Chapter 1




Folk Remedies

The Unveiling of Chemical Transmission


Basic Principles

Major Features of Chemical Transmission


The Autonomic Nervous System as a Model

Receptor Sites

Chemical Coding of Brain Functions


Convergence of Disciplines

Dynamics of Brain Chemistry and Behavior




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The birthplace of humanity will be marked not by bones, but by behavior. This is not to belittle the importance of bones; the fossil record will continue to sharpen the focus of our geographic and temporal origins. However, the defining characteristic of Homo sapiens is not the thumb and not the brain case, rather, it is the workings of the brain, the behaviors, the feelings, the mind (if you will).

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!


Basic Principles

The acceptance of the notion of chemical transmission in the early 1900's is a testament to the open-mindedness of the researchers. It was already known that trains of nerve impulses could be transmitted in very rapid succession, in some cases as many as 1000 per second. It required (and still requires) a bold imagination to cope with the notion that discrete chemical events could take place on such a restricted time scale. This section will examine this remarkable process more closely.

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.


The Autonomic Nervous System as a Model

If you look into the eyes of your family cat when it is purring on the back of the couch, the pupils will appear as tiny vertical slits. If you help the same cat down from a tree after it has been chased by a dog, the pupils will appear to fill the entire iris of the eye, being virtually round in shape. These differences in pupil size are the result of different forms of chemical transmission, and illustrate one of the most important features of this system, namely, chemical coding of different functions. Two types of fibers from the autonomic nervous system project to the smooth muscles of the eye: One set of fibers utilizes norepinephrine (NE) as the neurotransmitter and is termed sympathetic innervation. The other utilizes acetylcholine (ACh) as the neurotransmitter and is termed parasympathetic (literally meaning beside the sympathetic fibers) innervation.

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.


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.

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.

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.

These interactions are presented as six principles for understanding behavioral pharmacology (refer to Fig. 1-14):

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.

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:



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.



1. The brain is the organ of behavior.

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.



action potential

alpha receptor



autonomic nervous system

behavioral pharmacology

beta receptor



chemical transmission

chemical degradation










neuron doctrine




operant behavior






receptor sites

resting potential


semipermeable membrane

storage pools




synaptic vesicle


target organ

terminal bouton