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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 $s1.,Wi;SS.ti.ry"SSe,&iW #_*,t*irs+.;tift 482 C HAPTE R I 5 . 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 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). 483 484 CHAPTER I5 . C H E M I C ACLO N T R O L O F T HBEM I N A N D B E H A V I O R 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 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 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 487 488 C HAPTER I5 . 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). 489 490 C HAPTE R I 5 . 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 Constricts oculomolor^ pupil Dilates pupil : * : . .. . . - - n e r v e( l l l ) Inhibits Eye ''\l :l',T:11:' ."1".1,:-i Faciat N->' salivation n"r" 1Vtt1' ,,,,"n01:"tt*' -nerve \vu\*}f andtearing ,4==J/',:'-:"'"ii' ----< -,7 ) ('- ,r/,"::i-": -..:ll.:.-l:f::: .. -- Lacrimal^nd"to=it and' Lacrimal Lungs salivaryglands : " I " "".\ (lX) nerve (lii nerve Glossopharyngeal Glossopharyngeat Y Constricts bloodvessels Relaxes airways Accelerates heartbeat "".\ \ glucose Stimulates and Production release ( ,l / / l Stimulates digestion -'" "-* "-"1 ,x-"*"'q:r'" / Stimulates secretionof and epinephrine norepinephrine fromadrenal medulla. A A 'lcreas , Vaousnerve(X) , l ' ,l / pancreas -- -- -^" / Stimulates ;!."".*)./ to releaseinsulin ,i anddigestive enzvmes ; .i I t/ --l r .r*,*, - -'""tilates blood vesselsin gut Small intestine ,, \ /-r,^00", ,Y'---X.' urinary Stimulates Relaxes urinary Y Sympathetic bladder bladderto contract i chain NEneurons orgasm /t/ Stimulates Preganglionic neurons Postganglionic neurons sexual I Stimulates arousal Preganglionic 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