Although dopamine levels are low in Parkinson’s dis-ease, dopamine is not an effective treatment because itdoes not readily penetrate the blood–brain barrier. How-ever, knowledge of dopaminergic transmission has led tothe development of an effective treatment: L-dopa, thechemical precursor of dopamine, which readily pene-trates the blood–brain barrier and is converted todopamine once inside the brain.
Mr. d’Orta’s neurologist prescribed L-dopa, and itworked. He still had a bit of tremor; but his voice becamestronger, his feet no longer shuffled, his reptilian starefaded away, and he was once again able to perform withease many of the activities of daily life (e.g., eating,bathing, writing, speaking, and even making love withhis wife). Mr. d’Orta had been destined to spend the restof his life trapped inside a body that was becoming in-creasingly difficult to control, but his life sentence wasrepealed—at least temporarily.
Mr. d’Orta’s story does not end here. You will learnwhat ultimately happened to him in Chapter 10. Mean-while, keep him in mind while you read this chapter: Hiscase illustrates why knowledge of the fundamentals ofneural conduction and synaptic transmission is a mustfor any biopsychologist.
4.1Resting Membrane Potential
As you are about to learn, the key to understanding howneurons work—and how they malfunction—is the mem-brane potential. The membrane potential is the differ-ence in electrical charge between the inside and theoutside of a cell.
Recording the Membrane Potential
To record a neuron’s membrane potential, it is neces-sary to position the tip of one electrode inside the neu-ron and the tip of another electrode outside the neuronin the extracellular fluid. Although the size of the extra-cellular electrode is not critical, it is paramount that thetip of the intracellular electrode be fine enough topierce the neural membrane without severely damagingit. The intracellular electrodes are called microelectrodes;their tips are less than one-thousandth of a millimeter indiameter—much too small to be seen by the naked eye.
Resting Membrane Potential
When both electrode tips are in the extracellular fluid, thevoltage difference between them is zero. However, whenthe tip of the intracellular electrode is inserted into a neu-ron, a steady potential of about –70 millivolts (mV) isrecorded. This indicates that the potential inside the rest-ing neuron is about 70 mV less than that outside the
Chapter 3 introduced you to the anatomy of neurons.This chapter introduces you to their function—howneurons conduct and transmit electrochemical sig-
nals through your nervous system. It begins with a de-scription of how signals are generated in resting neurons;then, it follows the signals as they are conducted throughneurons and transmitted across synapses to other neu-rons. It concludes with a discussion of how drugs are usedto study the relation between synaptic transmission andbehavior. “The Lizard,” a case study of a patient withParkinson’s disease, Roberto Garcia d’Orta, will help youappreciate why a knowledge of neural conduction andsynaptic transmission is an integral part of biopsychology.
The Lizard, a Case of Parkinson’s Disease
“I have become a lizard,” he began. “A great lizard frozenin a dark, cold, strange world.”
His name was Roberto Garcia d’Orta. He was a tallthin man in his sixties, but like most pa-tients with Parkinson’s disease, he ap-peared to be much older than his actual
age. Not many years before, he had been an active, vigor-ous business man. Then it happened—not all at once, notsuddenly, but slowly, subtly, insidiously. Now he turnedlike a piece of granite, walked in slow shuffling steps, andspoke in a monotonous whisper.
What had been his first symptom?A tremor.Had his tremor been disabling?“No,” he said. “My hands shake worse when they are
doing nothing at all”—a symptom called tremor-at-rest.The other symptoms of Parkinson’s disease are not
quite so benign. They can change a vigorous man into alizard. These include rigid muscles, a marked poverty ofspontaneous movements, difficulty in starting to move,and slowness in executing voluntary movements oncethey have been initiated.
The term “reptilian stare” is often used to describe thecharacteristic lack of blinking and the widely opened eyesgazing out of a motionless face, a set of features thatseems more reptilian than human. Truly a lizard in theeyes of the world.
What was happening in Mr. d’Orta’s brain? A smallgroup of nerve cells called the substantia nigra (black sub-stance) were unaccountably dying. These neurons make aparticular chemical called dopamine, which they deliverto another part of the brain, known as the striatum. As thecells of the substantia nigra die, the amount of dopaminethey can deliver goes down. The striatum helps controlmovement, and to do that normally, it needs dopamine.
type of which is specialized for the passage of particularions.
In the 1950s, the classic experiments of neurophysiol-ogists Alan Hodgkin and Andrew Huxley provided thefirst evidence that an energy-consuming process is in-volved in the maintenance of the resting potential.Hodgkin and Huxley began by wondering why the highextracellular concentrations of Na� and Cl� ions and thehigh intracellular concentration of K� ions were not elim-inated by the tendency for them to move down their con-centration gradients to the side of lesser concentration.Could the electrostatic pressure of–70 mV across the membrane be thecounteracting force that maintainedthe unequal distribution of ions? To answer this question,Hodgkin and Huxley took a creative approach for whichthey received a Nobel Prize.
First, they calculated for each of the three ions theelectrostatic charge that would be required to offset thetendency for them to move down their concentration gra-dients. For Cl� ions, this calculated electrostatic chargewas –70 mV, the same as the actual resting potential.Hodgkin and Huxley thus concluded that when neurons
774.1 ■ Resting Membrane Potential
neuron. This steady membrane potential of about –70 mVis called the neuron’s resting potential. In its resting state,with the –70 mV charge built up across its membrane, aneuron is said to be polarized.
Ionic Basis of the Resting Potential
Why are resting neurons polarized? Like all salts in solu-tion, the salts in neural tissue separate into positively andnegatively charged particles called ions. The resting po-tential results from the fact that the ratio of negative topositive charges is greater inside the neuron than outside.Why this unequal distribution of charges occurs can beunderstood in terms of the interaction of four factors:two factors that act to distribute ions equally throughoutthe intracellular and extracellular fluids of the nervoussystem and two features of the neural membrane thatcounteract these homogenizing effects.
The first of the two homogenizing factors is randommotion. The ions in neural tissue are in constant randommotion, and particles in random motion tend to becomeevenly distributed because they are more likely to movedown their concentration gradients than up them; that is,they are more likely to move from areas of high concen-tration to areas of low concentration than vice versa. Thesecond factor that promotes the even distribution of ionsis electrostatic pressure. Any accumulation of charges, pos-itive or negative, in one area tends to be dispersed by therepulsion among the like charges in the vicinity and theattraction of opposite charges concentrated elsewhere.
Despite the continuous homogenizing effects of ran-dom movement and electrostatic pressure, no single classof ions is distributed equally on the two sides of the neu-ral membrane. Four kinds of ions contribute significantlyto the resting potential: sodium ions (Na�), potassiumions (K�), chloride ions (Cl�), and various negativelycharged protein ions. The concentrations of both Na� andCl� ions are greater outside a resting neuron than inside,whereas K� ions are more concentrated on the inside.The negatively charged protein ions are synthesized insidethe neuron and, for the most part, stay there (see Figure4.1). By the way, the symbols for sodium and potassiumwere derived from their Latin names: natrium (Na) andkalium (K), respectively.
Two properties of the neural membrane are responsiblefor the unequal distribution of Na�, K�, Cl�, and proteinions in resting neurons. One of these properties is passive;that is, it does not involve the consumption of energy. Theother is active and does involve the consumption of en-ergy. The passive property of the neural membrane thatcontributes to the unequal disposition of Na�, K�, Cl�,and protein ions is its differential permeability to thoseions. In resting neurons, K� and Cl� ions pass readilythrough the neural membrane, Na� ions pass through itwith difficulty, and the negatively charged protein ions donot pass through it at all. Ions pass through the neuralmembrane at specialized pores called ion channels, each
FIGURE 4.1 In its resting state, more Na� and Cl– ions are outside the neuron than inside, and more K� ions and negativelycharged protein ions are inside the neuron than outside.
78 Chapter 4 ■ Neural Conduction and Synaptic Transmission
are at rest, the unequal distribution of Cl� ions across theneural membrane is maintained in equilibrium by thebalance between the tendency for Cl� ions to move downtheir concentration gradient into the neuron and the 70 mVof electrostatic pressure driving them out.
The situation turned out to be different for the K� ions.Hodgkin and Huxley calculated that 90 mV of electro-static pressure would be required to keep intracellular K�
ions from moving down their concentration gradient andleaving the neuron—some 20 mV more than the actualresting potential.
In the case of Na� ions, the situation was much moreextreme because the effects of both the concentrationgradient and the electrostatic gradient act in the same di-rection. The concentration of Na� ions that exists outsideof a resting neuron is such that 50 mV of outward pres-sure would be required to keep Na� ions from movingdown their concentration gradient into the neuron,which is added to the 70 mV of electrostatic pressure
acting to move them in the same direction. Thus, theequivalent of a whopping 120 mV of pressure is acting toforce Na� ions into resting neurons.
Subsequent experiments confirmed Hodgkin andHuxley’s calculations. They showed that K� ions arecontinuously being driven out of resting neurons by20 mV of pressure and that, despite the high resist-ance of the cell membrane to the passage of Na� ions,those ions are continuously being driven in by the120 mV of pressure. Why, then, do the intracellularand extracellular concentrations of Na� and K� re-main constant in resting neurons? Hodgkin and Hux-ley discovered that there are active mechanisms in thecell membrane to counteract the influx (inflow) ofNa� ions by pumping Na� ions out as rapidly as theypass in and to counteract the efflux (outflow) of K�
ions by pumping K� ions in as rapidly as they passout. Figure 4.2 summarizes Hodgkin and Huxley’sfindings and conclusions.
Cl–Cl–
Cl–
Cl– Cl–Cl– Cl–
Cl–Cl–
70 mV of pressurefrom concentrationgradient
70 mV ofelectrostaticpressure
70 mV ofelectrostaticpressure
70 mV ofelectrostaticpressure
50 mV of pressurefrom concentrationgradient
90 mV of pressurefrom concentrationgradient
Sodium–potassiumpump
Na+
Na+Na+Na+
Na+
Na+Na+
Na+
Na+
Na+
Na+ Na+
K+K+
K+K+
K+K+
K+K+
K+K+
K+
FIGURE 4.2 The passive and active factors that influence the distribution of Na�, K�, and Cl�
ions across the neural membrane. Passive factors continuously drive K� ions out of the restingneuron and Na� ions in; therefore, K� ions must be actively pumped in and Na� ions must beactively pumped out to maintain the resting equilibrium.
It was subsequently discovered that the transport ofNa� ions out of neurons and the transport of K� ions intothem are not independent processes. Such ion transport isperformed by energy-consuming mechanisms in the cellmembrane that continually exchange three Na� ions in-side the neuron for two K� ions outside. These trans-porters are commonly referred to as sodium–potassiumpumps.
Since the discovery of sodium–potassium pumps, sev-eral other classes of transporters (mechanisms in themembrane of a cell that actively transport ions or mole-cules across the membrane) have been discovered (e.g.,Tzingounis & Wadiche, 2007). You will encounter more ofthem later in this chapter.
Table 4.1 summarizes the major factors that are re-sponsible for maintaining the differences between the in-tracellular and extracellular concentrations of Na�, K�,and Cl� ions in resting neurons. These differences plusthe negative charges of the various protein ions, which are
trapped inside the neuron, are largely responsible for theresting membrane potential.
Now that you understand these basic properties of theresting neuron, you are prepared to consider how neuronsrespond to input.
4.2Generation and Conduction ofPostsynaptic Potentials
When neurons fire, they release from their terminal but-tons chemicals called neurotransmitters, which diffuseacross the synaptic clefts and interact with specializedreceptor molecules on the receptive membranes of thenext neurons in the circuit. When neurotransmittermolecules bind to postsynaptic receptors, they typicallyhave one of two effects, depending on the structure ofboth the neurotransmitter and the receptor in question.They may depolarize the receptive membrane (decreasethe resting membrane potential, from –70 to –67 mV,for example) or they may hyperpolarize it (increase theresting membrane potential, from –70 to –72 mV, forexample).
Postsynaptic depolarizations are called excitatorypostsynaptic potentials (EPSPs) because, as you willsoon learn, they increase the likelihood that the neuronwill fire. Postsynaptic hyperpolarizations are calledinhibitory postsynaptic potentials (IPSPs) because theydecrease the likelihood that the neuron will fire. BothEPSPs and IPSPs are graded responses. This means thatthe amplitudes of EPSPs and IPSPs are proportional tothe intensity of the signals that elicit them: Weak signalselicit small postsynaptic potentials, and strong signalselicit large ones.
EPSPs and IPSPs travel passively from their sites ofgeneration at synapses, usually on the dendrites or cellbody, in much the same way that electrical signals travelthrough a cable. Accordingly, the transmission of post-synaptic potentials has two important characteristics.First, it is rapid—so rapid that it can be assumed to beinstantaneous for most purposes. It is important not toconfuse the duration of EPSPs and IPSPs with their rateof transmission; although the duration of EPSPs andIPSPs varies considerably, all postsynaptic potentials,whether brief or enduring, are transmitted at greatspeed. Second, the transmission of EPSPs and IPSPs isdecremental: EPSPs and IPSPs decrease in amplitude asthey travel through the neuron, just as a sound waveloses amplitude (the sound grows fainter) as it travelsthrough air. Most EPSPs and IPSPs do not travel morethan a couple of millimeters from their site of genera-tion before they fade out; thus, they never travel very faralong an axon.
794,2 ■ Generation and Conduction of Postsynaptic Potentials
TABLE 4.1 Factors Responsible for Maintaining the
Differences in the Intracellular and
Extracellular Concentrations of Na�, K�, and
Cl� Ions in Resting Neurons
Na� Na� ions tend to be driven into the neurons by
both the high concentration of Na� ions outside
the neuron and the negative internal resting
potential of –70 mv. However, the membrane is
resistant to the passive diffusion of Na�, and
the sodium–potassium pumps are thus able to
maintain the high external concentration of Na�
ions by pumping them out at the same slow rate
as they move in.
K� K� ions tend to move out of the neuron because
of their high internal concentration, although
this tendency is partially offset by the internal
negative potential. Despite the tendency for the
K� ions to leave the neuron, they do so at a
substantial rate because the membrane offers
little resistance to their passage. To maintain the
high internal concentration of K� ions, the
sodium–potassium pumps in the cell membrane
pump K� ions into neurons at the same rate as
they move out.
Cl� There is little resistance in the neural membrane
to the passage of Cl� ions. Thus, Cl� ions are
readily forced out of the neuron by the negative
internal potential. As chloride ions begin to
accumulate on the outside, there is an increased
tendency for them to move down their
concentration gradient back into the neuron.
When the point is reached where the electrostatic
pressure for Cl� ions to move out of the neuron is
equal to the tendency for them to move back in,
the distribution of Cl� ions is held in equilibrium.
4.3Integration of PostsynapticPotentials and Generation ofAction Potentials
The postsynaptic potentials created at a single synapsetypically have little effect on the firing of the postsynapticneuron (Bruno & Sakmann, 2006). The receptive areas ofmost neurons are covered with thousands of synapses,and whether or not a neuron fires is determined by thenet effect of their activity. More specifically, whether ornot a neuron fires depends on the balance between theexcitatory and inhibitory signals reaching its axon. Untilrecently, it was believed that action potentials were gener-ated at the axon hillock (the conical structure at the junc-tion between the cell body and the axon), but they areactually generated in the adjacent section of the axon(Palmer & Stuart, 2006).
The graded EPSPs and IPSPs created by the action ofneurotransmitters at particular receptive sites on a neu-ron’s membrane are conducted instantly and decremen-tally to the axon hillock. If the sum of the depolarizationsand hyperpolarizations reaching the section of the axonadjacent to the axon hillock at any time is sufficient todepolarize the membrane to a level referred to as itsthreshold of excitation—usually about –65 mV—an ac-tion potential is generated near the axon hillock. Theaction potential (AP) is a massive but momentary—last-ing for 1 millisecond—reversal of the membrane poten-tial from about –70 to about �50 mV. Unlike postsynapticpotentials, action potentials are not graded responses;their magnitude is not related in any way to the intensityof the stimuli that elicit them. To the contrary, they areall-or-none responses; that is, they either occur to theirfull extent or do not occur at all. See Figure 4.3 for an il-lustration of an EPSP, an IPSP, and an AP. Although manyneurons display APs of the type illustrated in Figure 4.3,others do not—for example, some neurons display APsthat are longer, that have lower amplitude, or that involvemultiple spikes.
In effect, each multipolar neuron adds together all thegraded excitatory and inhibitory postsynaptic potentialsreaching its axon and decides to fire or not to fire on thebasis of their sum. Adding or combining a number ofindividual signals into one overall signal is calledintegration. Neurons integrate incoming signals in twoways: over space and over time.
Figure 4.4 shows the three possible combinations ofspatial summation. It shows how local EPSPs that are pro-duced simultaneously on different parts of the receptivemembrane sum to form a greater EPSP, how simultaneousIPSPs sum to form a greater IPSP, and how simultaneousEPSPs and IPSPs sum to cancel each other out.
Figure 4.5 on page 82 illustrates temporal summa-tion. It shows how postsynaptic potentials produced inrapid succession at the same synapse sum to form agreater signal. The reason that stimulations of a neuroncan add together over time is that the postsynaptic po-tentials they produce often outlast them. Thus, if a par-ticular synapse is activated and then activated againbefore the original postsynaptic potential has completelydissipated, the effect of the second stimulus will be su-perimposed on the lingering postsynaptic potential pro-duced by the first. Accordingly, it is possible for a briefsubthreshold excitatory stimulus to fire a neuron if it isadministered twice in rapid succession. In the same way,
80 Chapter 4 ■ Neural Conduction and Synaptic Transmission
STIMULUS
STIMULUS
STIMULUS
Time (milliseconds)
Mem
bra
ne
Po
ten
tial
(m
illiv
olt
s)
–90–80–70–60–50–40–30–20–10
0+10+20+30+40+50+60
Action potential
EPSP
An EPSP and anAction Potential
Time (milliseconds)
Mem
bra
ne
Po
ten
tial
(mill
ivo
lts)
–70
An IPSP–65
Time (milliseconds)
Mem
bra
ne
Po
ten
tial
(mill
ivo
lts)
–70
An EPSP–65
FIGURE 4.3 An EPSP, and IPSP, and an EPSP followed by atypical AP.
an inhibitory synapse activated twice in rapid successioncan produce a greater IPSP than that produced by a sin-gle stimulation.
Each neuron continuously integrates signals over bothtime and space as it is continually bombarded with stim-uli through the thousands of synapses covering its den-drites and cell body. Remember that, although schematicdiagrams of neural circuitry rarely show neurons withmore than a few representative synaptic contacts, mostneurons receive thousands of such contacts.
The location of a synapse on a neuron’s receptivemembrane has long been assumed to be an importantfactor in determining its potential to influence the neu-ron’s firing. Because EPSPs and IPSPs are transmitteddecrementally, synapses near the axon trigger zone havebeen assumed to have the most influence on the firingof the neuron (see Mel, 2002). However, it has beendemonstrated that some neurons have a mechanism foramplifying dendritic signals that originate far fromtheir cell bodies; thus, in these neurons, all dendriticsignals reaching the cell body have a similar amplitude,
814.3 ■ Integration of Postsynaptic Potentials and Generation of Action Potentials
�70
�65A Stimulated B Stimulated
�75
�70
�65C Stimulated
�75
�70
�65D Stimulated
�75
�70
�65C + D Stimulated
A + B Stimulated
�70
�65
�70
�65
�75
�70
�65A Stimulated
�75
�70
�65C Stimulated
�75
�70
�65A + C Stimulated
Two simultaneous EPSPs sum to produce a greater EPSP
Mem
bra
ne
po
ten
tial
(m
illiv
olt
s)
A
B C
Excitatorysynapse
Inhibitory synapse
To oscilloscopeD
Two simultaneous IPSPs sum to produce a greater IPSP
A simultaneous IPSP and EPSP cancel each other out
FIGURE 4.4 The three possible combinations of spatial summation.
Before you learn how action potentials are conducted
along the axon, pause here to make sure that you under-
stand how action potentials are created. Fill in each
blank with the most appropriate term. The correct an-
swers are provided at the end of the exercise. Before
proceeding, review material related to your errors and
omissions.
1. Roberto Garcia d’Orta referred to himself as “a great
lizard frozen in a dark, cold, strange world.” He suf-
fered from ______.
2. Tremor-at-rest is a symptom of ______.
3. Microelectrodes are required to record a neuron’s
resting ______.
4. The ______ is about –70 mV.
5. In its resting state, a neuron is said to be ______.
6. Two factors promote the even distribution of ions
across neural membranes: ______ and electrostatic
pressure.
7. In the resting state, there is a greater concentration of
Na� ions ______ the neural membrane than ______
the neural membrane.
8. Natrium is Latin for ______.
9. Ions pass through neural membranes via specialized
pores called ______.
10. From their calculations, Hodgkin and Huxley inferred
the existence of ______ in neural membranes.
11. Neurotransmitters typically have one of two effects on
postsynaptic neurons: They either depolarize them or
______ them.
12. Postsynaptic depolarizations are commonly referred to
in their abbreviated form: ______.
13. Action potentials are generated near, but not at, the
______.
14. An action potential is elicited when the depolarization
of the neuron reaches the ______.
15. Unlike postsynaptic potentials, which are graded, ac-
tion potentials are ______ responses.
16. Neurons integrate postsynaptic potentials in two ways:
through spatial summation and through ______
summation.
Scan Your Brainanswers: (1) Parkinson’s disease, (2) Parkinson’s disease,
(3) potential, (4) resting potential, (5) polarized, (6) random motion,
(7) outside, inside, (8) sodium, (9) ion channels, (10) sodium–potassium
82 Chapter 4 ■ Neural Conduction and Synaptic Transmission
4.4Conduction of Action Potentials
Ionic Basis of Action Potentials
How are action potentials produced, and how are they con-ducted along the axon? The answer to both questions is ba-sically the same: through the action of voltage-activatedion channels—ion channels that open or close in responseto changes in the level of the membrane potential (seeArmstrong, 2007).
Recall that the membrane potential of a neuron atrest is relatively constant despite the high pressure act-ing to drive Na� ions into the cell. This is because theresting membrane is relatively impermeable to Na� ionsand because those few that do pass in are pumped out.But things suddenly change when the membrane poten-
tial of the axon is reduced to the thresh-old of excitation. The voltage-activatedsodium channels in the axon membraneopen wide, and Na� ions rush in, sud-denly driving the membrane potentialfrom about –70 to about �50 mV. Therapid change in the membrane potentialthat is associated with the influx of Na�
ions then triggers the opening of voltage-activated potassium channels. At thispoint, K� ions near the membrane aredriven out of the cell through thesechannels—first by their relatively highinternal concentration and then, whenthe action potential is near its peak, bythe positive internal charge. After about 1millisecond, the sodium channels close.This marks the end of the rising phase ofthe action potential and the beginning ofrepolarization by the continued efflux ofK� ions. Once repolarization has beenachieved, the potassium channels gradu-ally close. Because they close gradually,too many K� ions flow out of the neu-ron, and it is left hyperpolarized for abrief period of time. Figure 4.6 illus-trates the timing of the opening andclosing of the sodium and potassiumchannels during an action potential.
Two EPSPs elicited in rapid succession sum toproduce a larger EPSP
Mem
bra
ne
po
ten
tial
(m
illiv
olt
s)
Two IPSPs elicited in rapid succession sum toproduce a larger IPSP
–70
–65
A A
–70
–65
A A
–70
–65
B B
–70
–65
B B
A B
Excitatorysynapse
Inhibitory synapse
To oscilloscope
FIGURE 4.5 The two possible combinationsof temporal summation.
In some ways, the firing of a neuronis like the firing of a gun. Both reac-tions are triggered by graded re-
sponses. As a trigger is squeezed, it gradually moves backuntil it causes the gun to fire; as a neuron is stimulated, itbecomes less polarized until the threshold of excitation isreached and firing occurs. Furthermore, the firing of agun and neural firing are both all-or-none events. Just assqueezing a trigger harder does not make the bullet travelfaster or farther, stimulating a neuron more intenselydoes not increase the speed or amplitude of the resultingaction potential.
The number of ions that flowthrough the membrane duringan action potential is extremelysmall in relation to the totalnumber inside and around theneuron. The action potential in-volves only those ions right nextto the membrane. Therefore, a single action potential haslittle effect on the relative concentrations of various ionsinside and outside the neuron, and the resting ion concen-trations next to the membrane are rapidly reestablished bythe random movement of ions. The sodium–potassiumpumps play only a minor role in the reestablishment ofthe resting potential.
Refractory Periods
There is a brief period of about 1 to 2 milliseconds afterthe initiation of an action potential during which it is im-possible to elicit a second one. This period is called theabsolute refractory period. The absolute refractory pe-riod is followed by the relative refractory period—theperiod during which it is possible to fire the neuron again,but only by applying higher-than-normal levels of stimu-lation. The end of the relative refractory period is thepoint at which the amount of stimulation necessary tofire a neuron returns to baseline.
The refractory period is responsible for two impor-tant characteristics of neural activity. First, it is responsi-ble for the fact that action potentials normally travelalong axons in only one direction. Because the portionsof an axon over which an action potential has just trav-eled are left momentarily refractory, an action potentialcannot reverse direction. Second, the refractory period isresponsible for the fact that the rate of neural firing is re-lated to the intensity of the stimulation. If a neuron issubjected to a high level of continual stimulation, it firesand then fires again as soon as its absolute refractory pe-riod is over—a maximum of about 1,000 times per sec-ond. However, if the level of stimulation is of an intensityjust sufficient to fire the neuron when it is at rest, theneuron does not fire again until both the absolute andthe relative refractory periods have run their course. In-termediate levels of stimulation produce intermediaterates of neural firing.
Axonal Conduction of Action Potentials
The conduction of action potentials along an axon differsfrom the conduction of EPSPs and IPSPs in two impor-tant ways. First, the conduction of action potentials alongan axon is nondecremental; action potentials do not growweaker as they travel along the axonal membrane. Sec-ond, action potentials are conducted more slowly thanpostsynaptic potentials.
The reason for these two differences is that the conduc-tion of EPSPs and IPSPs is passive, whereas the axonal con-duction of action potentials is largely active. Once an actionpotential has been generated, it travels passively along theaxonal membrane to the adjacent voltage-activated sodiumchannels, which have yet to open. The arrival of the elec-trical signal opens these channels, thereby allowing Na�
ions to rush into the neuron and generate a full-blown ac-tion potential on this portion of the membrane. This sig-nal is then conducted passively to the next sodiumchannels, where another action potential is actively trig-gered. These events are repeated again and again until afull-blown action potential is triggered in all the terminalbuttons (Huguenard, 2000). However, because there areso many ion channels on the axonal membrane and theyare so close together, it is usual to think of axonal conduc-tion as a single wave of excitation spreading actively at aconstant speed along the axon, rather than as a series ofdiscrete events.
The wave of excitation triggered by the generation ofan action potential near the axon hillock always spreadspassively back through the cell body and dendrites of theneuron. Although little is yet known about the functionsof these backward action potentials, they are currently thesubject of intensive investigation.
The following analogy may help you appreciate themajor characteristics of axonal conduction. Consider arow of mouse traps on a wobbly shelf, all of them set andready to be triggered. Each trap stores energy by holding
834.4 ■ Conduction of Action Potentials
Potassiumchannelsstart toclose
–70
54321
–50
–30
–10
+10
+30
+50
Sodiumchannelsopen
Sodiumchannelsclose
+60
Potassiumchannelsopen
HYPERPOLARIZATION
REPOLARIZATION
RISING PHASE
Time (milliseconds)M
emb
ran
e P
ote
nti
al(m
illiv
olt
s)
FIGURE 4.6 The opening andclosing of voltage-activated sodiumand potassium channels during thethree phases of the action potential:rising phase, repolarization, and hyperpolarization.
back its striker against the pressureof the spring, in the same way thateach sodium channel stores energy
by holding back Na� ions, which are under pressure tomove down their concentration and electrostatic gradi-ents into the neuron. When the first trap in the row istriggered, the vibration is transmitted passively throughthe shelf, and the next trap is sprung—and so on downthe line.
The nondecremental nature of action potentialconduction is readily apparent from this analogy; the
last trap on the shelf strikes with no less intensity thandid the first. This analogy also illustrates the refrac-tory period: A trap cannot respond again until it hasbeen reset, just as a section of axon cannot fire againuntil it has been repolarized. Furthermore, the row oftraps can transmit in either direction, just like anaxon. If electrical stimulation of sufficient intensity isapplied to the terminal end of an axon, an action po-tential will be generated and will travel along the axonback to the cell body; this is called antidromic con-duction. Axonal conduction in the natural direction—
from cell body to terminalbuttons—is called orthodromicconduction. The elicitationof an action potential and thedirection of orthodromicconduction are summarizedin Figure 4.7.
Conduction inMyelinated Axons
In Chapter 3, you learned thatthe axons of many neurons areinsulated from the extracellularfluid by segments of fatty tissuecalled myelin. In myelinatedaxons, ions can pass throughthe axonal membrane only atthe nodes of Ranvier—thegaps between adjacent myelinsegments. Indeed, in myeli-nated axons, axonal sodiumchannels are concentrated atthe nodes of Ranvier (Salzer,2002). How, then, are actionpotentials transmitted inmyelinated axons?
When an action potentialis generated in a myelinatedaxon, the signal is conducted pas-sively—that is, instantly anddecrementally—along the firstsegment of myelin to the nextnode of Ranvier. Although thesignal is somewhat diminished
84 Chapter 4 ■ Neural Conduction and Synaptic Transmission
PSPs are conducted decrementally to the axon.
PSPs are elicited on thecell body and dendrites.
The AP is conducted nondecrementally down the axon to the terminal button.
When the summated PSPs exceed the threshold of excitation at the axon, an AP is triggered.
Arrival of the AP at the terminal button triggers exocytosis.
1
2
3
4
5 FIGURE 4.7 The direction ofsignals conducted orthodromicallythrough a typical multipolar neuron.
by the time it reaches that node, it is still strong enough toopen the voltage-activated sodium channels at the nodeand to generate another full-blown action potential. Thisaction potential is then conducted passively along theaxon to the next node, where another full-blown actionpotential is elicited, and so on.
Myelination increases the speed of axonal conduction.Because conduction along the myelinated segments of theaxon is passive, it occurs instantly, and the signal thus“jumps” along the axon from node to node. There is, ofcourse, a slight delay at each node of Ranvier while the ac-tion potential is actively generated, but conduction is stillmuch faster in myelinated axons than in unmyelinatedaxons, in which passive conduction plays a less prominentrole (see Poliak & Peles, 2003). The transmission of actionpotentials in myelinated axons is called saltatory conduc-tion (saltare means “to skip or jump”). Given the impor-tant role of myelin in neural conduction, it is hardlysurprising that the neurodegenerative diseases (diseasesthat damage the nervous system) that attack myelin havedevastating effects on neural activity and behavior—seethe discussion of multiple sclerosis in Chapter 10.
The Velocity of Axonal Conduction
At what speed are action potentials conducted along anaxon? The answer to this question depends on two prop-erties of the axon (see ffrench-Constant, Colognato, &Franklin, 2004). Conduction is faster in large-diameteraxons, and—as you have just learned—it is faster in thosethat are myelinated. Mammalian motor neurons (neuronsthat synapse on skeletal muscles) are large and myeli-nated; thus, some can conduct at speeds of 100 meters persecond (about 224 miles per hour). In contrast, small,unmyelinated axons conduct action potentials at about1 meter per second.
There is a misconception about the velocity of motorneuron action potentials in humans. The maximum ve-locity of motor neuron action potentials was found to beabout 100 meters per second in cats and was then as-sumed to be the same in humans: It is not. The maximumvelocity of conduction in human motor neurons is about60 meters per second (Peters & Brooke, 1998).
Conduction in Neurons without Axons
Action potentials are the means by which axons con-duct all-or-none signals nondecrementally over rela-tively long distances. Thus, to keep what you have justlearned about action potentials in perspective, it is im-portant for you to remember that many neurons inmammalian brains either do not have axons or havevery short ones, and many of these neurons do not nor-mally display action potentials. Conduction in these
interneurons is typically passive and decremental (Juusolaet al., 1996).
The Hodgkin-Huxley Model in Perspective
The preceding account of neural conduction is based heav-ily on the Hodgkin-Huxley model, the theory first proposedby Hodgkin and Huxley in the early 1950s (see Huxley,2002). Perhaps you have previously encountered some ofthis information about neural conduction in introductorybiology and psychology courses, where it is often presentedas a factual account of neural conduction and its mecha-nisms, rather than as a theory. The Hodgkin-Huxley modelwas a major advance in our understanding of neural con-duction (Armstrong, 2007). Fully deserving of the 1963Nobel Prize, the model provided a simple effective intro-duction to what we now understand about the general waysin which neurons conduct signals. The problem is that thesimple neurons and mechanisms of the Hodgkin-Huxleymodel are not representative of the variety, complexity, andplasticity of many of the neurons in the mammalian brain.
The Hodgkin-Huxley model was based on the study ofsquid motor neurons. Motor neurons are simple, large,and readily accessible in the PNS—squid motor neuronsare particularly large. The simplicity, size, and accessibil-ity of squid motor neurons contributed to the initial suc-cess of Hodgkin and Huxley’s research, but these sameproperties make it difficult to apply the model directly tothe mammalian brain. Hundreds of different kinds of neu-rons are found in the mammalian brain, and many of thesehave actions not found in motor neurons (see Debanne,2004; Markram et al., 2004; Nusser, 2009). Thus, theHodgkin-Huxley model must be applied to cerebral neu-rons with caution. The following are some properties ofcerebral neurons that are not shared by motor neurons:
● Many cerebral neurons fire continually even whenthey receive no input (Lisman, Raghavachari, & Tsien,2007; Schultz, 2007; Surmeier, Mercer, & Chan, 2005).
● The axons of some cerebral neurons can actively con-duct both graded signals and action potentials (Alle &Geiger, 2006, 2008).
● Action potentials of all motor neurons are the same,but action potentials of different classes of cerebralneurons vary greatly in duration, amplitude, and fre-quency (Bean, 2007).
● Many cerebral neurons have no axons and do not dis-play action potentials.
● The dendrites of some cerebral neurons can activelyconduct action potentials (Chen, Midtgaard, &Shepherd, 1997).
Clearly, cerebral neurons are far more complex thanmotor neurons, which have traditionally been the focus ofneurophysiological research, and thus, results of studies ofmotor neurons should be applied to the brain with caution.
4.5Synaptic Transmission: ChemicalTransmission of Signals amongNeurons
You have learned in this chapter how postsynaptic poten-tials are generated on the receptive membrane of a restingneuron, how these graded potentials are conducted pas-sively to the axon, how the sum of these graded potentialscan trigger action potentials, and how these all-or-none po-tentials are actively conducted down the axon to the termi-nal buttons. In the remaining sections of this chapter, youwill learn how action potentials arriving at terminal buttonstrigger the release of neurotransmitters into synapses andhow neurotransmitters carry signals to other cells. This sec-tion provides an overview of five aspects of synaptic trans-
mission: (1) the structure ofsynapses; (2) the synthesis,packaging, and transport ofneurotransmitter molecules;
(3) the release of neurotransmitter molecules; (4) the acti-vation of receptors by neurotransmitter molecules; and(5) the reuptake, enzymatic degradation, and recycling ofneurotransmitter molecules.
Structure of Synapses
Some communication among neurons occurs acrosssynapses such as the one illustrated in Figure 4.8. Neuro-transmitter molecules are released from buttons intosynaptic clefts, where they induce EPSPs or IPSPs in otherneurons by binding to receptors on their postsynapticmembranes. The synapses featured in Figure 4.8 areaxodendritic synapses—synapses of axon terminal buttonson dendrites. Notice that many axodendritic synapses termi-nate on dendritic spines (nodules of various shapes that arelocated on the surfaces of many dendrites)—see Figure 3.31on page 73. Also common are axosomatic synapses—synapses of axon terminal buttons on somas (cell bodies).
Although axodendritic and axosomatic synapses arethe most common synaptic arrangements, there are sev-eral others (Shepherd & Erulkar, 1997). For example,there are dendrodendritic synapses, which are interestingbecause they are often capable of transmission in eitherdirection. Axoaxonic synapses are particularly importantbecause they can mediate presynaptic facilitation and in-hibition. As illustrated in Figure 4.9, an axoaxonicsynapse on, or near, a terminal button can selectively fa-cilitate or inhibit the effects of that button on the postsy-naptic neuron. The advantage of presynaptic facilitationand inhibition (compared to EPSPs and IPSPs, whichyou have already learned about) is that they can selec-
tively influence one particularsynapse rather than the entirepresynaptic neuron.
The synapses depicted in Fig-ure 4.9 are directed synapses—synapses at which the site ofneurotransmitter release and thesite of neurotransmitter receptionare in close proximity. This is acommon arrangement, but thereare also many nondirected synapsesin the mammalian nervous sys-tem. Nondirected synapses aresynapses at which the site of re-lease is at some distance from thesite of reception. One type ofnondirected synapse is depictedin Figure 4.10. In this type ofarrangement, neurotransmittermolecules are released from a
86 Chapter 4 ■ Neural Conduction and Synaptic Transmission
series of varicosities (bulges orswellings) along the axon and itsbranches and thus are widelydispersed to surrounding tar-gets. Because of their appear-ance, these synapses are oftenreferred to as string-of-beadssynapses.
Synthesis, Packaging,and Transport ofNeurotransmitterMolecules
There are two basic categoriesof neurotransmitter mole-cules: small and large. Thesmall neurotransmitters areof several types; large neuro-
transmitters are all neuropep-tides. Neuropeptides are shortamino acid chains comprisingbetween 3 and 36 amino acids;in effect, they are short proteins.
Small-molecule neurotrans-mitters are typically synthesizedin the cytoplasm of the terminalbutton and packaged in synapticvesicles by the button’s Golgicomplex (see Brittle & Waters,2000). (This may be a goodpoint at which to review the in-ternal structures of neurons inFigure 3.6 on page 56.) Oncefilled with neurotransmitter, thevesicles are stored in clusters nextto the presynaptic membrane. In
contrast, neuropeptides, like other proteins, are assem-bled in the cytoplasm of the cell body on ribosomes; theyare then packaged in vesicles by the cell body’s Golgicomplex and transported by microtubules to the termi-nal buttons at a rate of about 40 centimeters per day.
874.5 ■ Synaptic Transmission: Chemical Transmission of Signals among Neurons
Presynaptic Facilitation and Inhibition
Axoaxonicsynapse
A
C
B
Neuron A synapses on the terminal button of neuron B.Some such axoaxonic synapses increase the effects of one neuron (B) on another (C) (presynaptic facilitation); others decrease the effects of one neuron (B) on another (C)(presynaptic inhibition). The advantage of presynaptic facilitation and inhibition is that they selectively influence single synapses, rather than the entire neuron.
FIGURE 4.9 Presynaptic facilita-tion and inhibition.
NeurotransmittermoleculesVaricosity
FIGURE 4.10 Nondirected neuro-transmitter release. Some neuronsrelease neurotransmitter moleculesdiffusely from varicosities along theaxon and its branches.
Watch Neurotransmitters: Communicators between Neuronswww.mypsychlab.com
The vesicles that contain neuropeptides are usually largerthan those that contain small-molecule neurotransmit-ters, and they do not usually congregate as closely to thepresynaptic membrane as the other vesicles do.
It was once believed that each neuron synthesizesand releases only one neurotransmitter, but it has beenclear for some time that many neurons contain twoneurotransmitters—a situation that is generally referredto as coexistence. It may have escaped your notice thatthe button illustrated in Figure 4.8 contains synaptic vesiclesof two sizes. This suggests that it contains two neurotrans-mitters: a neuropeptide in the larger vesicles and a small-molecule neurotransmitter in the smaller vesicles. So far,most documented cases of coexistence have involved onesmall-molecule neurotransmitter and one neuropeptide.
Release of Neurotransmitter Molecules
Exocytosis—the process of neurotransmitter release—isillustrated in Figure 4.11 (see Schweizer & Ryan, 2006).When a neuron is at rest, synaptic vesicles that containsmall-molecule neurotransmitters tend to congregatenear sections of the presynaptic membrane that are par-ticularly rich in voltage-activated calcium channels (seeRizzoli & Betz, 2004, 2005). When stimulated by actionpotentials, these channels open, and Ca2� ions enter thebutton. The entry of the Ca2� ions causes synaptic vesi-cles to fuse with the presynaptic membrane and emptytheir contents into the synaptic cleft (see Collin, Marty, &Llano, 2005; Schneggenburger & Neher, 2005). At many—but not all—synapses, one action potential causes the
88 Chapter 4 ■ Neural Conduction and Synaptic Transmission
Presynapticmembrane
Postsynapticmembrane
FIGURE 4.11 Schematic and photographic illustrations of exocytosis. (The photomicrograph was reproduced from J. E. Heuser et al., Journal of Cell Biology, 1979, 81, 275–300, by copyright permission of The Rockefeller University Press.)
release of neurotransmitter molecules from one vesicle(Matsui & Jahr, 2006).
The exocytosis of small-molecule neurotransmittersdiffers from the exocytosis of neuropeptides. Small-moleculeneurotransmitters are typically released in a pulse eachtime an action potential triggers a momentary influx ofCa2� ions through the presynaptic membrane; in con-trast, neuropeptides are typically released gradually in re-sponse to general increases in the level of intracellularCa2� ions, such as might occur during a general increasein the rate of neuron firing.
Activation of Receptors by Neurotransmitter Molecules
Once released, neurotrans-mitter molecules produce sig-nals in postsynaptic neuronsby binding to receptors in thepostsynaptic membrane. Each receptor is a protein thatcontains binding sites for only particular neurotransmitters;thus, a neurotransmitter can influence only those cells thathave receptors for it. Any molecule that binds to another is
referred to as its ligand, and a neurotransmit-ter is thus said to be a ligand of its receptor.
It was initially assumed that there is onlyone type of receptor for each neurotrans-mitter, but this has not proved to be thecase. As more receptors have been identi-fied, it has become clear that most neuro-transmitters bind to several different typesof receptors. The different types of recep-tors to which a particular neurotransmittercan bind are called the receptor subtypesfor that neurotransmitter. The various re-ceptor subtypes for a neurotransmitter aretypically located in different brain areas,and they typically respond to the neuro-transmitter in different ways (see Darlison& Richter, 1999). Thus, one advantage of re-ceptor subtypes is that they enable one neu-rotransmitter to transmit different kinds ofmessages to different parts of the brain.
The binding of a neurotransmitter to oneof its receptor subtypes can influence a post-synaptic neuron in one of two fundamen-tally different ways, depending on whetherthe receptor is ionotropic or metabotropic(Heuss & Gerber, 2000; Waxham, 1999).Ionotropic receptors are those receptorsthat are associated with ligand-activated ionchannels; metabotropic receptors are thosereceptors that are associated with signal pro-teins and G proteins (guanosine-triphos-phate–sensitive proteins); see Figure 4.12.
When a neurotransmitter molecule bindsto an ionotropic receptor, the associated ionchannel usually opens or closes immedi-ately, thereby inducing an immediate post-synaptic potential. For example, in someneurons, EPSPs (depolarizations) occur be-cause the neurotransmitter opens sodiumchannels, thereby increasing the flow of Na�
894.5 ■ Synaptic Transmission: Chemical Transmission of Signals among Neurons
An Ionotropic Receptor
A Metabotropic Receptor
Some neurotransmitter molecules bind to receptors on membranesignal proteins, which are linked to G proteins. When a neurotransmittermolecule binds to a metabotropic receptor, a subunit of theG protein breaks off into the neuron and either binds to an ionchannel or stimulates the synthesis of a second messenger.
Ionotropicreceptor
Neurotransmitter
Ion
Closedionchannel
Metabotropicreceptor
Signalprotein
Neurotransmitter
G Protein
Some neurotransmitter molecules bind to receptors on ion channels.When a neurotransmitter molecule binds to an ionotropic receptor, the channel opens (as in this case) or closes, thereby altering the flow of ions into or out of the neuron.
FIGURE 4.12 Ionotropic and metabotropic receptors.
Watch Synaptic Chemical Messengerswww.mypsychlab.com
ions into the neuron. In contrast, IPSPs (hyperpolariza-tions) often occur because the neurotransmitter openspotassium channels or chloride channels, thereby increas-ing the flow of K� ions out of the neuron or the flow ofCl� ions into it, respectively.
Metabotropic receptors are more prevalent thanionotropic receptors, and their effects are slower to de-velop, longer-lasting, more diffuse, and more varied.There are many different kinds of metabotropic recep-tors, but each is attached to a serpentine signal proteinthat winds its way back and forth through the cell mem-brane seven times. The metabotropic receptor is attachedto a portion of the signal protein outside the neuron; theG protein is attached to a portion of the signal protein in-side the neuron.
When a neurotransmitter binds to a metabotropic re-ceptor, a subunit of the associated G protein breaks away.Then, one of two things happens, depending on the par-ticular G protein. The subunit may move along the insidesurface of the membrane and bind to a nearby ion chan-nel, thereby inducing an EPSP or IPSP; or it may triggerthe synthesis of a chemical called a second messenger(neurotransmitters are considered to be the first messen-gers). Once created, a second messenger diffuses throughthe cytoplasm and may influence the activities of the neu-ron in a variety of ways (Neves, Ram, & Iyengar, 2002)—for example, it may enter the nucleus and bind to theDNA, thereby influencing genetic expression Thus, a neu-rotransmitter’s binding to a metabotropic receptor canhave radical, long-lasting effects—see the discussion ofepigenetics in Chapter 2.
One type of metabotropic receptor—autoreceptors—warrants special mention. Autoreceptors are metabotropicreceptors that have two unconventional characteristics:They bind to their neuron’s own neurotransmitter mole-cules; and they are located on the presynaptic, ratherthan the postsynaptic, membrane. Their usual functionis to monitor the number of neurotransmitter moleculesin the synapse, to reduce subsequent release when thelevels are high, and to increase subsequent release whenthey are low.
Differences between small-molecule and peptide neu-rotransmitters in patterns of release and receptor bindingsuggest that they serve different functions. Small-moleculeneurotransmitters tend to be released into directedsynapses and to activate either ionotropic receptors ormetabotropic receptors that act directly on ion channels.In contrast, neuropeptides tend to be released diffusely,and virtually all bind to metabotropic receptors that actthrough second messengers. Consequently, the functionof small-molecule neurotransmitters appears to be thetransmission of rapid, brief excitatory or inhibitory sig-nals to adjacent cells; and the function of neuropeptidesappears to be the transmission of slow, diffuse, long-lastingsignals.
Reuptake, Enzymatic Degradation, and Recycling
If nothing intervened, a neurotransmitter moleculewould remain active in the synapse, in effect clogging thatchannel of communication. However, two mechanisms
90 Chapter 4 ■ Neural Conduction and Synaptic Transmission
Enzymatic Degradation
Deactivatingenzyme
Two Mechanisms of Neurotransmitter Deactivation in Synapses
Reuptake
Neurotransmittermolecule
Transporter
FIGURE 4.13 The two mechanisms for terminating neurotransmitter action in the synapse: reuptake and enzymatic degradation.
terminate synaptic messages and keep that from happen-ing. These two message-terminating mechanisms arereuptake by transporters and enzymatic degradation(see Figure 4.13).
Reuptake is the more common of the two deactivatingmechanisms. The majority of neurotransmitters, oncereleased, are almost immediately drawn back into the pre-synaptic buttons by transporter mechanisms.
In contrast, other neurotransmitters are degraded(broken apart) in the synapse by the action ofenzymes—proteins that stimulate or inhibit biochemi-cal reactions without being affected by them. For exam-ple, acetylcholine, one of the few neurotransmitters forwhich enzymatic degradation is the main mechanism ofsynaptic deactivation, is broken down by the enzymeacetylcholinesterase.
Terminal buttons are models of efficiency. Once re-leased, neurotransmitter molecules or their breakdownproducts are drawn back into the button and recycled, re-gardless of the mechanism of their deactivation. Even thevesicles, once they have done their job, are drawn backinto the neuron from the presynaptic membrane and areused to create new vesicles (Südhof, 2004).
Glial Function and Synaptic Transmission
Once overlooked as playing merely supportive roles in thenervous system, glial cells have been thrust to center stage
by a wave of remarkable findings. For example, astrocyteshave been shown to release chemical transmitters, to con-tain receptors for neurotransmitters, to conduct signals,and to participate in neurotransmitter reuptake (see Fields& Burnstock, 2006; Miller & Cleveland, 2005). Indeed, it isbecoming inappropriate to think of brain function solelyin terms of neuron–neuron connections. Neurons are onlypart of the story.
The importance of glial cells in brain function issuggested by the greater prevalence ofthese cells in intelligent organisms. Willneuroscience prove to be a misnomer?Anybody for “gliascience”?
Gap Junctions Interest in gap junctions has recentlybeen rekindled. Gap junctions are narrow spaces betweenadjacent neurons that are bridged by fine tubular chan-nels, called connexins, that contain cytoplasm. Conse-quently, the cytoplasm of the two neurons is continuous,allowing electrical signals and small molecules to passfrom one neuron to the next (see Figure 4.14). Gap junc-tions are sometimes called electrical synapses.
Gap junctions are commonplace in invertebrate ner-vous systems, but their existence was more difficult to es-tablish in mammals (see Bennett, 2000). They were firstdemonstrated in mammals in the 1970s, but few mam-malian examples accumulated over the ensuing 30 years.Then technological developments led to the discovery ofgap junctions throughout the mammalian brain; they
seem to be an integral feature of local neu-ral inhibitory circuits (Hestrin & Galarreta,2005). In addition, astrocytes have beenshown to communicate with each other,neurons, and other cells through gap junc-tions (Bennett et al., 2003). Thus, thefocus on glial function is reviving interestin gap junctions.
The role of gap junctions in nervoussystem activity is both underappreciated(Conners & Long, 2004) and poorly un-derstood (Nagy, Dudek, & Rash, 2004). Al-though they are less selective thansynapses, gap junctions have two advan-tages. One is that communication acrossthem is very fast because it does not in-volve active mechanisms. The other ad-vantage is that gap junctions permitcommunication in either direction.
914.5 ■ Synaptic Transmission: Chemical Transmission of Signals among Neurons
Evolutiona Evolutionary Perspective Perspective
Prejunctionmembraneof one cell
Postjunctionmembraneof other cell
Pores connectingcytoplasm oftwo cells
Connexins
FIGURE 4.14 Gap junctions. Gap junctionsconnect the cytoplasm of two cells.
Now that you understand the basics of neurotransmitterfunction, let’s take a closer look at some of the well over100 neurotransmitter substances that have been identi-fied (see Purves et al., 2004). The following are threeclasses of conventional small-molecule neurotransmit-ters: the amino acids, the monoamines, and acetylcholine.Also, there is a fourth group of various small-moleculeneurotransmitters, which are often referred to asunconventional neurotransmitters because their mecha-nisms of action are unusual. In contrast to the small-molecule neurotransmitters, there is only one class oflarge-molecule neurotransmitters: the neuropeptides.Most neurotransmitters produce either excitation or inhi-bition, not both; but a few produce excitation when they
bind to some of their receptor subtypes and inhibitionwhen they bind to others. All of the neurotransmitterclasses and individual neurotransmitters that appear inthis section in boldface type are presented in Figure 4.17at the end of this section.
Amino Acid Neurotransmitters
The neurotransmitters in the vast majority of fast-acting,directed synapses in the central nervous system are aminoacids—the molecular building blocks of proteins. The fourmost widely studied amino acid neurotransmitters areglutamate, aspartate, glycine, and gamma-aminobutyricacid (GABA). The first three are common in the proteinswe consume, whereas GABA is synthesized by a simplemodification of the structure of glutamate. Glutamate isthe most prevalent excitatory neurotransmitter in themammalian central nervous system. GABA is the mostprevalent inhibitory neurotransmitter (see Jacob, Moss, &Jurd, 2008; Orser, 2007); however, it has excitatory effectsat some synapses (Szabadics et al., 2006).
Monoamine Neurotransmitters
Monoamines are another class of small-molecule neuro-transmitters. Each is synthesized from a single aminoacid—hence the name monoamine (one amine).Monoamine neurotransmitters are slightly larger thanamino acid neurotransmitters, and their effects tend to bemore diffuse (see Bunin & Wightman, 1999). Themonoamines are present in small groups of neuronswhose cell bodies are, for the most part, located in thebrain stem. These neurons often have highly branchedaxons with many varicosities (string-of-beads synapses),from which monoamine neurotransmitters are dif-fusely released into the extracellular fluid (see Figures4.10 and 4.15).
There are four monoamine neurotransmitters:dopamine, epinephrine, norepinephrine, and serotonin.They are subdivided into two groups, catecholamines andindolamines, on the basis of their structures. Dopamine,norepinephrine, and epinephrine are catecholamines. Eachis synthesized from the amino acid tyrosine. Tyrosine is con-verted to L-dopa, which in turn is converted to dopamine.Neurons that release norepinephrine have an extra enzyme(one that is not present in dopaminergic neurons), whichconverts the dopamine in them to norepinephrine. Simi-larly, neurons that release epinephrine have all the enzymespresent in neurons that release norepinephrine, along withan extra enzyme that converts norepinephrine to epineph-rine (see Figure 4.16). In contrast to the other monoamines,serotonin (also called 5-hydroxytryptamine, or 5-HT) is syn-thesized from the amino acid tryptophan and is classified asan indolamine.
Neurons that release norepinephrine are callednoradrenergic; those that release epinephrine are called
92 Chapter 4 ■ Neural Conduction and Synaptic Transmission
Before moving on to the discussion of specific neurotrans-
mitters, review the general principles of axon conduction
and synaptic transmission. Draw a line to connect each
term in the left column with the appropriate word or
phrase in the right column. The correct answers are pro-
vided at the end of the exercise. Before proceeding, review
material related to your errors and omissions.
a. axonal conduction of
action potentials
b. orthodromic
c. myelin
d. nodes of Ranvier
e. multiple
f. dendritic
g. compartmentalize
dendrites
h. somas
i. axoaxonic synapses
j. string-of-beads
k. neuropeptides
l. store neurotransmitters
m. G proteins
n. enzymatic degradation
o. gap junctions
1. fatty
2. sclerosis
3. cell bodies
4. dendritic spines
5. nondecremental
6. presynaptic facilitation
7. nondirected synapses
8. synaptic vesicles
9. from cell body to
terminal buttons
10. acetylcholinesterase
11. short amino acid chains
12. saltatory
13. metabotropic receptors
14. electrical synapses
15. spines
Scan Your Brainanswers: (1) c, (2) e, (3) h, (4) g, (5) a, (6) i, (7) j, (8) l, (9) b,
adrenergic. There are two reasons for this naming. One isthat epinephrine and norepinephrine used to be calledadrenaline and noradrenaline, respectively, by many scien-tists, until a drug company registered Adrenalin as abrand name. The other reason will become apparent toyou if you try to say norepinephrinergic.
Acetylcholine
Acetylcholine (abbreviated Ach) is a small-molecule neu-rotransmitter that is in one major respect like a professorwho is late for a lecture: It is in a class by itself. It is cre-ated by adding an acetyl group to a choline molecule.Acetylcholine is the neurotransmitter at neuromuscularjunctions, at many of the synapses in the autonomic nerv-ous system, and at synapses in several parts of the centralnervous system. As you learned in the last section, acetyl-choline is broken down in the synapse by the enzymeacetylcholinesterase. Neurons that release acetylcholine aresaid to be cholinergic.
Unconventional Neurotransmitters
The unconventional neurotransmitters act in ways thatare different from those that neuroscientists have cometo think of as typical for such substances. One class ofunconventional neurotransmitters, the soluble-gasneurotransmitters, includes nitric oxide and carbonmonoxide (Boehning & Snyder, 2003). These neuro-transmitters are produced in the neural cytoplasm andimmediately diffuse through the cell membrane into theextracellular fluid and then into nearby cells. They eas-ily pass through cell membranes because they are solu-ble in lipids. Once inside another cell, they stimulate theproduction of a second messenger and in a few secondsare deactivated by being converted to other molecules.They are difficult to study because they exist for only afew seconds.
Soluble-gas neurotransmitters have been shown tobe involved in retrograde transmission. At somesynapses, they transmit feedback signals from the post-synaptic neuron back to the presynaptic neuron. Thefunction of retrograde transmission seems to be to reg-ulate the activity of presynaptic neurons (Ludwig &Pittman, 2003).
Another class of unconventional neurotransmitters,the endocannabinoids, has only recently been discov-ered. Endocannabinoids are neurotransmitters that are
934.6 ■ Neurotransmitters
FIGURE 4.15 String-of-beads noradrenergic nerve fibers. Thebright, beaded structures represent sites in these multiple-branched axons where the monoamine neurotransmitter nor-epinephrine is stored in high concentration and released into thesurrounding extracellular fluid. (Courtesy of Floyd E. Bloom,M.D., The Scripps Research Institute, La Jolla, California.)
Epinephrine
Norepinephrine
Dopamine
L-dopa
Tyrosine
FIGURE 4.16 The steps in the synthesis of catecholaminesfrom tyrosine.
similar to delta-9-tetrahydrocannabinol (THC), the mainpsychoactive (producing psychological effects) constituentof marijuana (see Chapter 15). So far, two endocannabi-noids have been discovered (Van Sickle et al., 2005). Themost widely studied is anandamide (from the Sanskritword ananda, which means “eternal bliss”). Like the solu-ble gases, the endocannabinoids are produced immedi-ately before they are released. Endocannabinoids aresynthesized from fatty compounds in the cell membrane;they tend to be released from the dendrites and cell body;and they tend to have most of their effects on presynapticneurons, inhibiting subsequent synaptic transmission(see Glickfield & Scanziani, 2005).
Neuropeptides
Over 100 neuropeptides have been identified (see Ludwig& Leng, 2006). The actions of each neuropeptide dependon its amino acid sequence.
It is usual to loosely group neuropeptide transmittersinto five categories. Three of these categories acknowl-edge that neuropeptides often function in multiple capac-ities, not just as neurotransmitters: One category(pituitary peptides) contains neuropeptides that werefirst identified as hormones released by the pituitary; asecond category (hypothalamic peptides) contains neu-ropeptides that were first identified as hormones releasedby the hypothalamus; and a third category (brain–gutpeptides) contains neuropeptides that were first discov-ered in the gut. The fourth cate-gory (opioid peptides) containsneuropeptides that are similar instructure to the active ingredientsof opium, and the fifth(miscellaneous peptides) is acatch-all category that containsall of the neuropeptide transmit-ters that do not fit into one of theother four categories.
Figure 4.17 summarizes all theneurotransmitters that were in-troduced in this section. If it hasnot already occurred to you, thistable should be very useful for re-viewing the material.
94 Chapter 4 ■ Neural Conduction and Synaptic Transmission
4.7Pharmacology of SynapticTransmission and Behavior
In case you have forgotten, the reason I have asked you toinvest so much effort in learning about the neurotrans-mitters is that they play a key role in how the brain works.We began this chapter on a behavioral note by consideringthe pathological behavior of Roberto Garcia d’Orta, whichresulted from a Parkinson’s disease–related disruption ofhis dopamine function. Now, let’s return to behavior.
Most of the methods that biopsychologists use tostudy the behavioral effects of neurotransmitters arepharmacological (involving drugs). To study neurotrans-mitters and behavior, researchers administer to human ornonhuman subjects drugs that have particular effects onparticular neurotransmitters and then assess the effects ofthe drugs on behavior.
Drugs have two fundamentally different kinds of ef-fects on synaptic transmission: They facilitate it or theyinhibit it. Drugs that facilitate the effects of a particularneurotransmitter are said to be agonists of that neuro-
transmitter. Drugs that inhibitthe effects of a particular neu-rotransmitter are said to be itsantagonists.
How Drugs Influence Synaptic Transmission
Although synthesis, release, and action vary from neuro-transmitter to neurotransmitter, the following seven generalsteps are common to most neurotransmitters: (1) synthesisof the neurotransmitter, (2) storage in vesicles, (3) break-down in the cytoplasm of any neurotransmitter that leaksfrom the vesicles, (4) exocytosis, (5) inhibitory feedback viaautoreceptors, (6) activation of postsynaptic receptors, and(7) deactivation. Figure 4.18 on page 96 illustrates theseseven steps, and Figure 4.19 on page 97 illustrates someways that agonistic and antagonistic drugs influence them.
For example, some agonists of a particular neurotransmitterbind to postsynaptic receptors and activate them, whereassome antagonistic drugs, called receptor blockers, bind topostsynaptic receptors without activating them and, in sodoing, block the access of the usual neurotransmitter.
Behavioral Pharmacology: Three InfluentialLines of Research
You will encounter discussions of the putative (hypothet-ical) behavioral functions of various neurotransmitters insubsequent chapters. However, this chapter ends with de-scriptions of three particularly influential lines of researchon neurotransmitters and behavior. Each line of researchled to the discovery of an important principle of neuro-transmitter function, and each illustrates how drugs areused to study the nervous system and behavior.
Wrinkles and Darts: Discovery of Receptor SubtypesIt was originally assumed that there was one kind ofreceptor for each neurotransmitter, but this notion wasdispelled by research on acetylcholine receptors (seeChangeux & Edelstein, 2005). Some acetylcholine receptorsbind to nicotine (a CNS stimulant and major psychoactiveingredient of tobacco), whereas other acetylcholine recep-tors bind to muscarine (a poisonous substance foundin some mushrooms). These two kinds of acetylcholinereceptors thus became known as nicotinic receptors andmuscarinic receptors.
Next, it was discovered that nicotinic and muscarinicreceptors are distributed differently in the nervous sys-tem, have different modes of action, and consequentlyhave different behavioral effects. Both nicotinic and mus-carinic receptors are found in the CNS and the PNS. Inthe PNS, many nicotinic receptors occur at the junctionsbetween motor neurons and muscle fibers, whereas manymuscarinic receptors are located in the autonomic nerv-ous system (ANS). Nicotinic and muscarinic receptors areionotropic and metabotropic, respectively.
Many of the drugs that are used in research and inmedicine are extracts of plants that have long been usedfor medicinal and recreational purposes. The cholinergicagonists and antagonists illustrate this point well. For ex-ample, the ancient Greeks consumed extracts of the bel-ladonna plant to treat stomach ailments and to makethemselves more attractive. Greek women believed thatthe pupil-dilating effects of these extracts enhanced theirbeauty (belladonna means “beautiful lady”). Atropine,which is the main active ingredient of belladonna, is a re-ceptor blocker that exerts its antagonist effect by bindingto muscarinic receptors, thereby blocking the effects ofacetylcholine on them. The pupil-dilating effects of at-ropine are mediated by its antagonist actions on mus-carinic receptors in the ANS. In contrast, the disruptiveeffects of large doses of atropine on memory is mediatedby its antagonistic effect on muscarinic receptors in the
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CNS. The disruptive effect of high doses of atropine onmemory was one of the earliest clues that cholinergicmechanisms may play a role in memory (see Chapter 11).
South American natives have long used curare—an ex-tract of a certain class of woody vines—on the tips ofdarts they use to kill their game and occasionally theirenemies. Like atropine, curare is a receptor blocker atcholinergic synapses, but it acts at nicotinic receptors. Bybinding to nicotinic receptors, curare blocks transmissionat neuromuscular junctions, thus paralyzing its recipientsand killing them by blocking their respiration. You may besurprised, then, to learn that the active ingredient of curare
is sometimes administered to human pa-tients during surgery to ensure that theirmuscles do not contract during an inci-sion. When curare is used for this purpose, the patient’sbreathing must be artificially maintained by a respirator.
Botox (short for Botulinium toxin), a neurotoxin re-leased by a bacterium often found in spoiled food, isanother nicotinic antagonist, but itsmechanism of action is different: Itblocks the release of acetylcholine at neu-romuscular junctions and is thus a deadly poison. However,injected in minute doses at specific sites, it has applications
96 Chapter 4 ■ Neural Conduction and Synaptic Transmission
Seven Steps in Neurotransmitter Action
1
2
3
4
5
6
7
Neurotransmitter molecules are synthesized
from precursors under the influence of enzymes.
Neurotransmitter molecules are
stored in vesicles.
Neurotransmitter molecules that leak
from their vesicles are destroyed by enzymes.
Action potentials cause vesicles to fuse with the
presynaptic membrane and release their neurotransmitter molecules into the synapse.
Released neurotransmitter molecules bind with
autoreceptors and inhibit subsequent neurotransmitter release.
Released neurotransmitter molecules are deactivated
by either reuptake or enzymatic degradation.
Released neurotransmitter molecules bind to postsynaptic
receptors.
Synthesizingenzymes
Neurotransmitterprecursors
Degradingenzymes
Vesicle
Autoreceptor
Postsynapticreceptor
FIGURE 4.18 Seven steps in neurotransmitter action: (1) synthesis, (2) storage in vesicles, (3) breakdown of any neurotransmitter leaking from the vesicles, (4) exocytosis, (5) inhibitoryfeedback via autoreceptors, (6) activation of postsynaptic receptors, and (7) deactivation.
in medicine (e.g., reduction of tremors) and cosmetics(e.g., reduction of wrinkles; see Figure 4.20 on page 98).
Pleasure and Pain: Discovery of Endogenous OpioidsOpium, the sticky resin obtained from the seed pods ofthe opium poppy, has been used by humans since prehis-toric times for its pleasurable effects. Morphine, its majorpsychoactive ingredient, is highly addictive. But mor-phine also has its good side: It is an effective analgesic(painkiller)—see Chapters 7 and 15.
In the 1970s, it was discovered that opiate drugs such asmorphine bind effectively to receptors in the brain. Thesereceptors were generally found in the hypothalamus andother limbic areas, but they were most concentrated in thearea of the brain stem around the cerebral aqueduct, whichconnects the third and fourth ventricles; this part of the
brain stem is called the periaqueductalgray (PAG). Microinjection of mor-phine into the PAG, or even electrical
stimulation of the PAG, produces strong analgesia.
The existence of selective opiate receptors in the brainraised an interesting question: Why are they there? Theyare certainly not there so that once humans discoveredopium, opiates would have a place to bind. The existenceof opiate receptors suggested that opioid (opiate-like)chemicals occur naturally in the brain, and that possibil-ity triggered an intensive search for them.
Several families of endogenous (occurring naturallywithin the body) opioids have been discovered. First discov-ered were the enkephalins (meaning “in the head”). An-other major family of endogenous opioids are theendorphins (a contraction of “endogenous morphine”). Allendogenous opioid neurotransmitters are neuropeptides,and their receptors are metabotropic.
Tremors and Insanity: Discovery of Antischizo-phrenic Drugs Arguably, the most important event inthe treatment of mental illness has been the developmentof drugs for the treatment of schizophrenia (see Chapter 18).Surprisingly, Parkinson’s disease, the disease from which
974.7 ■ Pharmacology of Synaptic Transmission and Behavior
Drug increases the synthesis of neurotransmitter molecules (e.g., by increasing the amount of precursor).
Drug increases the number of neurotransmitter molecules by destroying degrading enzymes.
Drug increases the release of neurotransmitter molecules from terminal buttons.
Drug binds to autoreceptorsand blocks their inhibitory effect on neurotransmitter release.
Drug binds to postsynaptic receptors and either activates them or increases the effect on them of neurotransmitter
Drug blocks the deactivation of neurotransmitter molecules by blocking degradation or reuptake.
Drug blocks the synthesis of neurotransmitter molecules (e.g., by destroying synthesizing enzymes).
Drug causes the neurotransmitter molecules to leak from the vesicles and be destroyed by degrading enzymes.
Drug blocks the release of the neurotransmitter molecules from terminal buttons.
Drug activates autoreceptors and inhibits neurotransmitter release.
Drug is a receptor blocker; it binds to the postsynaptic receptors and blocks the effect of the neurotransmitter.
Some Mechanisms of Drug Action
Agonistic Drug Effects Antagonistic Drug Effects
FIGURE 4.19 Some mechanisms of agonistic and antagonistic drug effects.
Roberto Garcia d’Orta suffered, played a major role intheir discovery.
In the 1950s, largely by chance, two drugs were foundto have antischizophrenic effects. Although these twodrugs were not related structurally, theyboth produced a curious pattern of ef-fects: Neither drug appeared to have anyantischizophrenic activity until patients had been takingit for about 3 weeks, at which point the drug also startedto produce mild Parkinsonian symptoms (e.g., tremor-at-rest). Researchers put this result together with two then-recent findings: (1) that Parkinson’s disease is associatedwith the degeneration of the main dopamine pathway ofthe brain, and (2) that dopamine agonists—cocaine andamphetamines—produce a temporary disorder that re-sembles schizophrenia. Together, these findings suggestedthat schizophrenia is caused by excessive activity atdopamine synapses, and thus that potent dopamine antag-onists would be effective in its treatment.
It was ultimately discovered that one particulardopamine receptor, the D2 receptor, plays a key role inschizophrenia and that drugs that most effectively block itare the most effective antischizophrenic drugs.
It would be a mistake to think that antischizophrenicdrugs cure schizophrenia or that they help in every case.However, they help many patients, and the help is some-times enough to render hospitalization unnecessary. Youwill learn much more about this important line of re-search in Chapter 18.
98 Chapter 4 ■ Neural Conduction and Synaptic Transmission
FIGURE 4.20 A woman receiving cosmetic Botox injections.
Clinical Implications
Themes Revisited
The function of the nervous system, like the function ofany circuit, depends on how signals travel through it. Theprimary purpose of this chapter was to introduce you toneural conduction and synaptic transmission. Thisintroduction touched on three of the book’s four mainthemes.
The clinical implications theme was illustrated by theopening case of the Lizard, RobertoGarcia d’Orta. Then, this theme waspicked up again at the end of the chapter
during discussions of curare, Botox, endogenous opioids,and antischizophrenic drugs.
The evolutionary perspective theme was implicit through-out the entire chapter, because almost all neurophysiological
research is conducted on the neurons andsynapses of nonhuman subjects. However, theevolutionary perspective received explicitemphasis when the particularly high glial-cell-to-neuronratio of the human brain was noted.
The thinking creatively theme arose in two metaphors:the firing-gun metaphor of action potentials and the mouse-traps-on-a-wobbly-shelf metaphor ofaxonal conduction. Metaphors areuseful in teaching, and scientists findthem useful for thinking about the phenomena they study.The text also described the creative Nobel-Prize–winningresearch of Hodgkin and Huxley on the ionic bases of restingmembrane potentials.
1. Just as computers operate on binary (yes-no) signals, theall-or-none action potential is the basis of neural com-munication. The human brain is thus nothing more thana particularly complex computer. Discuss.
2. How have the findings described in this chapter changedyour understanding of brain function?
3. Why is it important for biopsychologists to understandneural conduction and synaptic transmission? Is it impor-tant for all psychologists to have such knowledge? Discuss.
4. The discovery that neurotransmitters can act directly onDNA via G proteins uncovered a mechanism throughwhich experience and genes can interact (see Chapter 2).Discuss.
5. Dendrites and glial cells are currently “hot” subjects ofneuroscientific research. Describe the findings that havegenerated such interest, and explain how they havechanged our conception of brain function.
100 Chapter 4 ■ Neural Conduction and Synaptic Transmission
Test your comprehension of the chapter with this brief practice test. You can find the answers to thesequestions as well as more practice tests, activities, and other study resources at www.mypsychlab.com.
1. IPSPs area. Inhibitory.b. graded.c. all-or-none.d. all of the abovee. both a and b
2. Which of the following ions triggers exocytosis by its influx into terminal buttons?a. Cl�
b. Ca2�
c. glutamated. glycinee. Na�
3. Which of the following is the most common mechanism ofdeactivating neurotransmitter molecules in synapses?a. enzymatic degradationb. acetylcholinesterasec. reuptake by transportersd. all of the abovee. both a and b
4. All of the following are monoamine neurotransmitters excepta. epinephrine.b. serotonin.c. norepinephrine.d. dopamine.e. acetylcholine.
5. Botox is aa. nicotinic agonistb. nicotinic antagonist.c. cholinergic agonist.d. cholinergic antagonist.e. poison used by some South American natives on
