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Science Brain and Behavior contiuned 17

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HOW DO NEURONS COMMUNICATE AND ADAPT? ! 161
Table 5-1 lists some of the best-known and most extensively studied small-molecule
transmitters. In addition to acetylcholine, four amines (related by a chemical structure
that contains an amine, or NH, group) and four amino acids are included in this list. A
few other substances are sometimes also classified as small-molecule transmitters. In the
future, researchers are likely to find more.
Figure 5-9 illustrates how acetylcholine molecules are synthesized and broken
down. As you know, ACh is present at the junction of neurons and muscles, including
the heart, as well as in the CNS. The molecule is made up of two substances, choline
and acetate.
Choline is among the breakdown products of fats, such as egg yolk, and acetate is a
compound found in acidic foods, such as vinegar. As depicted in Figure 5-9, inside the
cell, acetyl coenzyme A (acetyl CoA) carries acetate to the synthesis site, and the transmitter
is synthesized as a second enzyme, choline acetyltransferase (ChAT), transfers the
acetate to choline to form ACh. After ACh has been released into the synaptic cleft and
diffuses to receptor sites on the postsynaptic membrane, a third enzyme, acetylcholinesterase
(AChE), reverses the process by detaching acetate from choline. These
breakdown products can then be taken back into the presynaptic terminal for reuse.
Some of the transmitters grouped together in Table 5-1 also share common biochemical
pathways to synthesis and so are related. You are familiar with the amines
dopamine (DA), norepinephrine (NE), and epinephrine (EP). To review, DA loss has
a role in Parkinson’s disease, EP is the excitatory transmitter at the heart of the frog,
and NE is the excitatory transmitter at the heart of mammals.
Figure 5-10 charts the biochemical sequence that synthesizes these amines in succession.
The precursor chemical is tyrosine, an amino acid abundant in food. (Hard
AChE
AChE
Acetate
Choline
Postsynaptic membrane
ACh
The products of the
breakdown can be taken up
and reused.
4
In the synaptic cleft,
AChE detaches acetate
from choline.
3
Intracellular fluid (presynaptic)
Intracellular fluid (postsynaptic)
Acetate
Acetyl CoA
ChAT
Choline ACh
Synaptic cleft
Acetyl CoA carries acetate
to the transmittersynthesis
site.
1
ChAT transfers
acetate to
choline…
2
…to
form
ACh.
Presynaptic membrane
Products
Figure 5-9
Chemistry of Acetylcholine
Two enzymes combine the dietary
precursors of ACh within the cell and
a third breaks them down in the
synapse for reuptake.
Small-Molecule
Neurotransmitters
Acetylcholine (ACh)
Amines
Dopamine (DA)
Norepinephrine (NE)
Epinephrine (EP)
Serotonin (5-HT)
Amino acids
Glutamate (Glu)
Gamma-aminobutyric acid (GABA)
Glycine (Gly)
Histamine
Table 5-1
Tyrosine
Enzyme 1
L-Dopa
Enzyme 2
Dopamine
Enzyme 3
Norepinephrine
Epinephrine
Enzyme 4
Figure 5-10
Sequential Synthesis of Three Amines
A different enzyme is responsible for
each successive molecular modification
in this biochemical sequence
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cheese and bananas are good sources.) The enzyme tyrosine hydroxylase (enzyme 1 in
Figure 5-10) changes tyrosine into L-dopa, which is sequentially converted by other enzymes
into dopamine, norepinephrine, and, finally, epinephrine.
An interesting fact about this biochemical sequence is that the supply of the enzyme
tyrosine hydroxylase is limited. Consequently, so is the rate at which dopamine,
norepinephrine, and epinephrine can be produced, regardless of how much tyrosine
is present or ingested. This rate-limiting factor can be bypassed by orally ingesting
L-dopa, which is why L-dopa is a medication used in the treatment of Parkinson’s disease,
as described in “Awakening with L-Dopa.”
Two amino acid transmitters, glutamate and gamma-aminobutyric acid (GABA),
also are closely related.GABA is formed by a simple modification of the glutamate molecule,
as shown in Figure 5-11.These two transmitters are the workhorses of the brain because
so many synapses use them.
In the forebrain and cerebellum, glutamate is the main excitatory transmitter and
GABA is the main inhibitory transmitter. (The amino acid glycine is a much more
common inhibitory transmitter in the brainstem and spinal cord.) Type I excitatory
synapses, described earlier, thus have glutamate as a neurotransmitter and Type II inhibitory
synapses have GABA as a neurotransmitter. Interestingly, glutamate is widely
distributed in CNS neurons, but it becomes a neurotransmitter only if it is appropriately
packaged in vesicles in the axon terminal.
PEPTIDE TRANSMITTERS
More than 50 amino acid chains of various lengths form the families of the peptide
transmitters listed in Table 5-2. As you learned in Chapter 3, these molecular chains are
amino acids connected by peptide bonds, which accounts for the name. Neuropeptides
are made through the translation of mRNA from instructions contained in the neuron’s
DNA.
In some neurons, peptide transmitters are made in the axon terminal, but most are
assembled on the neuron’s ribosomes, packaged in a membrane by Golgi bodies, and
transported by the microtubules to the axon terminals. The entire process of neuropeptide
synthesis and transport is relatively slow compared with the nearly readymade
formation of small-molecule neurotransmitters. Consequently, peptide transmitters act
slowly and are not replaced quickly.
Neuropeptides have an enormous range of functions in the nervous system, as
might be expected from the large number that exist there. They act as hormones that
respond to stress, allow a mother to bond to her infant, regulate eating and drinking
and pleasure and pain, and they probably contribute to learning. Opium and related
synthetic chemicals such as morphine, long known to produce both euphoria
and pain reduction, appear to mimic the actions of three peptides: met-enkephalin,
162 ! CHAPTER 5
COOH
COOH
CH2
CH2
H2N CH
COOH
CH2
CH2
H2N CH
Glutamate GABA
Figure 5-11
Amino Acid Transmitters (Top)
Removal of a carboxyl (COOH) group
from the bottom of the glutamate
molecule produces GABA. (Bottom) Their
different shapes thus allow these amino
acid transmitters to bind to different
receptors.
Rate-limiting factor. Any enzyme that
is in limited supply, thus restricting the
pace at which a chemical can be
synthesized.
Glutamate. Amino acid neurotransmitter
that excites neurons.
Gamma-aminobutyric acid (GABA).
Amino acid neurotransmitter that inhibits
neurons.
Neuropeptide. A multifunctional chain
of amino acids that acts as a
neurotransmitter; synthesized from mRNA
on instructions from the cell’s D NA.
Peptide Neurotransmitters
Family Example
Opioids Enkephaline, dynorphin
Neurohypophyseals Vasopressin, oxytocin
Secretins Gastric inhibitory peptide, growth-hormone-releasing peptide
Insulins Insulin, insulin growth factors
Gastrins Gastrin, cholecystokinin
Somatostatins Pancreatic polypeptides
Table 5-2
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leu-enkephalin, and beta-endorphin. (The term enkephalin derives from the phrase “in
the cephalon,”meaning “in the brain or head,” whereas the term endorphin is a shortened
form of “endogenous morphine.”)
A part of the amino acid chain in each of these three peptide
transmitters is structurally similar to the others, as illustrated
for two of these peptides in Figure 5-12. Presumably,
opium mimics this part of the chain. The discovery of naturally
occurring opium-like peptides suggested that one or more
of them might take part in the management of pain. Opioid
HOW DO NEURONS COMMUNICATE AND ADAPT? ! 163
Awakening with L-Dopa
Focus on Disorders
He was started on L-dopa in March 1969. The dose
was slowly raised to 4.0 mg a day over a period of
three weeks without apparently producing any effect.
I first discovered that Mr. E. was responding to
L-dopa by accident, chancing to go past his room at
an unaccustomed time and hearing regular footsteps
inside the room. I went in and found Mr. E.,
who had been chair bound since 1966, walking up
and down his room, swinging his arms with considerable
vigor, and showing erectness of posture
and a brightness of expression completely new to
him. When I asked him about the effect, he said
with some embarrassment: “Yes! I felt the L-dopa
beginning to work three days ago—it was like a
wave of energy and strength sweeping through me.
I found I could stand and walk by myself, and that
I could do everything I needed for myself—but I
was afraid that you would see how well I was and
discharge me from the hospital.” (Sacks, 1976)
In this case history, neurologist Oliver Sacks describes administering
L-dopa to a patient who acquired postencephalitic
Parkinsonism as an aftereffect of severe influenza
in the 1920s. The relation between the influenza and symptoms
of Parkinson’s disease suggests that the flu virus entered
the brain and selectively attacked dopamine neurons in the
substantia nigra. L-Dopa, by increasing the amount of DA in
remaining synapses, relieved the patient’s symptoms.
Two separate groups of investigators had quite independently
given L-dopa to Parkinson patients beginning in
1961 (Birkmayer & Hornykiewicz, 1961; Barbeau, Murphy,
& Sourkes, 1961). Both research teams knew that the chemical
is catalyzed into dopamine at DA synapses (see Figure
5-10), but they did not know if it could relieve the symptoms
of Parkinsonism. The L-dopa turned out to dramatically reduce
the muscular rigidity that the patients suffered, although
it did not relieve their tremors.
L-Dopa has since become a standard treatment for Parkinson’s
disease. Its effects have been improved by administering
drugs that prevent L-dopa from being broken down
before it gets to dopamine neurons in the brain. L-Dopa is
not a cure. Parkinson’s disease still progresses during treatment
and, as more and more dopamine synapses are lost,
the treatment becomes less and less effective and eventually
begins to produce dyskinesia. When these side effects
eventually become severe, the L-dopa treatment must
be discontinued.
The movie Awakenings recounts the L-dopa trials conducted by
Oliver Sacks and described in his book of the same title.
Everett Collection, Inc.
Met-enkephalin
Tyr Gly Gly Phe Met
Leu-enkephalin
Tyr Gly Gly Phe Leu
Figure 5-12
Opioid Peptides Parts of the amino
acid chains of some neuropeptides are
similar in structure and are similar to
drugs such as opium and morphine,
which mimic their functions.
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peptides, however, appear to be in a number of locations and perform a variety of functions
in the brain, including the inducement of nausea. Therefore opium-like drugs are
still preferred for pain management.
Unlike small-molecule transmitters, neuropeptides do not bind to ion channels,
and so they have no direct effects on the voltage of the postsynaptic membrane. Instead,
peptide transmitters activate synaptic receptors that indirectly influence cell structure
and function. Because peptides are amino acid chains that are degraded by digestive
processes, they generally cannot be taken orally as drugs, as the small-molecule transmitters
can.
TRANSMITTER GASES
The gases nitric oxide (NO) and carbon monoxide (CO) are the most unusual neurotransmitters
yet identified. As soluble gases, they are neither stored in synaptic vesicles
nor released from them; instead, they are synthesized in the cell as needed. After
synthesis, each gas diffuses away, easily crossing the cell membrane and immediately
becoming active.
Nitric oxide serves as a chemical messenger in many parts of the body. It controls
the muscles in intestinal walls, and it dilates blood vessels in brain regions that are in
active use, allowing these regions to receive more blood. Because it also dilates blood
vessels in the sexual organs, NO is active in producing penile erections. Viagra, a drug
used to treat erectile dysfunction acts by enhancing the action of NO. Both NO and CO
activate metabolic processes in cells, including those modulating the production of
other neurotransmitters.
Receptors for Direct and Indirect Effects
When a neurotransmitter is released from a synapse, it crosses the synaptic
cleft and binds to a receptor. What happens next depends on the receptor
type. Each of the two general classes of receptor proteins has a
different effect. One directly changes the electrical potential of the postsynaptic
membrane, whereas the other induces cellular change indirectly.
Ionotropic receptors allow the movement of ions across a membrane
(the suffix tropic means “to move toward”). As Figure 5-13 illustrates,
an ionotropic receptor has two parts: (1) a binding site for a
neurotransmitter and (2) a pore or channel.When the neurotransmitter
attaches to the binding site, the receptor changes shape, either opening
the pore and allowing ions to flow through it or closing the pore and
blocking the flow of ions. Because the binding of the transmitter to the
receptor is quickly followed by the opening or closing of the receptor pore that affects
the flow of ions, ionotropic receptors bring about very rapid changes in membrane
voltage. Ionotropic receptors are usually excitatory in that they trigger an
action potential.
Structurally, ionotropic receptors are similar to the voltage-sensitive channels discussed
in Chapter 4. Their membrane-spanning subunits form the “petals” of the pore
that lies in the center.Within the pore is a shape-changing segment that allows the pore
to open or close, regulating the flow of ions through it.
In contrast, a metabotropic receptor has a binding site for a neurotransmitter but
lacks its own pore through which ions can flow. Through a series of steps, activated
metabotropic receptors indirectly produce changes in nearby ion channels or in the
cell’s metabolic activity (i.e., in activity that requires an expenditure of energy, which
is what the term metabolic means).
164 ! CHAPTER 5
Nitric oxide (NO). Acts as a chemical
neurotransmitter gas—for example, to
dilate blood vessels, aid digestion, and
activate cellular metabolism.
Carbon monoxide (CO). Acts as a
neurotransmitter gas in the activation of
cellular metabolism.
Ionotropic receptor. Embedded
membrane protein with two parts: a
binding site for a neurotransmitter and a
pore that regulates ion flow to directly
and rapidly change membrane voltage.
Metabotropic receptor. Embedded
membrane protein, with a binding site for
a neurotransmitter but no pore, linked to
a G protein that can affect other receptors
or act with second messengers to affect
other cellular processes.
G proteins. Family of guanyl
nucleotide–binding proteins coupled to
metabotropic receptors that, when
activated, bind to other proteins.
Ion
Transmitter
Extracellular
fluid
Intracellular
fluid
Pore
closed
Pore
open
Binding site
Transmitter binds
to the binding site.
The pore opens, allowing the
influx or efflux of ions.
Figure 5-13
Ionotropic Receptor When activated,
these embedded proteins bring about
direct, rapid changes in membrane
voltage.
On your Foundations CD, find the
section on the membrane potential in
the module on neural communication.
Review ionic flow across the cell
membrane. Imagine this flow being
associated with ionotropic-receptor
stimulation to induce action potentials
and neural signals.
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Figure 5-14A shows the first of these two indirect effects. The metabotropic receptor
consists of a single protein that spans the cell membrane, its binding site facing
the synaptic cleft. Receptor proteins are each coupled to one of a family of guanyl
nucleotide-binding proteins, G proteins for short, shown on the inner side of the cell
membrane in Figure 5-14A.
A G protein consists of three subunits: alpha, beta, and gamma. The alpha subunit
detaches when a neurotransmitter binds to the G protein’s associated metabotropic receptor.
The detached alpha subunit can then bind to other proteins within the cell
membrane or within the cytoplasm of the cell.
If the alpha subunit binds to a nearby ion channel in the membrane as shown at
the bottom of Figure 5-14A, the structure of the channel changes, modifying the flow
of ions through it. If the channel is open, it may be closed by the alpha subunit or, if
closed, it may opened. Changes in the channel and the flow of ions across the membrane
influence the membrane’s electrical potential.
The binding of a neurotransmitter to a metabotropic receptor can also trigger
more-complicated cellular reactions, summarized in Figure 5-14B. All of these reactions
begin when the detached alpha subunit binds to an enzyme. The enzyme in turn
HOW DO NEURONS COMMUNICATE AND ADAPT? ! 165
" !
(B) Metabotropic receptor coupled to an enzyme
Binding site
G protein
"
Receptor
" !
(A) Metabotropic receptor coupled to an
ion channel
Closed ion
channel
Transmitter
Binding site
G protein
Ion
#
" !
Open ion
channel
Receptor
" "
Enzyme
#
Alpha subunit
Second messenger
Activates
DNA
Forms new
ion channel
The alpha subunit of the
G protein binds to a
channel, causing a
structural change in the
channel that allows ions
to pass through it.
The alpha subunit binds
to an enzyme, which
activates a second
messenger.
The second messenger
can activate other cell
processes.
Transmitter binds
to receptor in both
types of reaction.
Transmitter
#
Alpha subunit
Receptor-bound
transmitter
Receptor-bound
transmitter
#
!
#
!
#
!
The binding of the
transmitter triggers
activation of G protein
in both types of
reactions.
Figure 5-14
Metabotropic Receptors When
activated, these embedded membrane
proteins trigger associated G proteins,
thereby exerting indirect effects (A) on
nearby ion channels or (B) in the cell’s
metabolic activity.
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activates a second messenger (the neurotransmitter is the first messenger) that carries
instructions to other structures inside the cell. As illustrated in at the bottom of Figure
5-14B, the second messenger can
bind to a membrane channel, causing the channel to change its structure and thus
alter ion flow through the membrane;
initiate a reaction that causes protein molecules within the cell to become incorporated
into the cell membrane, for example, resulting in the formation of new ion channels;
or
instruct the cell’s DNA to initiate the production of a new protein.
In addition, metabotropic receptors allow for the possibility that a single neurotransmitter’s
binding to a receptor can activate an escalating sequence of events called an
amplification cascade. The cascade effect causes many downstream proteins (second
messengers or channels or both) to be activated or deactivated. Ionotropic receptors
do not have such a widespread “amplifying” effect.
No one neurotransmitter is associated with a single receptor type or a single influence
on the postsynaptic cell. Typically, a transmitter may bind either to an ionotropic
receptor and have an excitatory effect on the target cell or to a metabotropic
receptor and have an inhibitory effect. Recall that acetylcholine has an excitatory effect
on skeletal muscles, where it activates an ionotropic receptor, but an inhibitory effect
on the heart, where it activates a metabotropic receptor. In addition, each transmitter
may bind with several different kinds of ionotropic or metabotropic receptors. Elsewhere
in the nervous system, for example, acetylcholine may activate a wide variety of
either receptor type.
NEUROTRANSMITTER SYSTEMS AND BEHAVIOR
When researchers began to study neurotransmission at the synapse a half century ago,
you’ll recall, they reasoned that any given neuron would contain only one transmitter
at all its axon terminals.New methods of staining neurochemicals, however, reveal that
this hypothesis, called Dale’s law after its originator, is an oversimplification.
A single neuron may use one transmitter at one synapse and a different transmitter
at another synapse, as David Sulzer (1998) and his coworkers have shown. Moreover,
different transmitters may coexist in the same terminal or synapse.Neuropeptides
have been found to coexist in terminals with small-molecule transmitters, and more
In Review .
Neurotransmitters are identified with the use of four experimental criteria: synthesis, release,
receptor action, and inactivation. The broad classes of chemically related neurotransmitters
are small-molecule transmitters, peptide transmitters, and transmitter gases.
All the classes are associated with both ionotropic and metabotropic receptors. An
ionotropic receptor contains a pore or channel that can be opened or closed to regulate
the flow of ions through it, which, in turn, directly brings about voltage changes on the
cell membrane. Metabotropic receptors activate second messengers to indirectly produce
changes in the function and structure of the cell. The more than 100 likely neurotransmitters
active in the nervous system are each associated with many different ionotropic
and metabotropic receptors.
166 ! CHAPTER 5
Second messenger. Activated by a
neurotransmitter (the first messenger), a
chemical that carries a message to initiate
a biochemical process.
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than one small-molecule transmitter may be found in a single synapse. In some cases,
more than one transmitter may even be packaged within a single vesicle.
All such findings make for a bewildering number of combinations of neurotransmitters
and receptors for them. They caution as well against the assumption of a simple
cause–effect relation between a neurotransmitter and a behavior.What are the functions
of so many combinations? Neuroscientists do not have a complete answer. Fortunately,
neurotransmission can be simplified by concentrating on the dominant transmitter
located within any given axon terminal. The neuron and its dominant transmitter can
then be related to a function or behavior.
We now consider some of the links between neurotransmitters and behavior.We
begin by exploring the two parts of the peripheral nervous system: somatic and autonomic.
Then we investigate neurotransmission in the central nervous system.
Neurotransmission in the Somatic
Nervous System
Motor neurons in the brain and spinal cord send their axons to the body’s skeletal muscles,
including the muscles of the eyes and face, trunk, limbs, fingers, and toes.Without
these somatic nervous system neurons, movement would not be possible. Motor
neurons are also called cholinergic neurons because acetylcholine is their
main neurotransmitter. (The term cholinergic applies to any neuron that
uses ACh as its main transmitter.) At a skeletal muscle, cholinergic neurons
are excitatory and produce muscular contractions.
Just as a single main neurotransmitter serves the SNS, so does a single
main receptor, an ionotropic, transmitter-activated channel called a nicotinic
ACh receptor (nAChr).When ACh binds to this receptor, the receptor’s
pore opens to permit ion flow, thus depolarizing the muscle fiber. The pore
of a nicotinic receptor is large and permits the simultaneous efflux of potassium
ions and influx of sodium ions. The molecular structure of nicotine,
a chemical found in tobacco, activates the nAChr in the same way that
ACh does, which is how this receptor got its name. The molecular structure
of nicotine is sufficiently similar to ACh that nicotine acts as a ligand, fitting
into acetylcholine receptor binding sites.
Although acetylcholine is the primary neurotransmitter at skeletal
muscles, other neurotransmitters also are found in these cholinergic axon
terminals and are released onto the muscle along with ACh. One of these
neurotransmitters is a neuropeptide called calcitonin-gene-related peptide (CGRP) that
acts through second messengers to increase the force with which a muscle contracts.
Neurotransmission in the Autonomic
Nervous System
The complementary divisions of the ANS, sympathetic and parasympathetic, regulate the
body’s internal environment (see Figure 2-29).Recall from Chapter 2 that the sympathetic
division rouses the body for action, producing the fight-or-flight response. Heart rate
is turned up, digestive functions are turned down. The parasympathetic division calms
the body down, producing an essentially opposite rest-and-digest response. Digestive
functions are turned up, heart rate is turned down, and the body is made ready to relax.
Figure 5-15 shows the neurochemical organization of the ANS. Both ANS divisions
are controlled by acetylcholine neurons that emanate from the CNS at two levels
HOW DO NEURONS COMMUNICATE AND ADAPT? ! 167
Cholinergic neuron. Neuron that uses
acetylcholine as its main neurotransmitter.
Nicotinic ACh receptor (nAChr).
Ionotropic receptor at which
acetylcholine and the drug nicotine act as
ligands to activate the flow of ions
through the receptor pore.
Axon
terminal
Muscle
cell
Muscle
plasma
membrane
0.1 " m
Nicotinic Acetylcholine Receptor From J. E.
Heuser and T. Reese, 1977, in E. R. Kandel, ed., The
Nervous System, vol. 1, Handbook of Physiology,
Oxford University Press, p. 266.
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of the spinal cord. The CNS neurons synapse
with parasympathetic neurons that also contain
acetylcholine, and with sympathetic neurons
that contain norepinephrine. In other words,
ACh neurons in the central nervous system synapse
with sympathetic NE neurons to prepare
the body’s organs for fight or flight. Cholinergic
(ACh) neurons in the CNS synapse with autonomic
ACh neurons in the parasympathetic system
to prepare the body’s organs to rest and
digest.
Whether acetylcholine synapses or norepinephrine
synapses are excitatory or inhibitory
on a particular body organ depends on that
organ’s receptors. During sympathetic arousal,
norepinephrine turns up heart rate and turns
down digestive functions because NE receptors
on the heart are excitatory, whereas NE receptors
on the gut are inhibitory. Similarly, acetylcholine
turns down heart rate and turns up
digestive functions because its receptors on these
organs are different. Acetylcholine receptors on
the heart are inhibitory, whereas those on the gut are excitatory. The activity of neurotransmitters,
excitatory in one location and inhibitory in another, allows the sympathetic
and parasympathetic divisions to form a complementary autonomic regulating
system that maintains the body’s internal environment under differing circumstances.
Neurotransmission in the Central Nervous System
Some CNS neurotransmitters take part in specific behaviors that occur only periodically,
each month or each year perhaps. For instance, neuropeptide transmitters act as
hormones specifically to prepare female white-tail deer for the fall mating season (luteinizing
hormone). Come winter, a different set of biochemicals facilitates the development
of the deer fetus. The mother gives birth in the spring, and yet another set of
highly specific neuropeptide hormones such as oxytocin, which enables her to recognize
her own fawn, and prolactin, which enables her to nurse, takes control.
Some of the same neuropeptides serve similar, specific hormonal functions in humans.
Others, such as neuropeptide growth hormones, have much more general functions
in regulating growth, and neuropeptide corticosteroids mediate general responses
to stress.
In contrast, regulating more general, routine, and continuously occurring (vegetative)
behaviors is mainly the work of small-molecule transmitters. For example, GABA
and glutamate, the most common neurotransmitters in the brains of all animals, regulate
neural excitability. Our minute-to-minute fluctuations in arousal levels are mediated
in part by the changing activity of these two neurotransmitters.
Each of four small-molecule transmitters—acetylcholine, dopamine, norepinephrine,
and serotonin—participates in its own neural activating system that coordinates
wide areas of the brain to act in concert. The cell bodies of each system’s neurons are
located in a restricted region of the brainstem, and their axons are distributed widely
throughout the brain. You can envision the activating systems as being analogous to
the power supply to a house. A branch of the power line goes to each room, but the
electrical devices powered in each room differ.
168 ! CHAPTER 5
Sympathetic division
“fight or flight”
Parasympathetic division
“rest and digest”
KEY
Acetylcholine
Norepinephrine
Figure 5-15
Neurochemistry of the ANS All the
neurons leaving the spinal cord have
acetylcholine as a neurotransmitter.
(Left) In the sympathetic division,
these ACh neurons activate NE neurons,
which stimulate organs required for
fight or flight and suppress the activity
of organs used to rest and digest.
(Right) In the parasympathetic division,
ACh neurons from the spinal cord
activate acetylcholine neurons in the
ANS, which suppress activity in organs
used for fight or flight and stimulate
organs used to rest and digest.
Activating system. Neural pathways
that coordinate brain activity through a
single neurotransmitter; cell bodies are
located in a nucleus in the brainstem and
axons are distributed through a wide
region of the brain.
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HOW DO NEURONS COMMUNICATE AND ADAPT? ! 169
Figure 5-16 shows a cross section of a rat brain stained for the enzyme
acetylcholinesterase, which breaks ACh down in synapses, as depicted earlier
in Figure 5-9.The darkly stained areas of the neocortex have high AChE
concentrations, indicating the presence of cholinergic terminals.High concentrations
of acetylcholine in the basal ganglia and basal forebrain also
render these stained structures very dark in Figure 5-16. The terminals emanate
from neurons that are clustered in a rather small area just in front of
the hypothalamus. Such an anatomical organization, in which a few neurons
send axons to widespread brain regions, suggests that these neurons
play a role in synchronizing activity throughout the brain.
Referred to by the transmitters that their neurons contain, the four major activating
systems are the cholinergic, dopaminergic, noradrenergic, and serotonergic. Figure
5-17 maps the location of each system’s nuclei, with arrow shafts mapping the pathways
of axons and arrowheads indicating axon-terminal locales. The activating systems are
Dopaminergic system
(dopamine)
Serotonergic system
(serotonin):
Cholinergic system
(acetylcholine):
Frontal
cortex
Nucleus
accumbens
in basal
ganglia
Ventral
tegmentum
Caudate nucleus
Thalamus
Locus coeruleus
Corpus callosum
Substantia nigra Cerebellum
Noradrenergic system
(norepinephrine):
Raphé nuclei
Midbrain nuclei
Basal
forebrain
nuclei
" Active in maintaining waking electroencephalographic
pattern of the cortex.
" Thought to play a role in memory by maintaining
neuron excitability.
" Death of cholinergic neurons and decrease in ACh in the
neocortex thought to be related to Alzheimer's desease
Nigrostriatial pathways (orange projections)
" Active in maintaining normal motor behavior
" Loss of DA related to muscle rigidity and dyskinesia
in Parkinson's disease
Mesolimbic pathways (purple projections)
" Dopamine release involved in feelings of reward and pleasure
" Thought to be the neurotransmitter system most affected
by addictive drugs
" Increases in DA activity may be related to schizophenia
" Active in maintaining emotional tone
" Decreases in NE activity thought to be related to depression
" Increases in NE are thought to be related to mania
(overexcited behavior)
" Active in maintaining waking electroencephalographic pattern
" Increases in serotonin activity related to obsessive-compulsive
disorder, tics, and schizophrenia
" Decreases in serotonin activity related to depression
Figure 5-17
Major Activating Systems Each
system’s cell bodies are gathered into
nuclei (large round circles) in the
brainstem. The axons project diffusely
through the brain and synapse on target
structures. Each activating system is
associated with one or more behaviors
or diseases.
Basal ganglia
Neocortex
Acetylcholine
synapses Basal forebrain
neurons
Basal ganglia
Figure 5-16
Cholinergic Activation The drawing
(left) shows the location of the
transverse-section micrograph (right),
stained to reveal AChE. Cholinergic
neurons of the basal forebrain are
located in the lower part of the section,
adjacent to the two white circles (which
are fibers in the anterior commissure).
These neurons project to the neocortex,
and the darkly stained bands in the
cortex show areas rich in cholinergic
synapses. The dark central parts of the
section, also rich in cholinergic neurons,
are the basal ganglia.
CH05.qxd 1/28/05 10:11 AM Page 169

similarly organized in that the cell bodies of their neurons are clustered together in only
a few nuclei in the brainstem, whereas the axons are widely distributed in the forebrain,
brainstem, and spinal cord.
As summarized on the right in Figure 5-17, each activating system is associated
with a number of behaviors.With the exception of dopamine’s clear link to Parkinson’s
disease, however, associations between activating systems and brain disorders are much
less certain than are their links to behaviors. All these systems are subjects of extensive
ongoing research.
The difficulty in making definitive correlations between activating systems and
behavior or activating systems and disorder is that the axons of these systems connect
to almost every part of the brain. One likely relation is the activating systems’ modulatory
roles in many behaviors and disorders.We will detail some of the documented
relations between the systems and behavior and disorders here and in many subsequent
chapters.
CHOLINERGIC SYSTEM
The cholinergic system plays a role in normal waking behavior, evidenced by its contribution
to the electroencephalographic activity recorded from the cortex and hippocampus
in an alert,mentally active person. Cholinergic activation is also thought to
play a role in memory. As detailed in Chapter 13, people who suffer from the degenerative
Alzheimer’s disease, which starts with minor forgetfulness and progresses to
major memory dysfunction, show a loss of these cholinergic neurons at autopsy. One
treatment strategy currently being pursued for Alzheimer’s is to develop drugs that
stimulate the cholinergic system to enhance alertness.
The brain abnormalities associated with Alzheimer’s disease are not limited to
the cholinergic neurons, however. Autopsies reveal extensive damage to the neocortex
and other brain regions. As a result, what role the cholinergic neurons play in the
progress of the disorder is not yet clear. Perhaps their destruction causes degeneration
in the cortex or perhaps the cause-and-effect relation is the other way around,
with cortical degeneration being the cause of cholinergic cell death. Then, too, the
loss of cholinergic neurons may be just one of many neural symptoms of Alzheimer’s
disease.
DOPAMINERGIC SYSTEM
The nigrostriatial dopaminergic system plays a role in coordinating movement. As described
throughout this chapter in relation to Parkinsonism, when DA neurons in the
substantia nigra are lost, the result is a condition of extreme rigidity. Opposing muscles
contract at the same time, making it difficult for an affected person to move.
Parkinson patients also exhibit rhythmic tremors, especially of the limbs, which signals
a release of formerly inhibited movement. Although Parkinson’s disease usually arises
for no known cause, it can actually be triggered by the ingestion of certain drugs, as
described in “The Case of the Frozen Addict.” Those drugs may act as selective neurotoxins
that kill dopamine neurons.
Dopamine in the mesolimbic DA system may be the neurotransmitter most affected
by addictive drugs, as described in Chapters 7 and 11. Many drugs that people abuse
act by stimulating the mesolimbic part of the system, where dopamine release triggers
feelings of reward or pleasure.
Excessive DA activity has a role in schizophrenia, a behavioral disorder characterized
by delusions, hallucinations, disorganized speech, blunted emotion, agitation or
immobility, and a host of associated symptoms. Schizophrenia is one of the most common
and debilitating psychiatric disorders, affecting 1 in 100 people. We examine its
possible causes in Chapter 7 and its neurobiology in Chapter 15.
170 ! CHAPTER 5
Alzheimer’s disease. Degenerative
brain disorder; first appears as progressive
memory loss and later develops into
generalized dementia.
Schizophrenia. Behavioral disorder
characterized by delusions,
hallucinations, disorganized speech,
blunted emotion, agitation or immobility,
and a host of associated symptoms.
Learn more about Parkinson’s disease
at the Brain and Behavior Web site
(www.worthpublishers.com/kolb).
Here you can find links to current
research as well as foundations
supporting investigations of this disorder.

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