The interpretation of the geological record goes well beyond physical structure. The skull
may
be found in proximity to various tools, the bones of animals (perhaps with damage that matches
tool structure), plant remains, evidence of households, and so forth. All of this can lead to an
educated guess about the culture and behavior of our ancestors. A guess about the function of
the brain. Indeed, it is no accident that the term skull is frequently replaced by the term brain
case, suggesting that the missing contents are more important than the empty skull. We agree.
The purpose of this brief excursion into our ancestry is to provide an extreme example of an old
philosophical issue, the mind-body problem (cf., Utall, 1978). Is the
mind or behavior of humans
a product of the body or is it a separate (spiritual) entity? Nearly all of us are willing to sit on
both sides of this philosophical fence:
On the one hand, we are easily convinced that brain cases tell us something about the nature
of
the contents. Although it is hard to imagine anything less dynamic than a million year old skull
ensconced in stone, we believe that this evidence can provide at least a global clue about behavior
potential. The surrounding artifacts (tools, etc.) supplement this evidence and enrich our
interpretation of the culture of our ancestors.
Paradoxically, as the evidence gets stronger, our beliefs tend to get weaker. Moving forward
in
time to our current existence, we have no difficulty accepting the fact that serious brain damage
leads to serious changes in behavior. The brain is obviously the organ of (abnormal) behavior.
The brain may be recognized as the organ of behavior, but each of us tenaciously hangs onto the
belief that we are more than the product of our brain physiology. There is a strong sensation that
we have an individual identity (self) and a free will which allows us to control our own brain.
Students of the brain and behavior are not immune to these feelings, but the feelings must be
suspended on occasion to pursue the fundamental belief that behavior has predictable causes, and
that these causes may be found in the workings of the brain.
The purpose of this text is to provide a better understanding of the vehicle for the feelings,
emotions, and motivations of the human experience. We will attempt to develop an
understanding of the interpenetration of brain, behavior, and environment. We will discuss the
chemistry of behavior in both the literal sense of neurochemistry and the figurative sense of an
analysis of the reactions with the environment.
Perhaps a word of reassurance is needed concerning the level of analysis that will be pursued.
There are three traditional and overlapping subdivisions of the material covered in this textbook:
Neurochemistry is the study of the
chemical reactions and functions of
the individual neuron or small populations of neurons.
Behavioral Pharmacology is the
analysis of the effects of drugs on
behavior (usually of animals), with particular emphasis on the development and
classification of drugs.
Psychopharmacology is the study of
the effects of drugs on behavior
(usually of humans), with particular emphasis on changes in mood, emotions, and
psychomotor abilities.
Each of these subdisciplines is reductionistic in its own way and tends to analyze the brain
and/or
behavior in a manner that seems sterile to most beginning students. We do not intend to reduce
behavior and chemistry to the simplest level in the way that a chemist would analyze a compound.
Indeed, our goal is to synthesize rather than analyze. We intend to further your appreciation by
increasing the awareness of the mechanisms of behavior. Connoisseurs of wine are
knowledgeable about climate, grapes, and fermentation; they are no less appreciative because they
know the vintner's craft. Aficionados of classical music are knowledgeable about tone, rhythm
and structure; they are no less appreciative because they know the score. Our goal is to enrich
your appreciation of behavior by explaining some of the processes that underlie your feelings.
Enough preambling. Let us trace some of the historical events in both the field and the
laboratory that have helped to shape our current conceptualizations of the chemical bases of
behavior.
Folk Remedies
The roots of behavioral pharmacology (no pun intended) go back many centuries. A working
knowledge of drug use clearly antedates the knowledge that the brain is the organ of behavior,
and probably antedates the appearance of the first medical practitioners. In fact, it seems likely
that medical practitioners arose as a result of the accumulating knowledge about folk remedies.
Those individuals who were especially knowledgeable about the remedies of their culture
probably became the medical practitioners. The history of specific drugs will be incorporated in
many of the later chapters, but a few examples at this point will provide the flavor of both the
power and the complexity of folk medicine. (Several of the specific histories that follow, and
numerous additional ones, are presented in more detail in the various editions of Gilman,
Goodman & Gilman; e.g., 1980.)
The old adage that one man's cure is another man's poison seems particularly relevant to the
history of pharmacology. Many of the compounds that are useful in medicine are derived from
arrow poisons, ordeal poisons (to detect practitioners of witchcraft), and pesticides.
A particularly good example of such multiple applications is the use of atropine by the
ancient
Hindus and Romans. This compound, an extract of the nightshade and related plants, was used
as a tool by the professional poisoners of the Middle Ages. At the same time, fashionable women
were placing drops of atropine solution into their eyes as a cosmetic. The dilation of the pupils
made the women more appealing by causing males to believe they were the object of emotional
attraction. These antithetical uses led Linne' to name the shrub Atropos belladonna (Atropos,
after one of the three fates, who cut the thread of life; belladonna means beautiful woman.)
Today, men and women alike have drops of atropine placed in their eyes, but primarily for the
purpose of eye examinations. It is also used for a wide range of medicinal purposes and, as we
will see throughout the text, continues to be widely used as a research tool.
An extract from the foxglove plant (Digitalis purpura--the flower looks like a purple
finger) was
used in an equally diverse fashion. The ancient Romans used digitalis as a tonic, a rat poison, a
diuretic, an emetic, an arrow poison and an ordeal poison. More recently, it has been used by
more modern physicians for the treatment of dropsy (a vaguely defined anemic disorder) and
various disorders of the heart muscle. Amazingly, there is reason to believe that this compound, a
stimulant of the sympathetic nervous system, was effective for each of these applications.
Societies that eat mushrooms have known for centuries that some species result in violent
illness
and possible death, others result in vivid hallucinations, and others are simply a tasty addition to
the diet. Claims and counterclaims about which species does what have been handed down
through the centuries, but certain species (most notably Amanita muscaria) were well
catalogued,
and the chemical known as muscarine played a pivotal role in
the development of 20th century
psychopharmacology.
It is not uncommon for a cure to take on religious significance within a culture. A curious
malady of the circulatory system appeared throughout Europe several centuries ago (a few cases
still appear). The disease appeared in epidemic cycles and began as a tingling and loss of
sensation in the limbs. As the disease progressed, the circulation of the feet and hands got
progressively worse, eventually resulting in gangrene. The blackened limbs would wither away
and were said to have been consumed by the Holy Fire. Early stages of the disease could be
successfully treated by a sojourn to the shrine of St. Anthony. This remedy was frequently
effective, not because of the religious conversion, but because the grain in the area of the shrine
was not infected with the ergot fungus that caused the disorder.
One of the best known of the ancient compounds is strychnine, which in addition to its
legendary properties as a poison, has been widely used (even by modern physicians) as a
stimulant. The compound can be extracted from a wide variety of shrubs and trees (of the genus
Strychnos) indigenous to Asia, Africa and Australia. Curiously, the South American
relatives of
these plants yield a slightly different chemical (curare) that
paralyzes the muscles. The latter
compound was a very effective arrow poison and is used today as a muscle relaxant during major
surgery.
Amidst all of these cures and poisons, almost every culture has managed to find one or more
recreational drugs. Coffee and tobacco from the Americas, opium and tea from the Orient,
cocaine from Africa, and alcohol from almost everywhere. All of these compounds have been
used for their specific ability to change moods and feelings. In some cases, the usage was
restricted to ceremonial purposes, but more commonly the use was routine and widespread
throughout the culture. We will deal with these compounds in considerably more detail later.
A final example will serve to illustrate the precision that folk medicine can attain within a
specific
environmental situation. Sickle cell anemia, a genetic disorder of the blood cells, has been a
curiosity because this deleterious recessive gene should not be so widespread. In the homozygous
condition, in which the afflicted individual possesses both recessive genes, the condition is almost
always fatal. However, the heterozygous individual who only has one such gene often shows
only mild symptoms of the disease. Why has the sickle cell gene remained in certain populations?
The answer lies in the fact that the disorder also confers an advantage in that the individual with
sickled cells is much more resistant to malaria, so that in environments where malaria is prevalent,
the heterozygous individual is actually better adapted to the environment than an individual who
does not carry genes for the disease.
With this part of the puzzle in place, we go on to certain African cultures that raise yams as a
primary staple in their diet. The yams are harvested at the beginning of the rainy season, but
because of religious proscriptions, are not eaten until the rainy season has ended, at which time a
yam feast is scheduled. The curious aspect of this is that there is frequently a shortage of food,
and the people endure hunger in the midst of plentiful stores of yams until the rains subside.
Although this practice has probably been carried out for centuries, it was only recently discovered
(Houston, 1973) that yams contain a compound that combats the
sickling of red blood cells. This
effect is very desirable except during the rainy season when mosquitoes are spreading malaria.
Thus, there emerges an incredibly complex interaction between genetic selection, a seasonal
disease, a plant remedy and, holding it all together, a set of behaviors that have assumed the status
of a religious custom (cf., Durham, 1982).
The case of the yams exemplifies the grandeur of the interactions of human behavior with the
environment. It also serves to place scientific knowledge in perspective. Scientific knowledge
does not always add substantively to our practices (knowing that yams reduce sickling does not
change their effectiveness). Yet, to the extent that it adds to our understanding, scientific
knowledge can greatly increase our appreciation for the functions of the brain. We will now go to
the laboratory to see some other stories unfold.
The
Unveiling of Chemical Transmission
We have just passed the centenary of one of the major discoveries in brain research. In the
1880's, a controversy was brewing between Camillo Golgi and Ramon y Cajal. Golgi claimed that
the nervous system was an interconnected net of protoplasm which, although complicated, was
essentially all one piece. The term syncitium was used to
describe such a network. Cajal claimed
that the nervous system only appeared to be a syncitium and that in reality it was composed of
individual cells (neurons) that were so closely juxtaposed that they appeared as a unitary
mass.
Looking through the microscope did not resolve the controversy. Nervous tissue is
disturbingly
translucent and gray in its natural state, thwarting attempts to see cellular detail. The structural
details only become apparent when the tissue has been stained with some sort of dye. The ironic
ending to this controversy came when Golgi (the syncitium proponent) developed a superb
staining procedure that provided enough detailed resolution to prove Cajal was correct. Thus the
knowledge that the nervous system consisted of many individual cells, the so-called "neuron
doctrine", became the state of the art.
The proof of the neuron doctrine was a double edged sword for students of the brain. On the
one hand, this evidence provided a comforting completion to the cell theory of biology; now, all
of the organ systems, including the brain, were consistent in structure. On the other hand, an
understanding of the function of the brain was complicated by the cellular structure.
The most serious complication involved the electrical activity of nerve cells (see Brazier, 1984,
for an intriguing exposition of the history and instrumentation of this era). In the early 1800's,
Galvani had formulated his notions of animal electricity when he noticed the twitching of frog legs
on a butcher's rack. Based on this and other observations, Helmholtz conducted some clever
experiments in the 1850's using reaction time to calculate the velocity at which nerves conduct
their electric impulses. He stimulated the sciatic nerve of the leg at two points, one near the hip
and one near the knee, and measured the difference in reaction time. He reasoned correctly that
the longer latency associated with the location near the knee was attributable to the longer
pathway to the brain. His calculations of conduction velocity were amazingly accurate.
The experiments of Galvani, Helmholtz and others clearly demonstrated a role for electrical
activity in nervous system function. The problem was that the known laws of electricity required
that all the "wires" be connected in a circuit. There was no known mechanism that would allow
these tiny signals to leap from one discrete cell to another. The enigma was this: Electrical
activity could only work with a syncitium, but the anatomical evidence showed discrete cells.
A British neurophysiologist, Sir Charles Sherrington, maintained a strong and occasionally
outspoken faith that the electrical problems could be solved with more information. With this
notion in mind, Sherrington (1906) began a long and exquisite series
of experiments to elucidate
the electrical activity of the nervous system. His major contribution was in the study of reflex
arcs, with special attention to the events that occur when information is transferred from one cell
to the next. He coined the term synapse to define the as yet,
unseen gap between adjacent (or
more accurately, successive) neurons. By making careful measurements of the electrical impulses
as they traveled through the reflex arc, he was able to establish the following important principles
(refer to Fig. 1-1):
1. Electrical impulses will only pass through a synapse in one direction.
2. There is a constant delay (of about one-half millisecond) between the arrival of an
electrical impulse at a synapse and the continuation of the impulse at the other side of the
synapse.
3. A volley of impulses arriving at a synapse is not faithfully reproduced on the other side of the synapse (e.g., 3 impulses might result in 0, 1, 3, 5 or some other number of impulses).
4. The arrival of an impulse at a synapse can result either in excitation or inhibition of
activity in the cell across the synapse.
Sherrington's experiments were carefully executed, sophisticated, replicable, and at that time, impossible to explain. It is even difficult to devise comparable electronic models today with modern, solid state devices. Yet, Sherrington was confident that convincing electrical explanations would be forthcoming.
At the same time that Sherrington was conducting his experiments (about 1895 to 1920),
other
investigators were cautiously zeroing in on the relationship between the electrical activity of the
nervous system and certain chemical events (see Gilman et al, 1980,
Chapter 4 for a thorough
historical account. Lewandosky (1898) and Langley (1901) both observed that injections of
extracts from the adrenal glands mimicked the effects of electrical stimulation of autonomic
nerves. Elliot (1904) made similar observations and proposed that
these nerves released an
adrenaline-like substance when they were stimulated. (As a graduate student, Elliot was advised
that it would be politically dangerous to publish scientific views that contradicted those of
Sherrington. He became disillusioned and left science.) A few years later, Dale (1914) noted the
similarity between injections of a mushroom extract (muscarine) and the stimulation of the vagus
nerve and proposed that this nerve released a muscarine-like chemical when it was stimulated. All
of these observations suffered from a common logical flaw: The fact that injections of chemicals
mimicked electrical stimulation did not prove that the nerves released these chemicals under
natural conditions.
A German investigator, Otto Loewi put the capstone on these
chemical theories in 1921.
Legend has it that Loewi's idea for his experiment came to him in a dream, but when he awoke on
that Easter Saturday, he was unable to recall the specifics. However, the dream recurred, and on
Easter Sunday, Loewi went into his laboratory and performed the experiment that was to prove
the notion of chemical neurotransmission and earn him the Nobel Prize. He dissected the heart
with attached vagus nerve from a living frog and placed it in a beaker containing a solution of
salts to keep it viable (see Fig. 1-2). Then, a second dissected
without the vagus nerve and
placed into a second beaker. Electrical stimulation of the vagus nerve resulted in slowing of the
heart beat (a phenomenon which had been known for many years). The key to Loewi's
experiment was that when he pumped fluid from the first beaker into the second, the beating of
the second heart slowed down even though there was no nerve attached. The chemical being
released from the vagus nerve could be pumped into the fluid of the denervated heart and produce
the same effect. Loewi called this chemical Vagusstoff,
proving some years later (Loewi &
Navratil, 1926) that it was acetylcholine (a
muscarine-like compound).
Sherrington and Loewi were not alone in recognizing the importance of the terminal portions of neurons: Claude Bernard had performed a classic series of experiments in 1856 to investigate the properties of curare. British explorers had brought back samples of this curious arrow poison from South America. He dissected the muscle from a frog's leg with the sciatic nerve attached. Stimulation of the nerve would cause the muscle to contract even if the nerve portion were bathed in a curare solution (see Fig. 1-3). If the muscle were immersed in the curare solution, it would not contract via nerve stimulation. But, it would contract when the stimulating electrode was placed directly on the muscle! Finally, Bernard demonstrated an ingenious preparation that involved a ligature (tourniquet) around the leg of an intact frog. Injection of curare caused paralysis of all the muscles except those of the ligatured leg (the blood supply had been cut off by the ligature so the drug could not enter). The key observation was that nerve stimulation in the region of the spinal cord could send impulses into the ligatured leg and cause contraction. Bernard concluded that curare had no effect on the nerve and no effect on the muscle-- rather, it acted at the junction between the nerve and the muscle. This clever set of experiments and the prescient conclusion that Bernard reached occurred long before it was even known that the nervous system was comprised of individual neurons, long before Sherrington had described the synapse, and long before it was known that chemical transmission was involved!
The electrical activity of the nervous system is only remotely similar to the electrical activity
that
occurs when you turn on the headlights of a car. In a car, the electrical current is carried through
the wires by electrons almost instantaneously (at the speed of light) from one side of the battery
through the light filament and returning to the other side. The electrical activity is conducted
through a complete circuit. In the nervous system, there is no complete circuit and the electrical
activity is propagated rather than conducted. This propagation of the electrical activity is
much
slower than conduction, the maximum being about 100 meters per second.
The source of power for the electrical activity of the nervous system comes from the uneven
distribution of charged particles across the membranes of neurons (see Fig. 1-4). (Refer to Ruch
et al, 1961, for detailed coverage of basic electrophysiology). The membranes of all of our
cells
are said to be semipermeable, a characteristic
that allows small particles to pass through, while it
is progressively more difficult for larger particles to pass through. In the case of neurons, there
are large negatively charged particles (anions) trapped inside the
cell membrane. The positively
charged sodium ion (a cation) is continuously removed from the
cell by a biochemical process
called the sodium pump. The combination of negatively charged particles on the inside and
continuous maintenance of an artificially high concentration of sodium on the outside creates a
difference in electrical potential of 70 millivolts across the cell membrane, the inside being
negative with respect to the outside. This polarization of charges across the neuronal membrane
is termed the resting potential of the cell. Although a difference of less than one tenth of a volt
may seem trivial, it must be remembered that this difference occurs across the very thin membrane
of a tiny cell. Translated into terms of an electric field, the charge separation is about 10,000
volts per millimeter, and the appearance of 10,000 volts across the diameter of a pencil lead seems
a little less trivial!
When an effective stimulus is applied to a neuron, local changes in the membrane take place
that
allow sodium ions to rush through the membrane (see Fig. 1-5).
This influx of positive charge
counteracts the negative resting potential and the inside of the cell at this location actually
becomes positively charged. The appearance of this local positive charge tends to spread and
depolarize the adjacent area of the cell, which causes sodium to rush in at this point, repeating the
process. As a result of this movement of charged particles, a wave of electrical activity is
observed to travel down the axon. This controlled wave of change in the electrical charge that
appears across the cell membrane is called the action
potential.
It is important to realize that the electrical action potential is itself a biochemical process. The
changes in permeability of the membrane that allow sodium to cross the membrane for a brief
period of time require structural changes (usually discussed as opening and closing of channels)
rather than the simple movement of charged particles through a medium. Although these changes
that are propagated along the axon of the cell are reflected in an electrical signal, it is deceptive to
view this as strictly an electrical event. It is a biochemical event that is probably as complicated as
the chemical transmission process that follows.
The action potential is a short-lived phenomenon. Upon reaching the terminal portion of the
neuron, it is propagated out to the ends of the various branches of the cell (called the terminal
boutons) and finally dissipates. The physical gap of the synapse is far too large for this
electrical
activity to influence the adjacent cell. (Actually, there are some anatomical situations, called tight
junctions, in which the electrical event is passed on directly, but these will not concern us here.)
The arrival of the action potential at a terminal bouton produces yet another change in the cell
membrane (see Fig. 1-6). As the action potential dissipates it causes
the ejection or release of the
relatively large molecules that are stored in the cell terminals. These molecules serve as chemical
messengers, (neurotransmitters) and influence the
membrane of the next cell. In the most
straightforward case, these molecules alter the electrical characteristics of the next cell, setting up
a new action potential that is propagated down the next cell where the whole process is repeated.
Thus, there is an alternation between the propagated action potential and the translation of this
event into the release of neurotransmitter substances. Both events are obviously biochemical
processes. Although the terminology is not typically used, it might be conceptually useful to
view the first process as chemical propagation to diminish the artificial contrast with chemical
transmission.
Major
Features of Chemical Transmission
Although Loewi's famous experiment was considered to be convincing evidence of chemical
transmission, the formal proof of this process requires that several
logical criteria be met (cf., Fig. 1-7):
1. Synthesis of the Chemical Transmitter
Although the details differ depending on the specific neurotransmitter, each type of neuron
has a
mechanism to actively and selectively bring precursor molecules
from the bloodstream into the
cell body. Once inside the cell, these precursor molecules are subjected to a series of enzyme
mediated changes, typically being transformed into several intermediate stages before the final
product, the neurotransmitter, is formed. Each type of cell contains the specific enzymes that are
required for these biosynthetic changes.
2. Transport and Storage of the Transmitter
Most of the metabolic machinery of the cell is localized within the cell body region of the
neuron.
Since the actual process of chemical transmission occurs at the distal portion of the cell, some
mechanism must be present to transport these materials to the axon terminal. There is a rather
general flow of protoplasm from the cell body to the terminal portions. In addition to general
maintenance functions, the neurotransmitter or intermediate molecules are also carried down the
axon.
Once the neurotransmitter or an intermediary has reached the terminal bouton region,
another
active transport mechanism sequesters the material into small packets called synaptic vesicles.
These vesicles serve as both a localized storage facility which also serves to isolate the transmitter
substance from other chemical activity within the cell. This compartmentalization of materials is
typical of cellular metabolism in general, and in the case of neurotransmitter control, there may be
several stages of storage (called storage pools) for the
transmitter substance and various
immediate precursors of the transmitter.
3. Release of the Neurotransmitter
This is perhaps the most obvious of the logical requirements for chemical transmission. In
order
for the information to be relayed from one cell to the next, it is necessary for the action potential
to cause the release of the neurotransmitter from its storage vesicles. Although the details of the
process remain unexplained, this appears to be accomplished in almost a mechanical manner. The
membrane adjacent to a vesicle is physically opened and the contents of one or more vesicles is
ejected into the synaptic space. It is this translation of the propagated electrical activity into a
physical disruption of the membrane that accounts for the half-millisecond delay that Sherrington
observed at the turn of the century.
4. Receptor Sites for the Neurotransmitter
The physical release of the neurotransmitter would be of little consequence if the next neuron
had
no mechanism to respond to this chemical. In fact, the membrane of the cell across the synapse
has specialized regions, called receptor sites, that are
chemically compatible with the structure of
the specific neurotransmitter that is being released. The most common analogy that has been used
to describe this system is that of the lock and key; the neurotransmitter is the key which fits the
locks or receptor sites of the next cell.
The complementary nature of the neurotransmitter release and receptor sites suggest that it is
more useful to think of a synapse, rather than an individual neuron, as the functional unit.
Accordingly, the terminology that has developed designates the cell that releases the transmitter
as the presynaptic cell and the cell that responds to the
neurotransmitter as the postsynaptic
cell.
The functional result of the chemical interaction depends more upon the nature of the
receptor
site than on the particular neurotransmitter molecule. Normally, we tend to think of systems in
the active or excitatory mode, in which case the arrival of the neurotransmitter would result in
depolarization of the postsynaptic membrane. If this
depolarization is sufficiently strong, it will
serve as an effective stimulus for the initiation and propagation of an action potential in the
postsynaptic cell.
Contrariwise, the receptor can interpret the arrival of the neurotransmitter in an inhibitory
fashion
(either via hyperpolarization or stabilization of the membrane potential) and diminish the
likelihood that excitatory influences (from other sources) will result in an action potential.
5. Inactivation of the Neurotransmitter
Regardless of whether the neurotransmitter is interpreted in an excitatory or inhibitory
fashion,
normal functioning requires some form of inactivation of the effect. Although other types of
systems could be imagined, the nature of the nervous system is to encode information in temporal
sequences. Thus, a weak stimulus might result in three consecutive action potentials, whereas a
strong stimulus might be encoded by twenty more closely spaced action potentials. (Since the
size of the action potential is fixed by the nature of the cell membrane and its metabolism, the
more obvious solution of encoding by different sized action potentials is not a biological option.)
The requirement for sequential transfer of information makes it essential to quickly terminate the
effect of the neurotransmitter so that successive releases of neurotransmitter material can result in
consecutive action potentials in the postsynaptic cell.
There are two basic types of inactivation that have been identified. One of these is the chemical
degradation of the neurotransmitter substance by specific enzymes. Typically, the
inactivating
enzyme is present in the synaptic cleft and literally removes the neurotransmitter molecule from
the synapse by breaking it down into components that are not active at local receptor sites. A
second mechanism is a curious phenomenon that has been termed reuptake. The presynaptic cell
that releases the transmitter has specialized sites on its own membrane that actively collect the
neurotransmitter back into the presynaptic cell. Both of these mechanisms are chemically specific
for the neurotransmitter and operate rapidly enough to account for the punctate nature of
neuronal function.
C. THE
ORGANIZATION AND LOGIC OF CHEMICAL
CODING
The smooth muscle fibers that control pupil diameter have two types of receptors: One type
of
receptor is chemically compatible with the structure of ACh and causes the muscle to contract,
thereby constricting the pupil (see Fig. 1-8). The other type of
receptor is chemically compatible
with NE and inhibits the muscle from contracting, thereby allowing the pupil to dilate. The dual
chemical transmitters and dual set of receptors provides for precise control of this system.
Furthermore, the system is very efficient by virtue of the fact that a single set of muscles performs
a dual function.
This same type of dual control can be observed throughout the autonomic nervous system
(see
Fig. 1-9). The rate of the heart beat, the diameter of blood vessels,
the peristaltic movement of
the intestines, the opening and closing of intestinal valves, salivation and sweating are all under
the dual control of the parasympathetic and sympathetic divisions of the autonomic nervous
system.
In addition to the somewhat antagonistic effects of ACh and NE, the two divisions are
further
differentiated by virtue of their anatomy. The parasympathetic division is characterized by
discrete fibers that go directly to each of the target organs. Thus, fine adjustments in pupil
diameter can occur independently of fine adjustments of peristalsis and salivation.
By contrast, the sympathetic division is anatomically overlapping and tends to operate in a
much
more global fashion. Thus, during episodes of stress, the changes in heart rate, blood pressure,
pupil dilation, sweating, and so forth, all occur simultaneously. Furthermore, the adrenal glands
release NE, a closely related compound called epinephrine
(E), and dopamine (DA) into the
bloodstream. These compounds can then simultaneously infuse into all of the target organs to
ensure an even more uniform action.
The autonomic nervous system exemplifies some of the fundamental concepts of nervous
system
organization and logic. A combination of different neurotransmitters, different receptors, and
different anatomical layout provide for a great deal of specificity in response.
Receptor Sites
One of the most common misconceptions when first learning about chemical transmission is to
assume that the specificity is inherent in the transmitter substance, e.g., to assume that ACh is
excitatory and NE is inhibitory, or vice versa. This is not the case. The different transmitter
molecules simply serve as signals and only set the stage for some sort of functional difference,
while the actual nature of this difference lies in the type of receptor that is in the membranes of the
target organ cells. Thus, a particular neurotransmitter molecule can have effects that are
excitatory or inhibitory, depending on the nature of the receptor and the effector cell that the
receptor serves.
The control of the urinary bladder provides an excellent illustration of this point (see Fig. 1-10).
Most of the time, the bladder function is controlled by a continuing, mild input from the
sympathetic nervous system. The release of norepinephrine inhibits the activity of smooth
muscles in the wall of the bladder, allowing it to passively fill. At the same time, the smooth
muscles that form the sphincter valve are stimulated by the norepinephrine and contract, thereby
preventing the leakage of urine from the bladder. The act of urination is under parasympathetic
control. The release of acetylcholine stimulates the smooth muscles of the bladder wall,
increasing the pressure. At the same time, the release of acetylcholine onto the smooth muscles of
the sphincter valve cause it to relax and allow the urine to be expelled. This system is a
particularly good example to remember, because it demonstrates both the arbitrary nature of the
neurotransmitter signal and the functional interaction of the two divisions of the autonomic
nervous system.
Further specificity in chemical transmission can be obtained by having receptors for different
portions of the transmitter molecule. Consider, for example, that the transmitter molecule is
shaped like a bird (cf., Fig. 1-11). It would be possible to have a
variety of different receptor
sites that were shaped like the head, tail, entire top side, or the belly. These different receptor
sites for a common transmitter provide utilization of the organism's biochemical resources.
The systems that utilize acetylcholine as a chemical transmitter provide an excellent example
of
the use of multiple receptors for a single transmitter substance. There are two basic types of
receptors for Ach: (a) muscarinic--so named because
the compound muscarine mimics ACh at
these sites, and (b) nicotinic--so named because
nicotine mimics ACh at these sites. The smooth
muscles that are target organs of the autonomic nervous system (e.g., pupils, blood vessels,
glands, etc.) utilize muscarinic receptors. The striated muscles (e.g, the voluntary muscles of the
arm) utilize nicotinic receptors. A slightly different type of nicotinic receptor exists at the
autonomic ganglia, which serve as relays for both the sympathetic and parasympathetic divisions
of the autonomic nervous system.
Similarly, there are two major types of receptors for NE, called alpha and beta receptors. These
receptors respond differently to a variety of different compounds, including the major naturally
occurring compounds of the autonomic nervous system, NE (strong alpha and weak beta action)
and E (strong beta and weak alpha action). When Ahlquist (1948)
first proposed these two
receptor types, there was considerable controversy, and Ahlquist correctly asserted that the
identification of the receptor type depended on the strength of response to various
compounds
and not on the direction (excitatory or inhibitory). In most cases, alpha receptors are associated
with excitation of the smooth muscles, while beta receptors are inhibitory. However, the muscles
of the heart have beta receptors that are excitatory and some of the alpha receptors in the
intestines are inhibitory. This exception proves the rule--neither the transmitter substance nor the
receptor structure determine the function. The individual cell can, in a sense, use a given type of
receptor for any type of function, and NE is very effective for both alpha-excitatory and
alpha-inhibitory effects.
Figure 1-12 (also, compare with Figure
1-9) shows a general outline of the autonomic nervous
system, which has served as a model for the organization of the nervous system in general.
Through a combination of differences in anatomical organization, two neurotransmitter
substances, at least two types of receptors for each transmitter, and the option of designating a
particular transmitter for either excitatory or inhibitory function, a highly sophisticated set of
controls can be obtained. The system is efficient in the use of chemicals, specific in function, and
compartmentalized to prevent "spillover" of one function to another.
Chemical
Coding of Brain Functions
The organization of the brain is chemically and anatomically far more complicated than the
autonomic nervous system. However, the same basic principles of organization apply. A
combination of anatomical, neurochemical, and receptor specificity serves to compartmentalize
the various behavioral functions of the brain.
There may be several dozen different neurotransmitter substances in the brain, several of
which
have been studied in considerable detail (cf., Snyder, 1984). The
major substances that will be of
interest for this textbook are acetylcholine, norepinephrine, serotonin, dopamine, and a class of
compounds called peptides. These systems will be treated in considerably more detail as they
become relevant in the chapters that follow. For the present purposes, a few selected examples
will serve to illustrate some of the principles that we have been discussing.
The hypothalamic region of the brain serves many functions, including feeding and drinking.
Anatomical organization can be easily demonstrated by experiments that show excessive eating
following damage near the midline of the hypothalamus and a failure to eat following damage near
the lateral borders. However, lateral damage impairs drinking as well as eating (cf., Teitelbaum
& Epstein, 1962), and it is here that the importance of chemical specificity can be
demonstrated
see Fig. 1-13). Injections of ACh directly into this region of the
brain caused the rats to drink,
but had no effect on eating. Conversely, injections of NE caused the rats to eat, but had no effect
on drinking (Grossman, 1960). Thus, the presence of two different
transmitter substances
provide for separate functions within the same anatomical region of the brain in a manner that is
directly comparable to the opposing effects of sympathetic and parasympathetic actions on the
muscles that control pupil diameter in the cat.
The notion of chemical transmission can be extended to include the various hormones of the
endocrine system. We have already seen one example of this in the case of the release of E and
NE from the adrenal gland in response to stress. One way of conceptualizing the action of the
hormones is to view the entire bloodstream as a single large synapse. The specificity of the
hormonal system is determined by the fact that only certain cells (target organs) have receptors
that respond to a particular hormone. Although exceptions can be cited, hormonal actions tend
to be much longer lasting than neural transmission, and they tend to influence systems in a more
global fashion.
In some sense, hormones prepare entire systems for activity or inactivity. Under conditions
of
emergency, the adrenal gland releases the hormones E and NE to produce a general influence on
the target organs of the sympathetic nervous system. Another example can be seen in the case of
sexual hormones preparing the seasonal breeder for a whole series of behaviors that occur only
during autumn.
It has become very obvious during the past couple of decades that the endocrine system
cannot
be considered separately from the nervous system proper. The same chemical compound (for
example, NE) can be a neurotransmitter when it is released in one manner and a hormone when it
is released in another manner. It is simply a special case of chemical control of neural events.
Accordingly, the more acceptable terminology is now the neuroendocrine system.
Consider, for example, that the behavior of drinking when thirsty might be controlled by the
release of acetylcholine by certain brain cells. It should be possible to artificially stimulate this
system by adding acetylcholine from another source. In the same way that Otto Loewi was able
to change the rate of the heart beating in the second beaker, it should be possible to get a
non-thirsty animal to drink by administering the appropriate drug. Conversely, it should be
possible to
prevent a thirsty animal from drinking by giving a drug that blocks the chemical messenger that is
being released by the brain cells. These and other more complicated forms of behavior were
simply substituted for the physiological test objects (e.g, heart, spleen, pupil, etc.) that were used
by Elliot, Dale, Loewi and other pioneers in the field. The experiments worked, and a new area
of research was born.
The ability to change behavior by altering brain chemistry underlined the importance of
objective
analysis of behavior. Behavior is more than a beating heart or a contracting eye muscle, and
methods for the reliable observation of behavior were clearly needed. At about the same time that
the early experiments in pharmacology were being conducted, a psychologist named B. F. Skinner
was formulating a new approach for the study of behavior which he called the analysis of operant
behavior. This approach was published in a book entitled Behavior of Organisms
(Skinner,
1938)-- a book which became a benchmark in the study of behavior. The basic principles
involved the careful control of the animal's environment and the measurements were limited
strictly to the observable, objective responses of the animal (e.g, lever presses or key pecks.)
Unobservables such as fear, hunger, or thirst were specifically excluded from this system of
analysis.
Skinner's system for the objective analysis of behavior was eagerly embraced by the students
of
the new pharmacology. The precision of the chemically specific transmitter systems could be
mirrored by the precision of the operant method of behavioral analysis. The convergence of these
two systems became synonymous with behavioral pharmacology, and set forth the basic principle
of the discipline: Specific changes in brain chemistry produce specific changes in behavior.
The combination of operant analysis of behavior with pharmacological methods formed a
powerful tool for researchers. It is an efficient and effective methodology for the development
and screening of new drugs and, to a somewhat lesser extent, for the characterization of drug
effects on behavior. But it is not enough. If we are to understand the broader implications of the
chemistry of behavior, our considerations must go well beyond the effects of drugs on behavior.
These interactions are presented as six principles for understanding behavioral pharmacology
(refer to Fig. 1-14):
The listing of these six principles is a formal way of stating the major considerations that must
accompany our study of behavioral pharmacology. We do not recommend that you commit these
principles to memory, because individually they represent an artificial analysis of the situation.
There is a single statement that embodies all of these principles:
D. INTERACTIONS OF BEHAVIOR, ENVIRONMENT AND BRAIN
CHEMISTRY
Convergence of Disciplines
When students of the brain learned that neurons communicate through chemical messengers, the
stage was set for developing a new area of inquiry: namely, behavioral pharmacology. This new
discipline was based on a simple logic--if the communication system of brain cells is mediated by
specific chemicals, then compounds that interact with these chemicals should change the
messages.
Dynamics of Brain Chemistry and Behavior
Behavior has no clear beginning or end. The analysis of behavior starts out innocently enough to
describe the interactions of the organism with the environment. More specifically, it is the
interaction of the organism's brain with the environment. The environment includes not only the
outside world, but also the organism's internal environment. Of course, the brain is a part of that
internal environment and the behavior itself becomes a part of the environment. Lest we become
tempted to pursue the logical proof that the universe is made up of behavior, let us return to some
more direct issues to illustrate that these considerations are not just idle philosophical
musings--we must understand the implications of these interactions in order to appreciate the
dynamics of brain chemistry and behavior.
Principle 1. Changes in brain
chemistry produce changes in behavior.
This is perhaps the most straightforward principle and, as indicated in our previous discussion,
the one that has guided most of the research in behavioral pharmacology. Manipulation of the
chemical system that controls behavior will change behavior.
Principle 2. Changes in
behavior produce changes in brain chemistry.
This principle is a bit more subtle and offers the opportunity to confuse cause and correlation.
The fact that behavioral change is correlated with the chemical changes that produced it is simply
a restatement of Principle 1. The important point here is that behavioral change can actually
produce changes in brain chemistry. One type of change is an increase in the efficiency of the
chemical system that produces the behavior (analogous to increased muscle efficiency with
exercise). This change may, in turn, produce changes in related chemical systems that were not
directly involved in the first bit of behavior.
Principle 3. Changes in the
environment produce changes in
behavior.
This principle is the simple definition of behavior and requires little in the way of explanation.
The major point that needs to be made is that the environment is quite extensive. It includes not
only the relationships and contingencies of the external world, but also the internal milieu--blood
pressure, gastrointestinal activity, level of energy stores, memory of past experiences, etc. Until
recently, the internal environment has been downplayed by the "black box" approach of
experimental psychology.
Principle 4. Changes in
behavior produce changes in the
environment.
In some sense, the only role of behavior is to change the environment. In the simplest case, the
behavior is operant and results in opened doors, captured prey, warmed cockles and the like. But
just as the environment was expanded in the preceding paragraph, so must our notions of the
effects of behavior be expanded to include, for example, changes in the internal environment
either directly (as in the case of autonomic responses to a fear arousing situation) or indirectly (as
in the case of nutritional changes).
Principle 5. Changes in the
environment produce changes in brain
chemistry.
We begin to complete the circuit through brain, behavior and environment by noting that
environmental changes can produce changes in brain chemistry. In some cases, the environment
has tonic influences on brain chemistry as exemplified by responses to seasonal changes,
temperature fluctuations, lighting changes and so forth. Other environmental changes are more
closely interactive with behavior, and include responses to crowding, members of the opposite
sex, complexity of the physical and behavioral environment, etc. These and many other types of
environmental manipulations have been shown to alter the status of the neurochemical transmitter
systems.
Principle 6. Changes in brain
chemistry produce changes in the
environment.
On the surface, this seems to be the least likely of the principles. Changes in brain chemistry
obviously cannot directly perform operants like opening doors. It can, however, produce
significant changes in the internal environment and set the stage for such operants to occur.
BRAIN CHEMISTRY, BEHAVIOR AND
THE ENVIRONMENT
HAVE INTERPENETRATING EFFECTS.
This statement is the major theme of the book, and emphasizes the need to appreciate the
complexities of the nervous system. Yes, drugs change behavior. But the effect of a drug can be
altered by the organism's behavior, which in turn has been produced by current and past changes
in the environment. Drugs do not possess some essence that magically induces a change in
behavior. They act through the normal channels of our physiological response to the
environment. As human organisms in a complex environment, we are fortunate that these
interactions are complicated. As students of behavior, these physiological interactions are pushed
to their limits in our feeble attempts to understand them. Do not despair; the thrill is in the
pursuit.
E. SUMMARY
2. Brain functions are controlled by unique interactions between neurotransmitter chemicals
and
specific receptor sites.
3. Ancient folk medicine and modern pharmacology are both based upon these principles of
chemical specificity.
4. The sympathetic and parasympathetic divisions of the autonomic nervous system have
served
as models for understanding the more complex systems of chemical coding in the brain.
5. Brain chemistry, behavior and the environment have interpenetrating effects.
Terms
acetylcholinesterase