chemical
structure; and the second-generation antidepressants, sometimes called atypical antidepressants,
that include fluoxetine (Prozac). Second-generation antidepressants do not
have a three-ringed structure, but they are similar to the tricyclics in their actions.
Antidepressants are thought to act by improving chemical neurotransmission at
serotonin, noradrenaline, histamine, and acetylcholine synapses, and perhaps at
dopamine synapses as well. Figure 7-11 shows their action at a serotonin synapse, the
synapse on which most research is focused.As you can see,MAO inhibitors and the tricyclic
and second-generation antidepressants have different mechanisms of action in
increasing the availability of serotonin.
Monoamine oxidase is an enzyme that breaks down serotonin within the axon terminal.
The inhibition of MAO by a MAO inhibitor therefore provides more serotonin
for release with each action potential. The tricyclic antidepressants and the secondgeneration
antidepressants block the reuptake transporter that takes serotonin back
into the axon terminal. The second-generation antidepressants are thought to be especially
selective in blocking serotonin reuptake, and, consequently, some are also called
selective serotonin reuptake inhibitors (SSRIs). Because the transporter is blocked,
serotonin remains in the synaptic cleft for a longer period, thus prolonging its action
on postsynaptic receptors.
There is,however, a significant problem in understanding how antidepressants function.
Although these drugs begin to affect synapses very quickly, their antidepressant
238 ! CHAPTER 7
Monoamine oxidase (MAO)
inhibitor. Antidepressant drug that
blocks the enzyme monoamine oxidase
from degrading neurotransmitters such as
dopamine, noradrenaline and serotonin.
Tricyclic antidepressant. Firstgeneration
antidepressant drug with a
chemical structure characterized by three
rings that blocks serotonin reuptake
transporter proteins.
Second-generation antidepressant.
Drug whose action is similar to tricyclics
(first-generation antidepressants) but more
selective in its action on the serotonin
reuptake transporter proteins; also called
atypical antidepressant.
Selective serotonin reuptake
inhibitor (SSRI). Tricyclic antidepressant
drug that blocks the reuptake of serotonin
into the presynaptic terminal.
Amphetamine
promotes the
release of
dopamine and
fosters symptoms
of schizophrenia.
Agonist
Both amphetamine and
cocaine block the reuptake
of dopamine and foster
symptoms of schizophrenia.
Agonist
Chlorpromazine, a drug that blocks symptoms of
schizophrenia, occupies the dopamine site on
the D2 receptor, preventing receptor activation
by dopamine.
Antagonist
Dopamine
Chlorpromazine D2 receptor
Dopamine
terminal
Figure 7-10
Drug Effects at D2 Receptors That
chlorpromazine can lessen schizophrenia
symptoms, whereas the abuse of
amphetamine or cocaine can produce
them, suggests that excessive activity at
the dopamine receptor is related to
schizophrenia.
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HOW DO DRUGS AND HORMONES INFLUENCE THE BRAIN AND BEHAVIOR? ! 239
actions take weeks to develop.No one is sure why.Of interest in this
respect is the fact that Prozac increases the production of new neurons
in the hippocampus, a limbic structure in the temporal lobes.
The hippocampus is vulnerable to stress-induced damage, and its
restoration by Prozac has been proposed to underlie the drug’s antidepressant
effects (Santarelli et al., 2003).We consider these effects
in detail in Chapter 15.
About 20 percent of patients with depression fail to respond
to antidepressant drugs. Accordingly, depression can likely have
many other causes including the dysfunction of other transmitter
systems and even damage to the brain, including the frontal lobes.
Some people cannot tolerate the side effects of antidepressants,
which can include increased anxiety, sexual dysfunction, sedation,
dry mouth, blurred vision, and memory impairment.
Although many scientists hoped that the second-generation
antidepressants would produce fewer side effects than do tricyclic
antidepressants, that hope has not been fully realized. In fact, how
SSRIs act on the brain is unclear, although slight modifications in
the molecular structure of an antidepressant can change its affinity
for different brain targets so that it can, for example, affect
noradrenaline or dopamine synapses or even affect corticotropinreleasing
factor, a stress hormone implicated in depression.
Even advertisements for Prozac, one of the more selective antidepressant compounds,
suggest that this drug can be used to treat not only depression but also obsessivecompulsive
disorder (OCD).The major symptoms of OCD are obsessive thoughts (ideas
that people cannot get out of their heads) and compulsive behaviors (ritual-like actions
that they endlessly perform). Although OCD is related to guilt and anxiety, as is depression,
it is usually classified as an anxiety disorder, a separate condition from depression.
Narcotic Analgesics
The term narcotic analgesics describes a group of drugs that have sleep-inducing
(narcotic) and pain-relieving (analgesic) properties. Many of these drugs are derived
from opium, an extract of the seeds of the opium poppy, Papaver somniferum, which
is shown in Figure 7-12. Opium has been used for thousands of years to produce euphoria,
analgesia, sleep, and relief from diarrhea and coughing.
In 1805, German chemist Friedrich Sertürner synthesized two pure substances
from the poppy plant: codeine and morphine. Codeine is often an ingredient in
prescription cough medicine and pain relievers. Morphine, named for Morpheus,
the Greek god of dreams, is a very powerful pain reliever. Despite decades of research,
no other drug has been found that exceeds morphine’s effectiveness as an
analgesic.
Opium antagonists such as nalorphine and naloxone
block the actions ofmorphine and so are useful
in treating morphine overdoses.Heroin, another opiate
drug, is synthesized from morphine. It is more fat
soluble than morphine and penetrates the blood–
brain barrier more quickly, allowing it to produce very
rapid relief from pain.Although heroin is a legal drug
in some countries, it is illegal in others, including the
United States.
Selective serotonin
reuptake inhibitors
block transporter
protein for serotonin
reuptake so that
serotonin stays in
synaptic cleft longer.
Agonist
MAO inhibitor
inhibits the
breakdown of
serotonin…
Agonist
Serotonin
MAO inhibitor
Serotonin
terminal
Both these drugs
reduce symptoms of
depression by
increased activation
of postsynaptic cells.
…so that more
serotonin is available
for release.
Figure 7-11
Drug Effects at Serotonin
Receptors Different antidepressant
drugs act on the serotonin synapse in
different ways to increase the
availability of serotonin.
Narcotic analgesic. Drug like
morphine, with sleep-inducing (narcotic)
and pain-relieving (analgesic) properties.
Figure 7-12
Potent Poppy Opium is obtained from
the seeds of the opium poppy (left).
Morphine (center) is extracted from
opium, and heroin (right) is in turn
synthesized from morphine.
Eye Ubiquitous/Corbis
National Archives
Bonnie Kamin/PhotoEdit
CH07.qxd 1/28/05 10:17 AM Page 239

240 ! CHAPTER 7
Among the opioids prescribed for clinical use in pain management are morphine,
hydromorphone, levorphanol, oxymorphone, methadone, meperidine, oxycodone,
and fentanyl (Inturrisi, 2002). The opioids are potently addictive; so, in addition to
using illegally manufactured and distributed drugs such as heroin, drug abusers often
obtain and abuse opioid drugs intended for pain management. People who suffer from
chronic pain and who use opiods for pain relief also can become addicted, although
such addictions are not common.
What are the effects of opiate drugs on the CNS? Candace Pert and Solomon Snyder
(1973) provided an important answer to this question by injecting radioactive opiates
into the brain and identifying special receptors to which the opiates bound. But
Major Depression
Focus on Disorders
P. H. was a 53-year-old high school teacher who, although
popular with his students, was feeling less and less satisfaction
from his work. His marriage was foundering because he
was becoming apathetic and no longer wanted to socialize
or go on holidays with his wife. He was having great difficulty
getting up in the morning and arriving at school on
time.
P. H. eventually consulted a physician with a complaint
of severe chest pains, which he thought signified that he was
about to have a heart attack. He informed his doctor that a
heart attack would be a welcome relief because it would end
his problems. The physician concluded that P. H. was suffering
from depression and referred him to a psychiatrist.
The psychiatrist arranged for P. H. to come in once a
week for counseling and gave him a prescription for an MAO
inhibitor. The psychiatrist informed P. H. that many foods
contain tyramine, a chemical that can raise blood pressure
to dangerous levels, and, because the action of this chemical
increases when taking MAO inhibitors, he should avoid
foods that contain tyramine. The psychiatrist gave him a list
of foods to be avoided and especially warned him against
eating cheese or drinking wine, the standard advice given to
patients for whom MAO inhibitors were prescribed.
A few days later, P. H. opened a bottle of wine, took a
two-pound block of cheese out of the refrigerator, and began
to consume them. That evening he suffered a massive lefthemisphere
stroke that left him unable to speak or to walk.
It seemed clear that P. H. had attempted to commit suicide.
Because of their dangers, MAO inhibitors are now seldom
prescribed.
Since the 1950s, depression has been treated with antidepressant
drugs, a variety of cognitive-behavior therapies
(CBTs), and electroconvulsive therapy (ECT), a treatment in
which electrical current is passed briefly through one hemisphere
of the brain. Of the drug treatments available, tricyclic
antidepressants, including the selective serotonin
reuptake inhibitors (SSRIs), are now favored because they are
safer and more effective than MAO inhibitors.
Although drugs are often useful in the treatment of depression,
their widespread prescription is associated with
considerable controversy and debate (Medwar & Hardon,
2004). For example, prompted in part by complaints from
family members that drug treatments have caused suicide,
especially in children, the U.S. Food and Drug Administration
has advised physicians to monitor the side effects of
SSRIs including fluoxetine (Prozac), sertraline (Zoloft), and
paroxetine (Paxil, Seroxat). The issue of suicide is complex in
part because many of these drugs have not been approved
by the FDA for children.
Nevertheless, findings from a number of studies show
no difference in the rate of suicide between groups receiving
serotonin reuptake inhibitors and a placebo (Khan, Khan,
Kolts, & Brown, 2003). At best, these findings suggest that
drug treatment is not effective in preventing suicide in this
suicide-prone population and that other suicide-prevention
measures should be used.
Visit the Chapter 7 Web links on
the Brain and Behavior Web site
(www.worthpublishers.com/kolb)
to read more about current events and
controversies surrounding antidepressants.