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Chemical Control of
the Brain and Behavior
INTRODUCTION
THE SECRETORYHYPOTHALAMUS
AN OVERVIEW
OFTHE HYPOTHALAMUS
Homeostosis
Structure
ond Connections
of the Hypotholomus
PATHWAYS
TO THE PITUITARY
Hypotholomic
Controlof the Posterior
Pituitory
Hypotholamic
Controlof the AnteriorPituitory
r Box 15.l OJ'Special
Inlerest:Stressand the Brain
THE AUTONOMIC NERVOUSSYSTEM
ANS CIRCUITS
Sympotheticond Parosympothetic
Divisions
The EntericDiyision
CentrolControlof the ANS
NEUROTRANSMITTERS
AND THE PHARMACOLOGYOF AUTONOMIC FUNCTION
Pregonglionic Neurotronsmitters
Postganglio nic Neurotronsmitters
THE DIFFUSEMODULATORYSYSTEMSOF THE BRAIN
ANATOMYANDFUNCTIONS
MODULATORY
OFTHE DIFFUSE
SYSTEMS
r Box 15.2 O.fSpecialInterest:YouEat What You Are
The Norodrenergic
LocusCoeruleus
TheSerotonergic
RopheNuclei
The Dopaminergic
Substontio
N(ro andVentrolTegmentol
Areo
r Box 15.) Pathof Discovery:Awakening
to Dopamine,by Arvid Carlsson
TheCholinergic
BosolForebroin
ond BroinStemComplexes
DRUGSAND THE DIFFUSE
MODULATORY
SYSTEMS
Hollucinogens
Stimulonts
CONCLUDING REMARKS
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V INTRODUCTION
It should be obvious by now that knowing the organization of synaptic
connections is essentialto understanding how the brain works. It's not
from a love of Greek and Latin that we belabor the neuroanatomyl Most
of the connectionswe have describedare preciseand specific.For example, in order for you to read thesewords, there must be a very fine-grained
neural mapping of the light falling on your retina-how elsecould you see
the dot on this question mark? The information must be carried centrally
and preciselydispersedto many parts of the brain for processing,coordinated with control of the motor neurons that closelyregulatethe six musclesof each eye as it scansthe page.
In addition to anatomical precision, point-to-point communication in
the sensoryand motor systemsrequires mechanismsthat restrict synaptic
communicationto the cleft betweenthe axon terminal and its target.It just
wouldn't do for glutamate releasedin somatosensorycortex to activate
neurons in motor cortexl Furthermore,transmissionmust be brief enough
to allow rapid responsesto new sensoryinputs. Thus, at these synapses,
only minute quantitiesof neurotransmitterare releasedwith eachimpulse,
and thesemoleculesare then quickly destroyedenzymaticallyor taken up
by neighboring cells. The postsynapticactions at transmitter-gatedion
channelslast only as long as the transmitter is in the cleft, a few milliseconds
at most. Many axon terminalsalsopossesspresynaptic"autoreceptors"that
detectthe transmitter concentrationsin the cleft and inhibit releaseif they
get too high. Thesemechanismsensurethat this type of synaptictransmission is tightly constrained,in both spaceand time.
The elaboratemechanismsthat constrain point-to-point synaptictransmission bring to mind a telecommunicationsanalogy.Telephonesystems
make possiblevery specificconnectionsbetween one place and another;
your mother in Tacomacan talk just to you in Providence,reminding you
that her birthday was last week. The telephone lines can act like precise
synapticconnections.The influenceof one neuron (your mother) is targeted
to a small number of other neurons (in this case,only you). The embarrassingmessageis limited to your earsonly. For a real neuron in one of the
sensoryor motor systemsdiscussedso far, its influence usually extendsto
the few dozen or few hundred cellsit synapseson-a conferencecall, to be
sure, but still relatively specific.
Now imagine your mother being interviewed on a television talk show,
which is broadcastvia a cable network. In this case,the widespreadcable
connectionsmay allow her to tell millions of people that you forgot her
birthday, and the loudspeaker in each television set will announce the
messageto anyone within earshot. Likewise, certain neurons communicate with hundreds of thousandsof other cells.Thesewidespreadsystems
also tend to act relatively slowly, over secondsto minutes. Becauseof
their broad, protracted actions, such systemsin the brain can orchestrate
entire behaviors, ranging from falling asleep to falling in love. Indeed,
many of the behavioral dysfunctionscollectively known as mental disorders are believed to result specificallyfrom imbalancesof certain of these
chemicals.
In this chapter,we take a look at three componentsof the nervous system
that operatein expandedspaceand time (Figure l5.I). One component is
L}resecretory
hypothalamus.
By secretingchemicalsdirectly into the bloodstream, the secretoryhypothalamus can influence functions throughout
both the brain and the body. A secondcomponent, controlled neurally by
the hypothalamus, is the autonomicnervoussystem(,4NS),introduced in
Chapter 7. Through extensiveinterconnectionswithin the body, the ANS
V INTRODUCTION
o
(a)
:
-
F
t
FIGURE
I5.I
Patternsof communicationin the nervoussystem.(a) Mostof the systems
we
properfunctioning
havediscussed
inthisbookmaybe described
aspoint-to-point.The
of
thesesystems
requires
restricted
synaptic
activation
of targetcellsandsignals
of briefduration.In contrast,
threeothercomponents
of the nervous
system
actovergreatdistances
andfor longperiods
of time,(b) Neurons
of thesecretory
hypothalamus
affect
their
(c) Networlaof intermanytargetsby releasing
hormones
directlyintothe bloodstream.
connected
neurons
of theANScanworktogether
to activate
tissues
alloverthe body.
(d) Diffuse
modulatory
systems
extend
theirreach
withwidelydivergent
axonal
proJectrons.
simultaneouslycontrols the responsesof many internal organs,blood vessels, and glands. The third component exists entirely within the central
nervous system(CNS)and consistsof severalrelated cell groupsthat differ
with respectto the neurotransmitterthey use. All of these cell groups extend their spatialreach with highly divergent axonal projectionsand prolong their actionsby using metabotropicpostsynapticreceptors.Members
of this component of the nervous system are called t}:'e diffusemodulatory
systems
of the brain. The diffuse systemsare believed to regulate, among
other things, the level of arousaland mood.
This chapter servesas a general introduction to these systems.In later
chapters, we will see how they contribute to specificbehaviors and brain
states:motivation (Chapter l6), sexual behavior (Chapter l7), emotion
(Chapterl8), sleep (Chapter t9), and psychiatricdisorders(Chapter22).
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V THE SECRETORYHYPOTHALAMUS
Recallfrom Chapter 7 that the hypothalamus sits below the thalamus, along
the walls of the third ventricle. Ir is connecredby a stalk to the piruitary
gland, which danglesbelow the base of the brain, just above the roof of
your mouth (Figure 15.2). Although this tiny cluster of nuclei makes up
lessthan Io/oof.the brain'smass,the influenceof the hypothalamuson body
physiology is enormous. Let's take a brief tour of the hypothalamus and
then focus on some of the ways in which it exerts its powerful influence.
An Overview of the Hypothalamus
The hypothalamus and dorsal thalamus are adjacentto one another, but
their functions are very different. As we saw in the previous seven chapters, the dorsalthalamuslies in the path of all the point-to-point pathways
whose destinationis the neocortex.Accordingly,the destructionof a small
part of the dorsalthalamuscan produce a discretesensoryor motor deficit:
a little blind spot, or a lack of feeling on a portion of skin. In contrast,the
hypothalamusintegrates
somaticand visceralresplnses
in accordance
with the needs
of the brain. A tiny lesion in the hypothalamus can produce dramatic and
often fatal disruptionsof widely dispersedbodily functions.
Opticchiasm Pituitary Hypothalamus
FIGURE
I5.2
Locations of the hypothalamus and
pituitary.Thisis a midsagittal
section.
Notice
thatthe hypothalamus,
whosebordersare
indicated
with a dashedline,formsthe wall
of the thirdventricleandsitsbelowthe dorsal
thalamus.
Homeostasis. In mammals, the requirements for life include a narrow
range of body temperaturesand blood compositions.The hypothalamus
regulatestheselevelsin responseto a changingexternal environment. This
regulatory processis called homeostasis, the maintenance of the body's
internal environment within a narrow physiologicalrange.
Considertemperatureregulation.Biochemicalreactionsin many cellsof
the body are fine-tuned to occur at about )7.C. A variation of more than
a few degreesin either direction can be catastrophic.Temperature-sensitive
cells in the hypothalamus detect variations in brain temperature and orchestratethe appropriateresponses.For example, when you stroll naked
through the snow, the hypothalamusissuescommandsthat causeyou to
shiver (generatingheat in the muscles),develop goosebumps(a futile attempt to fluff up your nonexistent fur-a reflexive remnant from our
hairier ancestors),and turn blue (shuntingblood awayfrom the cold surface
tissuesto keep the sensitivecore of the body warmer). In contrast,when
you go for a jog in the tropics,the hypothalamusactivatesheat-lossmechanismsthat make you turn red (shuntingblood /o the surfacetissueswhere
heat can be radiated away) and sweat (cooling the skin by evaporation).
Other examplesof homeostasisare the tight regulation of blood volume,
pressure,salinity, acidity, and blood oxygen and glucose concentrations.
The means by which the hypothalamus achievesthese different types of
regulation are remarkablydiverse.
Structure and Connections of the Hypothalamus. Each side of the
hypothalamushas three functional zones:lateral, medial, and periventricular (Figure 15.3).The lateral and medial zoneshave extensiveconnections
with the brain stem and the telencephalonand regulate certain types of
behavior,as we will see in Chapter 16. Here we are concernedonly with
the third zone,which actuallyreceivesmuch of its input from the other two.
The periventricular zone is so named because,with the exception of
a thin finger of neurons that are displacedlaterally by the optic tract
(calledthe supraopticnucleus),the cellsof this region lie right next to the
wall of the third ventricle. Within this zone existsa complex mix of neurons
with different functions. one group of cells constitutes the suprachiasmatic
nucleus(SCN),which lies just above the optic chiasm. These cells receive
V THE SECRETORY
HYPOTHALAMUS
485
1,,,"
)
thalamus
Periventricular -,l
Third
ventricle
FIGURE
I5.3
hasthreefunctional
zones:
lateral,
Zonesof the hypothalamus.
Thehypothalamus
periventricular
zonereceives
inputsfromthe otherzones,
the
medial,
andperiventricular:The
zonesecrete
andthetelencephalon.
Neurosecretory
cellsinthe periventricular
brainstem,
nervous
intothebloodstream.
cellscontrol
theautonomic
hormones
Otheroeriventricular
system.
direct retinal innervation and function to synchronize circadian rhythms
with the daily light-dark cycle (seeChapter 19). Other cellsin the periventricular zone control the ANS, and regulate the outflow of the sympathetic
and parasympatheticinnervation of the visceral organs.The cells in a third
group, calledneurosecretory
neurons,extend axons down toward the stalk of
the pituitary gland. These are the cells that now command our attention.
Pathways to the Pituitary
We have said that the pituitary danglesdown below the base of the brain,
which is true if the brain is lifted out of the head. In a living brain, the
pituitary is gently held in a cradle of bone at the base of the skull. It requires this specialprotection becauseit is the "mouthpiece" from which
much of the hypothalamus "speaks"to the body. The pituitary has two
lobes, posterior and anterior. The hypothalamus controls the two lobes in
different ways.
Hypothalamlc Control of the Posterior Pituitary. The largest of the
hlpothalamic neurosecretory cells, magnocellular neurosecretory cells,
extend axons around the optic chiasm, down the stalk of the pituitary and
into the posterior lobe (Figure 15.4). In the late 1930s,Ernst and Berta
Scharrer,working at the University of Frankfurt in Germany,proposedthat
these neurons releasechemical substancesdirectly into the capillariesof the
posterior lobe. At the time, this was quite a radical idea. It was well established that chemical messengerscalled hormones were releasedby glands
into the bloodstream, but no one anticipated that a neuron could act like
a gland or that a neurotransmitter could act like a hormone. The Scharrers
were correct, however. The substancesreleasedinto the blood by neurons
are now called neurohormones.
The magnocellular neurosecretory cells releasetwo neurohormones into
the bloodstream,oxytocin and vasopressin.Both of these chemicalsare peptides, each consistingof a chain of nine amino acids.Oxytocin, releasedduring the final stagesof childbirth, causesthe uterus to contract and facilitates
485
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FIGURE
I5.4
lrlagnocellularncurprecl€tory cellr of thc lrypothelamur.Thisisa midsagittal
view
of the hypothalamus
andpituitaryMagnocellular
neurosecretory
cellssecrete
oxytocinand
vasopressin
directlyintocapillaries
in the posterior
lobeof the pituitary
the delivery of the newbom. It also stimulates the ejection of milk from the
mammary glands. All lactating mothers know about the complex "letdown" reflex that involves the oxytocin neurons of the hypothalamus.
Oxytocin releasemay be stimulated by the somatic sensationsgeneratedby
a suckling baby. But the sight or cry of a baby (even someone else,s)can
also trigger the release of milk beyond the mother's conscious control. In
each case,information about a sensory stimulus-somatic, visual, or auditory-reaches the cerebralcortex via the usual route, the thalamus, and the
cortex ultimately stimulates the hypothalamus to trigger oxytocin release.
The cortex can also suppresshypothalamic functions, as when anxiety inhibits the letdown of milk.
Vasopressin, also called antidiuretic hormone (ADH), regulates
blood volume and salt concentration. When the body is deprived of water,
the blood volume decreasesand blood salt concentration increases.These
changes are detected by pressure receptors in the cardiovascular system
and salt concentration-sensitive cells in the hypothalamus, respectively.
vasopressin-containingneurons receive information about these changes
and respond by releasing vasopressin,which acts directly on the kidneys
and leads to water retention and reduced urine production.
Under conditions of lowered blood volume and pressure,communication
between the brain and the kidneys actually occurs in both directions (Figure 15.5).The kidneys secretean enzymeinto the blood calledrmin.Blevated
renin sets off a sequenceof biochemical reactions in the blood. Angiotensinogen, alarge protein releasedfrom the liver, is converted by renin to angiotensin
HYPOTHALAMUS
THE SECRETORY
Loweredblood
pressure
FIGURE
I5.5
of lowered
Communicationbetweenthe kidneysand the brain.Underconditions
Renininthe
reninintothe bloodstream,
or pressure,
the kidney
secretes
bloodvolume
in
ll,whichexcites
theneurons
angiotensin
bloodpromotes
thesynthesis
of the peptide
an
neurons
the hypothalamus,
causing
organ.The
subfornical
stimulate
thesubfornical
(ADH)oroduction
in vasooressin
anda feelins
of thirst,
increase
1, which breaks down further to form another small peptide hormone,
I1. AngiotensinII has direct effectson the kidney and blood vesangiotensin
sels,which help increaseblood pressure.But angiotensinII in the blood is
organ,a part of the telencephalonthat lacks
also detectedby the subfornical
a blood-brain barrier. Cellsin the subfornicalorgan project axons into the
hypothalamuswhere they activate,among other things, the vasopressincontaining neurosecretorycells.In addition, however, the subfornical organ
activatescellsin the lateral area of the hypothalamus,somehowproducing
an overwhelming thirst that motivates drinking behavior. It may be difficult to accept,but it's true: To a limited extent, our brain is controlled by
our kidneyst This example also illustrates that the means by which the
hypothalamus maintains homeostasisgo beyond control of the visceral
organs and can include the activation of entire behaviors.In Chapter 16,
we will explore in more detail how the hypothalamusincitesbehavior.
Hypothalamic Control of the Anterior Pituitary. Unlike the posterior
Iobe, which really is a part of the brain, the anterior lobe of the pituitary is
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C H E M I C ACLO N T R O L
O F T H EB R A I N A N DB E H A V I O R
Table15.I Hormones of the Anterior Pituitary
HORMONE
TARGET
ACTION
Follicle-stimulating
hormone (FSH)
Luteinizinghormone (LH)
Thyroid-stimulatinghormone
(TSH);also called
thyrotropin
Adrenocorticotropic
hormone (ACTH);
also called corticotropin
Gonads
Ovu lation,spermatogenesis
Gonads
Thyroid
Ovarian,sperm maturation
Thyroxin secretion (increases
metabolic rate)
Adrenal cortex
Cortisol secretion (mobilizes
energy stores;inhibits
immune system;other
actions)
Stimulationof protein
synthesis
Growth and milk secretion
Growth hormone (GH)
All cells
Prolactin
Mammary
glands
an actual gland. The cells of the anterior lobe synthesizeand secretea wide
range of hormones that regulate secretionsfrom other glands throughout
the body (together constituting the endocrine system). The pituitary hormones act on the gonads, the thyroid glands, the adrenal glands, and the
mammary glands (Table 15.1). For this reason, the anterior pituitary was
traditionally describedas the body's "master gland." But what controls the
master gland? The secretory hypothalamus does. The hypothalamusitself is
the true mastergland of the endocrinesystem.
The anterior lobe is under the control of neurons in the periventricular
area called parvocellular neurosecretory
cells. These hypothalamic
neurons do not extend axons all the way into the anterior lobe; instead,
they communicate with their targers via the bloodstream (Figure 15.6).
These neurons secrete what are called hypophysiotropic
hormones into
a uniquely specialized capillary bed at the floor of the third ventricle. These
tiny blood vesselsrun down the stalk of the pituitary and branch in the
anterior lobe. This network of blood vessels is called the hypothalamopituitary portal circulation. Hypophysiotropic hormones secreted by
hypothalamic neurons into the portal circulation travel downstream until
they bind to specific receptors on the surface of pituitary cells. Activation
of these receptors causes the pituitary cells to either secrete or stop secreting hormones into the general circulation.
Regulation of the adrenal glands illustrates how this system works. Located
just above the kidneys, the adrenal glands consist of two parts, a shell called
the adrenal cortex and a center called the adrenal medulla. The adrenal
cortex produces the steroid hormone cortisol; when it is released into the
bloodstream, cortisol acts throughout the body to mobilize energy reserves
and suppress the immune system, preparing us to carry on in the face of
life's various stresses.In fact, a good stimulus for cortisol release is stress,
ranging from physiological stress, such as a loss of blood; to positive emotional stimulation, such as falling in love; to psychological stress, such as
anxiety over an upcoming exam.
Parvocellular neurosecretory cells that control the adrenal cortex determine
whether a stimulus is stressful or not (as defined by the release of cortisol).
These neurons lie in the periventricular hypothalamus and release a peptide
V THE SECRETORY
HYPOTHALAMUS
FIGURE
I5.6
neurosecreParvocellular
cellsof the hypothalamus.
Parvocellular
neunosecretory
capillary
bedsof thehypothalhormones
intospecialized
hypophysiotropic
torycellssecrete
lobeof thepituitary,
portalcirculation.These
hormones
travelto theanterior
amo-pituitary
cells.
hormones
fromsecretory
the release
of pituitary
wheretheytrigger
or inhibit
hormone(CRII) into the blood of the portal circalled corticotropin-releasing
culation. CRH travels the short distanceto the anterior pituitary, where,
or adrenowithin about l5 seconds,it stimulatesthe releaseof corticotropin,
corticotropic
hormone\ACIH\. ACTH enters the general circulation and travels
to the adrenal cortex where, within a few minutes, it stimulates cortisol
release(Figure15.7).
Blood levels of cortisol are, to some extent, self-regulated.Cortisol is a
steroid,which is a classof biochemicalsrelatedto cholesterol.Thus, cortisol
is a lipophilic ("fat-loving") molecule, which will dissolve easily in lipid
membranesand readily crossthe blood-brain barrier. In the brain, cortisol
interactswith specificreceptorsthat lead to the inhibition of CRH release,
thus ensuring that circulating cortisol levels do not get too high. Surprisingly, however, neurons with cortisol receptorsare found widely distributed
in the brain, not just in the hypothalamus.In theseother CNSlocations,cortisol has been shown to have significant effectson neuronal activity. Thus,
we seethat the releaseof hypophysiotropic hormones by cells in the secretory hypothalamuscan producewidespreadalterationsin the physiologyof
both the bodv and the brain (Box l5.l).
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CHEMICALCONTROF
L T H EB M I N A N D B E H A V I O R
FIGURE
I5.7
The stress resPonse.Underconditions
of physiological,
emotional,
or psychological
stimulalionor stress,
the periventricular
hypothalamus
secretes
corticotropin-releasing
hormone
(CRH)intothe hypothalamo-pituitary
portalcirculation.This
triggersthe release
of adrenocorticotropic
hormone(ACTH)intothe generalcirculation.
ACTH stimulates
the release
of
cortisolfromthe adrenalcortex.Cortisolcanact directlyon hypothalamic
neurons,
aswell
as on otherneuronselsewhere
in the brain.
V THE AUTONOMIC NERVOUS SYSTEM
Besidescontrolling the ingredients of the hormonal soup that flows in
our veins, the periventricular zone of the hypothalamusalso controls the
autonomic nervous system (ANs). The ANS is an extensivenetwork of
interconnectedneurons that are widely distributedinside the body cavity.
From the Greekautonomia,autonomic roughly means ,,independence,,;
autonomic functionsare usually carriedout automatically,without conscious,
voluntary control. They are also highly coordinatedfunctions. Imagine a
sudden crisis. In a morning class,as you are engrossedin a crossword
puzzle, the instructor unexpectedly calls you to the blackboard to solve an
impossible-lookingequation.You are facedwith a classicfight-or-flight situation, and your body reacts accordingly,even as your consciousmind
frantically considerswhether to blunder through it or beg off in humiliation.
Your ANS triggers a host of physiologicalresponses,including increased
heart rate and blood pressure,depresseddigestivefunctions,and mobilized
glucose reserves.These responsesare all produced by the sympathetic
division of the ANS. Now imagine your relief as the class-endingbell
suddenly rings, savingyou from acute embarrassmentand the instructor's
anger. You settle back into your chair, breath deeply, and read the clue for
24 DOWN. Within a few minutes, your sympatheticresponsesdecreaseto
low levels, and the functions of your parasympathetic division crank up
Jii THEAUTONOMIC
NERVOUS
SYSTEM
491
Stressand the Brain
Biologicalstressis created by the brain,in resPonseto
responses
real or imaginedstimuli.Themanyphysiological
associatedwith stress help protect the body, and the
brain, from the dangersthat triggered the stress in the
first place.But stressin chronic dosescan haveinsidious
harmful effects as well. Neuroscientistshave only begun
to understandthe relationshipbetweenstress,the brain,
and brain damage.
Stressleadsto the releaseof the steroidhormonecortisol from the adrenalcortex. Cortisol travelsto the brain
through the bloodstreamand binds to recePtorsin the
cytoplasmof many neurons.Theactivatedreceptorstravel
to the cell nucleus,where they stimulategene transcripof
One consequence
tion and ultimatelyproteinsynthesis.
cortisol'sactionis that neuronsadmit more Ca2+through
This may be due to a direct
ion channels.
voltage-gated
or it may be indirectlycausedby
changein the channels,
changesin the cell's energy metabolism.Whatever the
presumablyin the short term, cortisol makes
mechanism,
the brain better ableto cope with the stress-perhaps by
helpingit figure out a way to avoid it!
But what about the effects of chronic, unavoidable
stress?In Chapter 6, we learnedthat too much calcium
can be a bad thing.lf neuronsbecome overloadedwith
The questionnaturally
calcium,they die (excitotoxicity).
arises:Can cortisol kill?BruceMcEwenand his colleagues
at RockefellerUniversity,and Robert Sapolskyand his
at StanfordUniversity,havestudiedthis quescolleagues
tion in the rat brain.They found that daily iniectionsof
corticosterone (rat cortisol) for severalweeks caused
dendritesto wither on manyneuronswith corticosterone
receotors.Afew weeks later,these cellsstartedto die.A
similarresult was found when, insteadof daily hormone
injections,the rats were stressedevery day.
Sapolsky'sstudies of baboons in Kenya further reveal
the scourgesof chronicstress.Baboonsin the wild maintain a complex social heirarchy,and subordinatemales
steer clearof dominantmaleswhen they can.During one
year when the baboonpopulationboomed,localvillagers
caged many of the animalsto prevent them from de"toP baboons"
stroyingtheir crops.Unableto escapethe
in the cages,manyof the subordinatemalessubsequently
died-not from wounds or malnutrition,but apparently
from severe and sustainedstress-inducedeffects.They
h a d g a s t r i cu l c e r s ,c o l i t i s ,e n l a r g e da d r e n a lg l a n d s a, n d
extensivedegenerationof neuronsin their hippocampus.
Subsequentstudiessuggestthat it is the direct effect of
These effectsof
cortisol that damagesthe hippocampus.
effects
of aging on the
cortisol and stress resemblethe
s
h
o
w
n that chronic
b r a i n .I n d e e d ,r e s e a r c hh a s c l e a r l y
the
brain.
stresscausesprematureagingof
In humans,exDosureto the horrors of combat,sexual
abuse,and other types of extreme violencecan lead to
posttraumaticstressdisorder,with symptomsof heightened
a n x i e t y ,m e m o r y d i s t u r b a n c e sa,n d i n t r u s i v et h o u g h t s .
lmaging studies have consistentlyfound degenerative
changesin the brainsof victims,particularlyin the hippocampus.In Chapter22, we will see that stress,and the
brain'sresponseto it, playsa central role in severalpsychiatricdisorders.
again: Your heart rate slows and blood pressure drops, digestive functions
work harder on breakfast, and you stop sweating.
Notice that you may not have moved out of your chair throughout this
unpleasant event. Maybe you didn't even move your pencil. But your
body's internal workings reacted dramatically. Unlike the somaticmotlr system,
whose alpha motor neurons can rapidly excite skeletal muscles with pinpoint accuracy,the actions of the ANS are typically multiple, widespread,
and relatively slow. Therefore, the ANS operates in expanded space and
time. In addition, unlike the somatic motor system, which can only excite
its peripheral targets, the ANS balances synaptic excitation and inhibition
to achieve widely coordinated and graded control.
ANS Circuits
Together,the somatic motor system and the ANS constitute the total neural output of the CNS. The somatic motor system has a single function: It
innervates and commands skeletal muscle fibers. The ANS has the complex
492
cHAprER
| 5 . cHEMtcALcoNTRoLoFTHEBRAINANDBEHAVIoR
FIGUREI5.8
The organization ofthe three neural
outputs of the CNS. The sole output of
the somatic motor system is the lower motor
neuronsin the ventral horn ofthe spinalcord
and the brain stem,which Sherrinetoncalled
the finalcommon pathwayfor thJgeneration
of behavior:Br.rtsome behaviors,such as salivating,sweating,and genitalstimulation,depend insteadon the ANS.Thesevisceralmotor responsesdepend on the sympatheticand
parasympathetic
divisionsof the ANS, whose
lower motor neurons(i.e.,postganglionic
neurons)lie outsidethe CNS in autonomic
ganglra.
ANS
Somaticmotor
Sympathetic
Parasympathetic
CNS
Preganglionic
fibers
Autonomic
(sympathetic)
ganglion
PNS
Autonomic
(parasympathetic)
ganglion
Postganglionic
fibers
task of commandingeveryothertissu,e
and organ in the body that is innervated.Both systemshave upper motor neurons in the brain that send commands to lower motor neurons, which actually innervate the peripheral
target structures.However,they have some interestingdifferences(Figure
15.8). The cell bodies of all somatic lower motor neurons lie within the
cNS, in either the ventral horn of the spinal cord or the brain stem. The
cell bodies of all autonomic lower motor neurons lie outside the cNS,
within cell clusterscalledautonomic ganglia. The neurons in theseganglia
are called postganglionic neurons. postganglionicneurons are driven by
preganglionic neurons, whose cell bodies are in the spinal cord and brain
stem. Thus, the somatic motor system controls its peripheral targets via a
monosynaptic
pathway,while the ANS uses a disynapticpathway.
sympathetic and Parasympathetic Divisions. The sympathetic and
parasympatheticdivisions operate in parallel, but they use pathways that
are quite distinct in structure and in their neurotransmitter systems.preganglionic axons of the sympathetic division emerge only from the middle
third of the spinal cord (thoracicand lumbar segments).In conrrasr,preganglionic axons of the parasympatheticdivision emerge only from the
brain stem and the lowest (sacral)segmentsof the spinal cord, so the two
systemscomplementeach other anatomically (Figure I5.9).
FIGURE
I5.9>
The chemicaland anatomicalorganizationof the sympatheticand parasympatheticdivisionsof the ANS. Noticethatthepreganglionic
inputs
of bothdivisions
useAChasa neurotransmitter:The
postganglionic
parasympathetic
innervation
of thevisceral
organs
alsouses
ACh,butthepostganglionic
sympathetic
innervation
usesnorepinephrine
(with the exceptionof innervationof the sweat glandsand vascularsmooth musclewithin
skeletalmuscle,which use ACh).The adrenalmedullareceivespreganglionic
sympatheticinnervation and secretesepinephrine into the bloodstream when activated.Note the pattern
of innervation by the sympatheticdivision:Targetorgans in the chest cavity are contacted by
postganglionic
neuronsoriginatingin the sympatheticchain,and target organsin the abdominal cavity are contacted by postganglionicneurons originatingin the collateral ganglia.
W THEAUTONOMICNERVOUS
SYSTEM
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Lacrimal
Lungs
salivaryglands
:
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I
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(lX)
nerve (lii
nerve
Glossopharyngeal
Glossopharyngeat
Y
Constricts
bloodvessels
Relaxes
airways
Accelerates
heartbeat
"".\
\
glucose
Stimulates
and
Production
release
(
,l
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/
l
Stimulates
digestion
-'" "-* "-"1
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Stimulates
secretionof
and
epinephrine
norepinephrine
fromadrenal
medulla.
A
A
'lcreas
, Vaousnerve(X)
,
l
'
,l
/
pancreas
-- -- -^" / Stimulates
;!."".*)./ to releaseinsulin
,i anddigestive
enzvmes
;
.i
I
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r
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vesselsin gut
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intestine
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urinary
Stimulates
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bladder
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orgasm /t/
Stimulates
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sexual
I Stimulates
arousal
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neurons
AChneurons
' li
r {
l
494
CHAPTER
I5
.
C H E M I C A L C O N T R O L O F T H E B R A I NB
AE
NH
DA V I O R
The preganglionic neurons of the sympathetic division lie within the intermediolateral
gray matterof the spinal cord. They send their axons through
the ventral roots to synapseon neurons in the ganglia of the sympathetic
chain, which lies next to the spinal column, or within collateral ganglia
found within the abdominal cavity. The preganglionic parasympathetic
neurons, on the other hand, sit within a variety of brain stem nuclei and
the lower (sacral)spinal cord, and their axons travel within severalcranial
nervesas well as the nerves of the sacralspinal cord. The parasympathetic
preganglionicaxons travel much farther than the sympatheticaxons, becausethe parasympatheticganglia are typically located next to, on, or in
their targetorgans(seeFigures15.8and I5.9).
The ANS innervates three types of tissue: glands, smooth muscle, and
cardiacmuscle.Thus, almost every part of the body is a target of the ANS,
as shown in Figure 15.9. The ANS:
I Innervatesthe secretoryglands(salivary sweat,tear, and variousmucusproducing glands).
r Innervates the heart and blood vesselsto control blood pressureand
flow
t Innervatesthe bronchi of the lungs to meet the oxygen demandsof the
body.
I Regulatesthe digestiveand metabolic functions of the liver, gastrointestinal tract, and pancreas.
t Regulatesthe functions of the kidney, urinary bladder, large intestine,
and rectum.
r Is essentialto the sexualresponses
of the genitalsand reproductiveorgans.
t Interactswith the body's immune system.
The physiological influences of the sympathetic and parasympathetic
divisionsgenerallyopposeeach other. The sympatheticdivision tends to be
most activeduring a crisis,real or perceived.The behaviorsrelatedto it are
summarizedin the puerile (but effective)mnemonic used by medical students, calledthe four Fs: fight, flight, fright, and sex. The parasympathetic
division facilitatesvarious non-four-F processes,
such as digestion,growth,
immune responses,and energy storage.In most cases,the activity levelsof
the two ANS divisionsare reciprocal;when one is high, the other tends to
be low and vice versa.The sympatheticdivision freneticallymobilizesthe
body for a short-term emergencyat the expenseof processesthat keep it
healthy over the long term. The parasympatheticdivision works calmly for
the long-term good. Both cannot be stimulatedstrongly at the sametime;
their generalgoalsare incompatible.Fortunately,neural circuitsin the cNS
inhibit activity in one division when the other is active.
some exampleswill help illustrate how the balance of activity in the
sympatheticand parasympatheticdivisions controls organ functions. The
pacemakerregion of the heart triggerseach heartbeatwithout the help of
neurons,but both divisionsof the ANS innervate it and modulate it; sympatheticactivity resultsin an increasein the rate of beating,while parasympathetic activity slows it down. The smooth musclesof the gastrointestinal
tract are also dually innervated,but the effect of each division is the opposite of its effecton the heart. Intestinal motility, and thus digestion,is stimulated by parasympatheticaxons and inhibited by sympatheticaxons. Not
all tissuesreceiveinnervation from both divisions of the ANS. For example, blood vesselsof the skin, and the sweat glands,are innervated only by
excitatory sympatheticaxons. Lacrimal (tear-producing)glandsare excited
only by parasympatheticinput.
1T THEAUTONOMICNERVOUS
SYSTEM
Another example of the balance of parasympathetic-sympatheticactivity
is the curious neural control of the male sexual response.Erection of the
h u m a n p e n i s i s a h y d r a u l i c p r o c e s s .I t o c c u r s w h e n t h e p e n i s b e c o m e s
engorged with blood, which is triggered and sustained by parasympathetic
activity. The curious part is that orgasm and ejaculation are triggered by
sympatheticactivity. You can imagine how complicated it must be for the
nervous system to orchestratethe entire sexual acu parasympatheticactivity gets it going (and keeps it going), but a shift to sympathetic activity is
necessaryto terminate it. Anxiety and worry, and their attendant sympathetic activity, tend to inhibit erection and promote ejaculation. Not surprisingly, impotence and premature ejaculation are common complaints
o f t h e o v e r s t r e s s e dm a l e . ( W e w i l l d i s c u s s s e x u a l b e h a v i o r f u r t h e r i n
C h a p t e r1 7 . )
"little brain," as the enteric division of the
The Enteric Division. The
ANS is sometimes called, is a unique neural system embedded in an unlikely place: the Iining of the esophagus,stomach, intestines,pancreas,and
gallbladder. It consists clf two complicated networks, each with sensory
nerves, interneurons, and autonomic motor neurons, called the myenteric
plexus (Figure 15.10). These
(Auerbach's)plexus and submucous(Meissner's)
networks control many of the physiologicalprocessesinvolved in the transport and digestion of food, from oral to anal openings. The enteric system
is not small; it contains about the same number of neurons as the entire
spinal cord !
Blood
vessel
Axon
Small
intestine
i
t
\
FIGURE
I5.IO
view of the smai ntestrneshows
The enteric division of the ANS. This cross-sectional
tne rrlente'ic plexusand t"e subnucousplex-s.
rhe two networ\s o{ tr^eente'ic divis'o^:
They both containvsceralsensoryand motor neuronsthat contro the functonsofthe
d gestrveorgans.
495
495
C HAPTE R I 5
.
CHEMICALCONTROL
OFTHEBRATNAND
BEHAVIOR
If the enteric division of the ANS qualifies as ,,brain,,(which may be overstating the case),it is becauseit can operate with a great deal of independence.Entedc sensoryneurons monitor tension and stretchof the gastrointestinal walls, the chemical statusof stomach and intestinal contents,
and hormone levels in the blood. This information is used by the enteric
interneuronal circuits to control the activity levels of enteric output motor
neurons,which govern smooth musclemotility, the production of mucous
and digestivesecretions,and the diameter of the local blood vessels.For
example, consider a partially digestedpizza making its way through the
small intestine. The myenteric plexus ensuresthat lubricating mucus and
digestiveenzymesare delivered, that rhythmic (peristaltic)muscle action
works to mix the pizza and enzymes thoroughly, and that intestinal blood
flow increasesto provide a sufficient fluid sourceand transport newly acquired nutrients to the rest of the body.
The enteric division is not entirely autonomous. It receivesinput indirectly from the "real" brain via axons of the sympatheticand parasympathetic divisions.Theseprovide supplementarycontrol and can supersede
the functions of the enteric division in some circumstances.For example,
the enteric nervous system and digestive functions are inhibited by the
strong activation of the sympathetic nervous system that occurs during
acute stress.
central control of the ANS. As we have said, the hypothalamusis the
main regulator of the autonomic preganglionicneurons. Somehow this
diminutive structureintegratesthe diverseinformation it receivesabout the
body's status,anticipatessome of its needs,and providesa coordinatedset
of both neural and hormonal outputs. Essentialto autonomic control are
the connectionsof the periventricular zone to the brain stem and spinal
cord nuclei that contain the preganglionicneurons of the sympatheticand
parasympatheticdivisions.The nucleus of the solitary tract, located in
the medulla and connectedwith the hypothalamus,is another important
center for autonomic control. In fact, some autonomic functions operate
well even when the brain stem is disconnectedfrom all structuresaboveit,
including the hypothalamus.The solitary nucleus integratessensoryinformation from the internal organsand coordinatesoutput to the autonomic
brain stem nuclei.
Neurotransmitters and the
Pharmacologyof Autonomic Function
Even people who have never heard the word neurotransmitterknow what
it means to "get your adrenaline flowing." (In the United Kingdom the
compound is called adrenaline,while in the united states we call it epinephrine.) Historically, the ANS has probably taught us more than any
other part of the body about how neurotransmitterswork. Becausethe
ANS is relatively simple compared to the cNS, we understand the ANS
much better. In addition, neurons of the peripheral parts of the ANS are
outsidethe blood-brainbarrier,so all drugsthat enter the bloodstreamhave
direct accessto them. The relative simplicity and accessibilityof the ANS
have led to a deeperunderstandingof the mechanismsof drugs that influence synaptictransmission.
Preganglionic Neurotransmitters. The primary transmitter of the peripheral autonomic neurons is acetylcholine
(AChl, the sametransmitter used
at skeletal neuromuscular junctions. Thepreganglionic
neuronsof bothsympa-
SYSTEM
V THEAUTONOMICNERVOUS
ACh.The immediate effect is that the
divisionsrelease
theticand parasympathetic
ACh binds to nicotinic ACh receptors(nAChR),which are ACh-gatedchannels, and evokes a fast excitatory postsynapticpotential (EPSP)that usually
triggers an action potential in the postganglioniccell. This is very similar to
the mechanismsof the skeletal neuromuscular junction, and drugs that
block nAChRs in muscle, such as curare, also block autonomic output.
GanglionicACh does more than neuromuscularACh, however. It also
activatesmuscarinicACh receptors(mAChR), which are metabotropic
(G-protein-coupled) receptorsthat can causeboth the opening and the
closingof ion channelsthat lead to very slow EPSPsand inhibitory postsynaptic potentials (IPSPs).These slow mAChR events are usually not evident unlessthe preganglionicnerve is activatedrepetitively.In addition to
ACh, some preganglionicterminals releasea variety of small, neuroactive
intestinalpolypep'
Yl and WP (vasoactive
peptides such as NPY (neuropeptide
tide\.Thesealso interact with G-protein-coupledreceptorsand can trigger
small EPSPsthat last for severalminutes. The effectsof peptidesare modulatory; they do not usually bring the postsynapticneuronsto firing threshold, but they make them more responsiveto the fast nicotinic effectswhen
they do come along. Becausemore than one action potential is required to
stimulatethe releaseof thesemodulatory neurotransmitters,the pattern of
firing in preganglionic neurons is an important variable in determining the
type of postganglionicactivity that is evoked.
Postganglionic Neurotransmitters. Postganglioniccells-the autonomic
motor neurons that actuallytrigger glandsto secrete,sphinctersto contract
or relax, and so on-use different neurotransmittersin the sympathetic
and parasympatheticdivisionsof the ANS. Postganglionicparasympathetic
neurons releaseACh, but those of most parts of the sympatheticdivision
(NEl. Parasympathetic
ACh has a very local effect on its
use norepinephrine
targets and acts entirely through mAChRs. In contrast, sympathetic NE
often spreadsfar, even into the blood where it can circulate widely.
The autonomic effectsof a variety of drugs that interact with cholinergic
and noradrenergic systemscan be confidently predicted, if you understand some of the autonomic circuitry and chemistry (seeFigure 15.9)' In
general, drugs that promote the actions of norepinephrine or inhibit the
they cause effects
muscarinic actions of acetylcholine are sympathomimetic;
that mimic activationof the sympatheticdivision of the ANS. For example,
atropine,an antagonistof mAChRs, producessigns of sympatheticactivation, such as dilation of the pupils. This responseoccursbecausethe balance of ANS activity is shifted toward the sympathetic division when
parasympatheticactions are blocked. On the other hand, drugs that promote the muscarinicactionsof ACh or inhibit the actionsof NE are parasympathomimetic;
they cause effectsthat mimic activation of the parasympathetic division of the ANS. For example,propranolol,an antagonistof the
p receptorfor NE, slows the heart rate and lowers blood pressure.For this
reason,propranolol is sometimesused to prevent the physiologicalconsequencesof stagefright.
But what about the familiar flow of adrenaline?Adrenaline (epinephrine)
is the compound releasedinto the blood from the adrenal medulla when activated by preganglionic sympathetic innervation. Epinephrine is actually
made from norepinephrine (noradrenaline in the United Kingdom), and it
has effectson target tissuesalmost identical to those causedby sympathetic
activation. Thus, the adrenal medulla is really nothing more than a modified sympatheticganglion. You can imagine that as the epinephrine (adrenaline) flows, a coordinated, bodywide set of sympathetic effectskicks in.
497
498
C HAPTE R I 5
.
C H E M I C A L C O N T R O L O F TBHREA I N A N DB E H A V I O R
V THE DIFFUSEMODULATORYSYSTEMS
OF THE BRAIN
Considerwhat happenswhen you fall asleep.The internal commands,,you
are becomingdrowsy" and "You are falling asleep"are messages
that must
be receivedby broad regions of the brain. Dispensingthis information requires neurons with a particularly widespreadpattern of axons.The brain
has severalsuch collectionsof neurons, each using a particular neurotransmitter and making widely dispersed,diffuse, almost meanderingconnections.Rather than carrying detailedsensoryinformation, thesecells often perform regulatoryfunctions,modulatingvastassemblies
of postsynaptic
neurons (suchas the cerebralcortex, the thalamus,and the spinal cord) so
that they becomemore or lessexcitable,more or lesssynchronouslyactive,
and so on. collectively,they are a bit like the volume, treble,and basscontrols on a radio, which do not change the lyrics or melody of a song but
dramaticallyregulatethe impact of both. In addition, different systemsappear to be essentialfor aspectsof motor control, memory, mood, motivation, and metabolicstate.Many psychoactivedrugs affectthesemodulatory
systems,and the systemsfigure prominently in current theoriesabout the
biologicalbasisof certain psychiatricdisorders.
Anatomy and Functions of the Difruse Modulatory Systems
The diffuse modulatory systems differ in structure and function, yet
they have certain principlesin common:
r Typically,the core of each system has a small set of neurons (several
thousand).
r Neurons of the diffuse systemsarise from the central core of the brain,
most of them from the brain stem.
r Each neuron can influence many others,becauseeach one has an axon
that may contactmore than 100,000postsynapticneurons spreadwidely
acrossthe brain.
r The synapsesmade by many of these systemsreleasetransmitter molecules into the extracellularfluid, so they can diffuse to many neurons
rather than be confined to the vicinity of the synapticcleft.
We focus on the modulatory systemsof the brain that use either NE,
serotonin (5-HT), dopamine (DA), or ACh as a neurotransmitter. Recall
from chapter 6 that all of thesetransmittersactivatespecificmetabotropic
(G-protein-coupled)receptorsand that these receptorsmediatemost of
their effects;for example,the brain has 10-100 times more metabotropic
ACh receptorsthan ionotropic nicotinic ACh receptors.
Becauseneuroscientistsare still working hard to determine the exact functions of these systemsin behavior, our explanationshere will necessarily
be vague.It is clear,however, that the functions of the diffusemodulatory
systemsdepend on how electrically active they are, individually and in
combination, and on how much neurotransmitter is availablefor release
(Box15.2).
The Noradrenergic Locus coeruleus. Besidesbeing a neurotransmitter
in the peripheral ANS, NE is also used by neurons of the tiny locus
coeruleus in the pons (from the Latin for "blue spot,,becauseof the pigment in its cells).Each human locus coeruleushas about 12,000neurons.
We have two of them, one on each side.
A major breakthrough occurredin the mid-1960s,when Kjell Fuxe and
his colleaguesat the KarolinskaInstitute in sweden developeda technique
$ THEDIFFUSE
MODULATORY
SYSTEMS
OFTHEBRAIN
499
You Eat What You Are
Americans,it seems,are alwaystrying to lose weight.The
low-fat, high-carbohydratediets (think bagels)that were
all the rage in the | 990s have now been replacedby the
"low-carb"
craze(think omelets).Changingyour diet can
alter caloricintakeand the body'smetabolism;
it can also
alter how your brain functions.
The influenceof diet on the brain is most clear in the
caseof the diffusemodulatorysystems.
Considerserotonin.
Serotoninis synthesizedin two steps from the dietary
amino acid tryptophan(see Figure6. 14).Thefirst step is
catalyzedby the enzymetryptophan hydroxylase.Thelow
affinityof the enzymefor tryptophan makesthis step rotelimitingfor serotonin synthesis-that is, serotonin can be
produced only as fast as this enzyme can hydroxylate
try/ptophan.And a lot of tryptophan is required to push
the syntheticreaction as fast as it can go. However,brain
tryptophanlevelsare well below the levelrequiredto saturate the enzyme.Thus,
the rate of serotoninsynthesisis
determined,in part,by the availability
of tryptophanin the
brain-more tryptophan, more serotonin; less tryptophan,lessserotonin.
Brain tryptophan levelsare controlled by how much
tryptophanthere is in the blood,and by how efficientlyit
is transportedacrossthe blood-brainbarrier.Tryptophan
in the blood is derivedfrom the proteinswe digestin our
diet,so a high-proteindiet will lead to sharplyincreased
blood levelsof tryptophan.Surprisingly,
however,there is
a declinein brain tryptophan(and serotonin)for several
hours after a hearty,high-proteinmeal.Theparadoxwas
resolvedby Richard\ y'urtmanand his colleagues
at MIT
who observedthat severalother amino acids (tyrosine,
phenylalanine,
leucine,isoleucine,
and valine)competewith
tryptophanfor transport acrossthe blood-brainbarrier.
These other amino acidsare rich in a high-proteindiet,
and they suppressthe entry of the tryptophan into the
brain.Thesituationis reversedwith a high-carbohydrate
meal(that alsocontainssome protein).Insulin,releasedby
decreases
the
the pancreasin responseto carbohydrates,
b l o o d l e v e l so f t h e c o m p e t i n ga m i n o a c i d s r e l a t i v et o
tryptophan.So the tryptophan in the blood is efficiently
transportedinto the brain,and serotoninlevelsrise.
Increasedbrain tryptophan correlateswith elevated
mood, decreasedanxiety,and increasedsleepiness,
likely
due to changesin serotoninlevels.Inadequate
tryptophan
may explain the phenomenonof carbohydratecraving
that has been reported in humanswith seasonalaffective
disorder-the depressionof mood brought on by reduced
daylightduringwinter. lt may also explainwhy clinicaltrials
for treating obesity with extreme carbohydratedeprivation had to be stopped becauseof complaintsof mood
(depression,
disturbances
irritability)and insomnia.
Basedon these and other observations,Wurtman
and
his wife Judith made the intriguingsuggestionthat our
dietarychoicesmay reflectour brain'sneedfor serotonin.
Consistentwith this notion, drugs that elevateextracellular serotonin can be effectivefor weight loss (as well as
possiblyby reducingthe bodys demandfor
depression),
We will discussthe involvementof serocarbohydrates.
tonin in appetiteregulationfurther in Chapter l6 and in
the regulationof mood in Chapter 22.
that enabled the catecholaminergic (noradrenergic and dopaminergic)
neurons to be visualized selectively in histological sections prepared from
t h e b r a i n ( F i g u r e 1 5 . 1 1 ) .T h i s a n a l y s i sr e v e a l e dt h a t a x o n s l e a v e t h e k r c u s
coeruleus in several tracts, but then fan out to innervate just about every
part of the brain: all of the cerebral cortex, the thalamus and the hypothalan-rus,the olfactory bulb, the cerebellum, the midbrain, and the spinal
c o r d ( F i g u r e 1 5 . 1 2 ) .T h e l o c u s c o e r u l e u sm u s t m a k e s o m e o f t h e m o s t d i f fuse connections in the brain, considering that just one of its neurons can
m a k e m o r e t h a n 2 5 0 , 0 0 0 s y n a p s e sa, n d i t c a n h a v e o n e a x o n b r a n c h i n t h e
cerebralcortex and another in the cerebellarcortex!
Locus ccleruleuscells seem to be involved in the regulation of attention,
arousal, and sleep-wake cycles, as well as learning and memory, anxiety
and pain, mood, and brain metabolism. This makes it sound as if the locus
coeruleus may run the whole show. But the key word is "involved," which
can mean almost anything. For example, our heart, liver, lungs, and kidneys
are also involved in every brain function, for without them, all behavior
would fail utterly. Becauseof its widespreadconnections,the locus coeruleus
500
C H A P T E RI 5
CHEMICAL
CONTROLOFTHEBRAINAND BEHAVIOR
F I G U RIE5 . II
Norepinephrine.containing
neuronsof the locus coeruleus.The reacton of
noradrenergic
neurons
with formadehyde
gascauses
themto lJuoresce
green,
enabling
anatom
calinvest
gationof ther w despread
prolect
ons.(Source:
Courtesy
of Dr:KjellFuxe.)
can ittflLlence
v i r t u a l l y a l l p a r l s o l l h e b r a i n . B r r t t o u n t l e r s l a n cilt s a c t u a l
i t t n c t i o n s ,w e s 1 a 1 b
1 y d e t e r m i n i n g w h a t a c t i v a t c si t s n c u r o r . r sR
. ecorclings
l r o m a w a k e , l r e l t a v i r - trga t s a n d r n o n k c y ss h o w t h a l l o c u s c < l e n r l ue s n c u r o n s
a r e b e s t a c t i v a t e db y n e w , u n e x p c c t e d , n o n p a i n f u l s e n s o r y s l i r l u l i i n t h e
a n i m a l ' se n v i r o n n r e n t T
. h e y a r e l e a s ta c t i v ew h c n t h c a n i u t a l sa r e n o l v i g i l a l t t , . j u s st i t t i n ga r o u n d q L r i e t l yd, i g c s t i n ga n r c a l .T h c l < l c u sc o c n r l c u sn t a y
p a r t i c i p a t ei n a g e n e r a la r o u s a lo [ t h e b r a i n c l u r i n gi n t e r c s l i n l e] v c n t si n t h c
tlr,rtsidw
e o r l d . B e c a u s eN E c a n l n a k e n e u r o n s o f l h e c c r c t r r a lc o r l e x n t o r e
r c s l t o t t s i v et t l s a l i e n l s e n s o r ys t i r l r . r l i ,t h c l < l c u sc o e r u l e u sr n a y l u n c t i o n
g e n e r a l l yt o i n c r e a s ei r r a i n r c s p o n s i v e
n c s s ,s p e e c l i n gi n l o r r n a t i < l np r o c c s s i n g
b y t h e p < l i n l - t o - p o i n 1s e n s o r ya n c l r r o t o r s y s t e n r sa n d u r a k i n g l h c r n r n o r c
ellicient.
Norepinephrinesystem
(/,
Hypothalamus
lernporat t(JtJe
a/
Locuscoeruleus-
To spinalcord
F I G U R EI 5 , I 2
The noradrenergic diffuse modulatory system arising from the locus
coeruleus. The smallclusterof ocuscoeruleusneu[onsprojectaxonsthat nnervatevast
areasof the CNS, nc ud ng the spinalcord,cerebeum,thalamus,
and cerebracortex,
" THE DIFFUSE
MODULATORY
SYSTEMS
OFTHEBRAIN
The Serotonergic Raphe Nuclei. Serotonin-containing neurons are
mostly clusteredwithin the nine raphe nuclei. Raphemeans "ridge" or
"seam" in Greek,and indeed the raphe nuclei lie to either side of the midline of the brain stem. Each nucleus projects to different regions of the
brain (Figure 15.13).Thosemore caudal,in the medulla, innervate the
spinal cord, where they modulate pain-relatedsensorysignals(seeChapter
t2). Thosemore rostral, in the pons and midbrain, innervate most of the
brain in much the samediffuse way as do the locus coeruleusneurons.
Similar to neurons of the locus coeruleus,raphe nuclei cells fire most
rapidly during wakefulness,when an animal is arousedand active. Raphe
neurons are the most quiet during sleep.The locus coeruleusand the raphe
nuclei are part of a venerable concept called the ascending
reticularactivating
system,
which implicatesthe reticular "core" of the brain stem in processes
that arouse and awaken the forebrain. This simple idea has been refined
and redefinedin countlessways since it was introduced in the 1950s,but
its basic senseremains.Raphe neurons seemto be intimately involved in
the control of sleep-wakecycles,as well as the different stagesof sleep.It
is important to note that severalother transmitter systemsare involved in
a coordinatedway as well. We will discussthe involvement of the diffuse
modulatory systemsin sleepand wakefulnessin Chapter 19.
Serotonergicraphe neurons have also been implicated in the control of
mood and certain types of emotional behavior.We will return to serotonin
and mood when we discussclinical depressionin Chapter 22.
The Dopaminergic Substantia Nigra and Ventral Tegmental Area.
For many years,neuroscientiststhought that dopamineexistedin the brain
only as a metabolicprecursorfor norepinephrine.However, researchconducted in the 1960sby Arvid Carlssonof the University of Gothenburgin
Swedenproved that dopaminewas indeed a crucial CNSneurotransmitter
(Box 15.3). This discovervwas honored with the 2000 Nobel Prize in
Medicine.
Serotonlnsystem
Basalganglia
F I G U R IE5 . I 3
The serotonergic difruse modulatory systems arising from the raphe nuclei.
The raphenucleiare clustered
alongthemidlineof the brainstemand pro1ect
extensively
to all levelsof the CNS.
50 I
502
C HAPTE R I 5
.
C H E M I C A L C O N T R O L O FB
TR
HA
EI N A N D
BEHAVIOR
Awakening
to Dopamine
by Arvid Carlsson
Our discoveryof dopaminein the brain emergedfrom a
"Eureka!"
kind of experiment.We had treated rabbitsand
mice with reserpine,a drug commonlyused in the 1950s
as an antipsychotic
agent.These
animalshad obvioussigns
of sedationand a characteristictype of immobility known
as catalepsy(FigureA, top). We then treated them with
l-dopa,a precursor to norepinephrineand epinephrine.
We were amazedto see that within l5 minutesof an intravenousinjection of r--dopa,
there was a dramatic reversalof the whole syndromeinducedby reserpine.The
animalswere up and running,fully awake,and mobile (Figure A, bottom).
We had previously found that following reserpine
treatment, NE disappearsalmost entirely from brain and
other tissues.lf the behavioralaction of reserpinewas due
to depletionof NE, we reasonedit shouldbe possibleto
restore the behaviorby replenishing
the NE stores.This
could not be done by injectingNE itselfbecausethe catecholaminecannot cross the blood-brainbarrier.r--dopa,
however,like many other amino acids,might be able to
penetrateinto the brain and then be converted to NE by
the appropriateenzymes.
lndeed,our experimentsseemed
to confirm our hypothesis.However,when we analyzed
the brainsof the animalsshowingthis dramaticawakening response,the NE level remainedat about zero, and
our hypothesiswas obviouslyfalse.
We then turned our attention to dopamine,which in
those dayswas supposedto be only a precursorto NE.We
developeda specificand sensitivechemicalmethod for assayingdopamineand found that dopamineoccurs normally
in the brain in levelscomparableto NE. Dopaminestores,
like those of NE and serotonin,were depleted by reserpine.Unlike NE, however,the DA levelswere restored after l-dopa treatment with a time course closelyrelatedto
the awakeningresponse.Moreover,most of the dopamine
in the brain was found in the basalganglia-structuressupoosedto be involvedin the control of movements.ln the
meantime,we had learnedthat a common side effectof reserpinein humanswas a movementdisorderfaithfullymimickingthe syndromeof Parkinson'sdisease.
A t a n i n t e r n a t i o n a lc a t e c h o l a m i n es y m p o s i u m i n
Bethesda,Maryland,in October 1958,we could,on the
basisof these observations,
proposethat dopamineis involved in the control of movements.that a lack of DA can
lead to the developmentof the syndrome of Parkinson's
disease,
and that the replenishmentof DA stores by r-dopa could alleviateParkinson's
symptoms.Thus,
for the
first time, a putative neurotransmitterin the CNS had
been shown to exert a profound effect on brain function
and on an important pathophysiological
mechanism.
lmagineour surpriseto learn that these findingswere
m e t w i t h a n a l m o s t u n a n i m o u sd i s b e l i e fb y t h e m o s t
prominentresearchers
in this field!Among the objections
were that dopaminehad not shown any physiological
activity before and that this type of amine had not been
demonstratedin neurons.In addition,the prevailingview
in those days was that communicationbetween nerve
c e l l s i n t h e C N S o c c u r r e d v i a e l e c t r i c a lr a t h e r t h a n
chemicalsignals.Fortunately,thanks to a histochemical
method developedin our lab by Nils-Ake Hillarpand his
colleagues,
we were ableto demonstratethat DA, NE,and
serotonin are indeed located to nerve cell bodies and
axons in the CNS in a fashionvery similarto the distribution of NE in the peripheralnervoussystem.Moreover,
we presentedadditionalpharmacological
and biochemical
e v i d e n c ef o r c h e m i c a lt r a n s m i s s i o ni n t h e C N S .T h u s ,
within a few years,our views on chemicaltransmissionin
the CNS were Senerallyaccepted,thereby heraldinga
paradigmshift in brain research.
F I G U RAE
Rabbits
rmmobilized
(top) and reawakened
by reserptne
by dopa
(botton). (Courtesy
of ArvidCarlsson.)
V THE DIFFUSE
MODULATORY
SYSTEMS
OFTHE BMIN
Dopamlnesystem
I
F I G U RI E
5.I4
The dopaminergicdifrusemodulatorysystemsarisingfrom the substantia
nigra and the ventral tegmental area.Thesubstantia
nigraandventraltegmental
area
lieclosetogether
prolect
inthemidbrain,They
(caudate
to thestriatum
nucleus
and
putamen)
andlimbicandfrontalcortical
regions,
respectively,
Although there are dopamine-containingneurons scatteredthroughout
the CNS,including some in the retina, the olfactorybulb, and the periventricular hypothalamus, two closely related groups of dopaminergic cells
have the characteristicsof the diffuse modulatory systems(Figure 15.14).
One of these arises in the substantianigra in the midbrain. Recall from
Chapter 14 that these cells project axons to the striatum (the caudatenucleus and the putamen), where they somehow facilitate the initiation of
voluntary movements. Degenerationof the dopamine-containingcells in
the substantia nigra is all that is necessaryto produce the progressive,
dreadful motor disordersof Parkinson'sdisease.Although we do not entirely understandthe function of DA in motor control, in generalit facilitatesthe initiation of motor responsesby environmental stimuli.
The midbrain is also the origin of the other dopaminergicmodulatory
system,a group of cells that lie very closeto the substantianigra, in the
ventraltegmentalarea. Axons from these neurons innervate a circumscribed
region of the telencephalonthat includesthe frontal cortex and parts of the
limbic system. (The limbic systemwill be discussedin Chapter lS.) This
dopaminergicprojection from the midbrain is sometimescalled Ihe mesocorticolimbic
dopaminesystem.A number of different functions have been ascribed to this complicatedprojection. For example,evidenceindicatesthat
it is involved in a "reward" systemthat somehow assignsvalue to, or reinforces,certainbehaviorsthat are adaptive (seeChapter 16). We will see in
Chapter 18 that if rats (or humans) are given a chanceto do so, they will
work to electrically stimulate this pathway. In addition, this projection has
been implicated in psychiatricdisorders,as we will discussin Chapter 22.
The Cholinergic Basal Forebrain and Brain Stem Complexes. Acetylcholineis the familiar transmitterat the neuromuscularjunction, at synapses
in autonomic ganglia, and at postganglionic parasympathetic synapses.
Cholinergic interneurons also exist within the brain-in the striatum and
the cortex, for example.In addition, there are two major diffuse modulatory
cholinergic systemsin the brain, one of which is called the basal forebrain
503
504
CHAPTER
I5
.
CHEMICALCONTROLOFTHEBMINANDBEHAVIOR
F I G U RI E
5.I5
The cholinergicdifrusemodulatory systemsarisingfrom the basalforebrain
project
and brain stem.Themedial
septal
nuclei
andbasal
nucleus
widely
of Meynert
pontomesencephalotegmental
uponthecerebral
cortex,
including
the hippocampus.The
projects
complex
to thethalamus
andpartsof theforebrain.
complex. It is a "complex" becausethe cholinergicneurons lie scattered
among severalrelated nuclei at the core of the telencephalon,medial and
ventral to the basalganglia.The best known of these are the medialseptal
nuclei,which provide the cholinergicinnervation of the hippocampus,and
the basalnucleusof Meynert,which provides most of the cholinergic innervation of the neocortex.
The function of the cells in the basalforebrain complex remains mostly
unknown. But interest in this region has been fueled by the discoverythat
these are among the first cells to die during the courseof Alzheimer'sdisease,which is characterizedby a progressiveand profound lossof cognitive
functions. (However, there is widespreadneuronal death in Alzheimer's
disease,and no specificlink between the diseaseand cholinergicneurons
has been established.)Like the noradrenergicand serotonergicsystems,the
cholinergic system has been implicated in regulating general brain excitability during arousaland sleep-wakecycles.The basalforebraincomplex
may also play a specialrole in learning and memory formation.
The seconddiffuse cholinergicsystemis called t}re pontomesencephalotegmental complex.
Theseare ACh-utilizing cellsin the pons and midbrain tegmentum. This systemactsmainly on the dorsalthalamus,where, togetherwith
the noradrenergicand serotonergicsystems,it regulatesthe excitability of
the sensoryrelay nuclei. Thesecells also project up to the telencephalon,
providing a cholinergic link between the brain stem and basal forebrain
complexes.Figure I5.I5 shows the cholinergicsystems.
Drugs and the Difruse Modulatory Systems
Psychoactive
drugs, compounds with "mind-altering" effects, all act on the
CNS, and most do so by interfering with chemical synaptictransmission.
Many abuseddrugs act directly on the modulatory systems,particularly the
noradrenergic,dopaminergic,and serotonergicsystems.
V THE DIFFUSE
MODUTATORY
SYSTEMS
OFTHEBRAIN
I
Hallucinogens. The use of hallucinogens,
drugs that produce hallucinations,
goesback thousandsof years.Hallucinogeniccompoundsare containedin
a number oI plants consumedas part of religious ritual, for example, the
Psiloqtbe
mushroom by the Maya and the peyote cactusby the Aztec. The
modern era of hallucinogenicdrug use was unwittingly ushered in at the
laboratoryof SwisschemistAlbert Hofmann. In 1938,Hofmann chemically
synthesizeda new compound, lysergicacid diethylamide(LSD). For 5 years,
the LSD sat on the shelf. Then one day in 1943, Hofmann accidentally
ingestedsome of the powder. His report on the effectsattractedthe immediate interest of the medical community. Psychiatristsbeganto use LSD in
attemptsto unlock the subconsciousof mentally disturbedpatients.Later,
the drug was discoveredby intellectuals,artists,students,and the U.S. Defense Department,which investigatedits "mind-expanding" effects.(A
chief advocateof LSD use was former HarvardpsychologistTimothy Leary.)
In the I960s, LSD made its way to the street and was widely abused.Today, the possessionof LSD is illegal.
LSD is extremely potent. A dose sufficient to produce a full-blown hallucinogeniceffectis only 25 micrograms(comparedto a normal doseof aspirin at 650 milligrams,which is 25,000 times larger).Among the reported
behavioraleffectsof LSD is a dreamlike statewith heightenedawarenessof
sensorystimuli, often with a mixing of perceptionssuch that sounds can
evoke images,imagescan evoke smells,and so on.
The chemical structure of LSD (and the active ingredients of.Psilocybe
mushrooms and peyote) is very closeto that of serotonin,suggestingthat
it acts on the serotonergicsystem.Indeed, LSD is a potent agonist at the
serotonin receptorson the presynapticterminals of neurons in the raphe
nuclei. Activation of these receptorsmarkedly inhibits the firing of raphe
neurons.Thus, one known CNSeffect of LSD is a reduction in the outflow
of the brain's serotonergicdiffuse modulatory system.It is interesting to
note in this regard that decreasedactivity of the raphe nuclei is also characteristicof dream-sleep(seeChapterI9).
Can we concludethat LSDproduceshallucinationsby silencingthe brain's
serotonin systems?If only drug effectson the brain were that simple.Unfortunately, there are problems with this hypothesis.For one, silencing
neurons in the raphe nuclei by other means-by destroyingthem, for example-does not mimic the effectsof LSD in experimental animals. Furthermore, animals still respondas expectedto LSD after their raphe nuclei
have been destroyed.
In recentyears,researchershave focusedon direct LSD actionsat serotonin
receptorsin the cerebralcortex. Current researchsuggeststhat LSD causes
hallucinationsby supersedingthe naturally modulated releaseof serotonin
in cortical areaswhere perceptionsnormally are formed and interpreted.
Stimulants. In contrast to the uncertainties about hallucinogens and
serotonin, it is clear that the powerful CNS stimulants cocaineand amphetamineboth exert their effectsat synapsesmade by dopaminergicand noradrenergic systems.Both drugs give users a feeling of increasedalertness
and self-confidence,a senseof exhilaration and euphoria, and a decreased
appetite. Both are also sympathomimetic-they cause peripheral effects
that mimic activation of the sympathetic division of the ANS: increased
heart rate and blood pressure,dilation of the pupils, and so on.
Cocaineis extractedfrom the leavesof the cocaplant and has been used
by Andean Indians for hundreds of years.In the mid-nineteenth century,
cocaineturned up in Europe and North America as the magic ingredient
in a wide range of concoctionstouted by their salesmenas having medicinal value. (An example is Coca-Cola,originally marketed in 1886 as a
505
s06
CHAPTER
I5
.
C H E M I C A L C O N T R O L O F TBHREA I N A N DB E H A V I O R
therapeutic agent, which contained both cocaineand caffeine.) Cocaineuse
fell out of favor early in the twentieth century only to reemerge with a
vengeancein the late 1960s as a recreational drug. Ironically, one of the
main reasonsfor the rise in cocaine use during this period was the tightening of regulations against amphetamines.First chemically synthesizedin
1887, amphetamines did not come into wide use until World War II, when
they were taken by soldiers of both sides (particularly aviators) to sustain
them in combat. Following the war, amphetamines became available as
nonprescription diet aids, as nasal decongestants,and as "pep-pills." Regulations were finally tightened after recognition that amphetamines are, like
cocaine, highly addictive and dangerousin large doses.
The neurotransmitters dopamine and norepinephrine are catecholamines,
named for their chemical structure (see Chapter 6). The actions of catecholamines releasedinto the synaptic cleft are normally terminated by
specificuptake mechanisms.Cocaineand amphetamine both block this catecholamine uptake (Figure 15.16). However, recent work suggeststhat
cocaine targets DA reuptake more selectively;amphetamine blocks NE and
DA reuptake and stimulates the releaseof DA. Thus, these drugs can prolong and intensify the effects of releasedDA or NE. Is this the means by
which cocaine and amphetamine cause their stimulant effects? There is
good reason for thinking so. For example, experimental depletion of brain
catecholaminesby using synthesisinhibitors (such as o-methyltyrosine)
will abolish the stimulant effects of both cocaine and amphetamine.
Besideshaving a similar stimulant effect, cocaineand amphetamine share
another, more insidious behavioral action: psychological dependence, or
addiction. Userswill develop powerful cravings for prolonging and continuing drug-induced pleasurablefeelings. These effects are believed to result
a-Methyltyrosine
\
Activatespostsynapticand
presynaptic
r€ceptors
,t/
\ Z
Cocaineor
amphetamin€
Activatespostsynapticand
presynapticreceptors
FIGURE
I5.16
Stlmulant drug actlon on the catecholamlne axon termlnal. On the left is a
noradrenergic
terminaland on the right is a dopaminergic
terminal.Both neurotransmitters
are catecholamines
synthesized
from the dietaryaminoacidtyrosine.Dopa (3,4-dihydroxypheynylalanine)
is an intermediatein the synthesis
of both.Theactionsof NE and DA are
usuallyterminatedby uptakebackinto the axonterminal.Amphetamineand cocaineblock
this uptake,therebyallowingNE and DA to remainin the synapticcleft longer:
CONCLUDINGREMARKS
specificallyfrom the enhanced transmission in the mesocorticolimbic
dopamine system during drug use. Remember, this system may normally
function to reinforce adaptive behaviors. By short-circuiting the system,
these drugs instead reinforce drug-seekingbehavior. Indeed, just as rats wiil
work to electrically stimulate the mesocorticolimbic projection, they will
also work to receive an injection of cocaine. We'll discussthe involvement
of dopamine pathways in motivation and addiction further in Chapter 16.
,,,f'
CONCLUDING REMARKS
I n t h i s c h a p t e r ,w e h a v e e x a m i n e d t h r e e c o m p o n e n t s o f t h e n e r v o u s s y s tem that are characterizedby the great reach of their influences. The secretory hypothalamusand autonomic nervous system communicate with
c e l l s a l l o v e r t h e b o d y , a n d t h e d i f f u s e m o d u l a t o r y s y s t e m sc o m m u n i c a t e
with neurons in many differentparts of the brain. They are alsocharacterized by the duration of their direct effects,which can range fmm mir.rutes
t o h o u r s . F i n a l l y , t h e y a r e c h a r a c t e r i z e db y t h e i r c h e m i c a l n e u r o t r a n s m i t ters. In many instances,the transmitter definesthe system. For example, in
t h e p e r i p h e r y ,w e c a n u s e t h e w o r d s " n o r a d r e n e r g i c "a n d " s y m p a t h e t i c "i n t e r c h a n g e a b l yT. h e s a m e t h i n g g o e sf o r " r a p h e " a n d " s e r o t o n i n " i n t h e f o r e b r a i n , a n d " s u b s t a n t i an i g r a " a n d " d o p a m i n e " i n t h e b a s a l g a n g l i a .T h e s e
chemical idiosyncrasieshave allowed interpretations of drug effects on beh a v i o r t h a t a r e n o t p o s s i b l ew i t h m o s t o t h e r n e u r a l s y s t e m s T
. hus, we have
a g o o d i d e a w h e r e i n t h e b r a i n a m p h e t a m i n e a n d c o c a i n ee x e r t t h e i r s t i n t ulant effects,and where in the periphery they act to raise blood pressure
and heart rate.
A t a d e t a i l e dl e v e l , e a c h o f t h e s y s t e m sd i s c u s s e di n t h i s c h a p t e rp e r f u r n t s
different functions. But at a general level, they all maintain brain homeostasri: They regulate different processeswithin a certain physiological range.
F o r e x a m p l e , t h e A N S r e g u l a t e sb l o o d p r e s s u r ew i t h i n a r a n g e t h a t i s a p p r o p r i a t e .B l o o d p r e s s u r ev a r i a t i o n so p t i m i z e a n a n i m a l ' s p e r f o r m a n c eu n der different conditions. In a similar way, the noradrenergic krcus coeruleus
a n d s e r o t o n e r g i cr a p h e n u c l e i r e g u l a t e l e v e l s o f c o n s c i o u s n e s as n d m o o d .
T h e s e l e v e l sa l s o v a r y w i t h i n a r a n g e t h a t i s a d a p t i v e t o t h e o r g a n i s m .I n
t h e n e x t s e v e r a l c h a p t e r s ,w e w i l l e n c o u n t e r t h e s e s y s t e m sa g a i n i n t h e
c o n t e x t o f s p e c i f i cf u n c t i o n s .
..l,,t,il
>v)
U J :
Y e
llJ
F
The Secretory Hypothalamus
homeostasis
(p.a8a)
periventricular
zone(p.a8a)
magnocellular
neurosecretory
cell
(p.a8s)
(p.485)
neurohormone
oxytocin(p.485)
vasopressin
$.486)
antidiuretichormone(ADH)
(p.486)
parvocellular
neurosecretory
cell
(p.488)
hypophysiotropic
hormone
(p.488)
hypothalamo-pitu
itary portal
circulation (p. 488)
adrenalcortex (p.488)
adrenalmedulla (p. 488)
coftisol (p.488)
preganglionicneuron (p. 492)
sympatheticchain (p. 494)
enteric division(p. 495)
nucleusof the solitary tract
The Autonomic Nervous
System
autonomic nervous system (ANS)
The Diffuse Modulatory
Systems of the Brain
diffusemodulatorysystem
(p.aeo)
sympatheticdivision (p. 490)
parasympatheticdivision (P.490)
autonomic ganglia$. 492)
postganglionicneuron @. 492)
$. ae6)
(p.ae8)
(p.498)
locuscoeruleus
raphenuclei(p.501)
basalforebraincomplex(p.503)
507
508
CHAPTER
,r/
|
il'1
-|-!v
f
l- o2
UJF
d, rtl
ur
f,
o
I5
.
C H E M I C A L C O N T R O L O F TBHMEI N A N D B E H A V I O R
l. Battlefieldtraumavictimswho harelost largevolumesof blood often exprcssa cravingto drink water.Why?
2. You'vesayed up all night tryrnt to meet a term paperdeadline.You
now are typingfrantically,keepingone
eye on the paper and dre other on ttre clock How hasthe periventricularzone of the hypothalamus
orchestratedyour bod's physiological
responseto this stressfulsituationlDescribein deail.
3.Wly is the adrenalmedullaoften referred to as a modifiedsympatheticganglion?
Why isnt the adrenal
cort€r(includedin this descriptionl
4. A numberof famousathletesand enterainers haveaccidenallykilled themselvesby aking largequantities
of cocaine.Usually,tlre causeof death is heart failure.How would you explainthe peripheralactionsof
cocainel
5. How do the diftrse modulatoryand point-to-pointsynapticcommunicationsystemsin the brain difierl List
four ways.
6. Under what behavioralconditionsare the noradrenergicneunonsof the locus coeruleusactivelThe noradrenergicneuronsof the ANSI