Published in: Companion Encyclopedia of Psychology Vol. 1
Colman, A. (Ed) London: Routledge, 1994
FROM FOLK MEDICINE TO MODERN PHARMACOLOGY
The human experience is frequently characterized by our feelings toward certain aspects of our environment. We are frightened by things we do not understand, calmed by familiarity, anxious in the face of uncertainty, exhilarated by our accomplishments and depressed by our losses. Gradually, over the course of our individual development, we come to expect certain situations to produce certain types of feelings.
There are many chemical substances that have the power to alter this relationship between environment and feeling. Anxiety can be transformed into tranquility, exhilaration into sobriety, and torpor into vigor. When these substances are administered in a formal manner, they are called drugs, and the study of the effects of these drugs on mood and other behaviours defines the field of psychopharmacology.
Historically, the more common chemical substances that change behaviour have been plant products that were widely available and self-administered. Tea and opium were available in the Orient; tobacco and coffee in the Americas; and alcohol throughout the world. The substances were valued by each culture for the effects that they had on behaviour, but each culture also developed written or unwritten guidelines to regulate the use of the substances.
In addition to the commonly available plants, each geographic region has more obscure plants that may contain psychologically active substances. Information about the identifying features and effectiveness of these plants were passed on to family elders and to religious leaders. These individuals became valued for their knowledge of the effects of chemical substances, and became the informal practitioners of folk medicine. This gave way to the development of still more formal knowledge of these effects, and to the gradual development of formal medical practitioners.
Today, we have literally hundreds of different drugs that are known to change behaviour. Some of these have been borrowed directly from folk medicine and simply represent the modern processing and reformulation of a drug application that may be centuries old. Others have been discovered by accident when a chemical reaction has gone awry or when a drug has been administered to treat one malady and it ends up being effective for some totally different problem. Although important contributions have been made from both of these sources, the vast majority of our modern drugs have been developed through systematic research on the relationships among drugs, behaviour, and the underlying chemistry of the brain.
CLASSIFICATION OF PSYCHOACTIVE DRUGS
Psychoactive drugs have two basic uses: (a) to alter mood and states of consciousness, and (b) to treat psychopathology.
Table 1 lists some examples of each type of drug.
Drugs that are used to alter moods and general states of consciousness can be divided into three broad categories based on the type of change they produce in the nervous system. Stimulant drugs produce an exaggeration of the conditions that are normally associated with alert wakefulness; in high dosages, these drugs produce overt seizure activity. Depressant drugs produce an exaggeration of the conditions that are normally associated with relaxation and sleep; in high dosages these drugs can produce unconsciousness. Hallucinogens produce a distortion of normal perception and thought processes; in high dosages these drugs can produce episodes of behaviour that can be characterized as psychotic. Although there are exceptions, a general rule is that these drugs produce their effects rather immediately by direct action on the neurons of the brain.
Drugs that are used to treat psychopathology can also be divided into three broad categories based on the type of symptoms that they can ameliorate. The antianxiety drugs are used to treat the day-to-day fears and anxieties of individuals who lead basically normal lives. The antidepressant drugs are used to treat feelings of negative affect that may range from mild melancholy to abject depression accompanied by suicidal tendencies. Finally, the antipyschotic drugs are used to treat severe forms of mental illness, most notably schizophrenia, in which patients lose contact with reality and engage in behaviours that fall considerably outside the realm of normalcy. Again, there are exceptions, but a general rule is that these drugs tend to act indirectly: Although they have immediate effects on the neurons of the brain, the therapeutic effects often require several weeks to appear, suggesting that the behavioural changes must await some long term, chronic adjustment of the neurons to the drug's actions (i.e., neuromodulation).
There are many drugs that are not listed in the general classification schema of Table 1. Such a table can never remain complete for very long because new drugs are continually being developed, new applications may be found for some drugs, old drugs are sometimes phased out of the marketplace, and new theory may change the boundaries of classification. Detailed and current information that would expand this table is compiled regularly and published in a variety of sources (e.g., Goodman & Gilman's The Pharmacological Bases of Therapeutics and the Physicians' Desk Reference). Paperback summaries of this information for prescription and nonprescription drugs are available in most bookstores and libraries. We shall return to Table 1 later for a discussion of the mechanisms of actions for these drugs.
Click here to see Table 1.
SOME PRINCIPLES OF PHARMACOLOGY
In order for a drug to have an effect on behaviour, it must come into contact with the appropriate neurons in the brain. This can be accomplished in numerous ways, and the decision about the route of administration is based on a combination of factors including convenience, effects of the drug on local tissue, solubility of the drug, ionic characteristics of the drug, size of the drug molecule, and vulnerability of the drug to metabolism. The most common mode of administration is oral, with the drug being absorbed into the bloodstream through the walls of the stomach and intestines. Subcutaneous, transdermal, and intramuscular routes tend to produce slower and more sustained rates of delivery. Inhalation of drug vapors or injection of drugs directly into the bloodstream (intraarterial or intravenous) tend to produce very rapid onset of the drug effects. Minute quantities of drugs can be injected directly into the brain (intracranial) or into the spinal cord (intrathecal) to produce rapid effects that are restricted to the local area of injection.
The duration of drug action is determined primarily by the rate of metabolic inactivation of the drug. Most commonly, the drugs are metabolized into some inactive form by enzymes that are produced by the liver, the digestive tract, or by the nervous system tissue per se. These drug metabolites are removed from the body as waste products in the bowel, in the urine, through the skin, or by exhalation through the lungs. Drugs can sometimes be present in the body but have little or no effect because the drug molecules have been sequestered into a metabolically inactive pool. Examples of such pools include the bladder, fat deposits, or chemical bonding of drug molecules to larger protein molecules.
The relationship between the dosage of a drug and the response to that drug poses one of the thorniest problems in psychopharmacology. Common experience can provide a general description of the dose-response effect: For example, a sip of coffee will be subthreshold and will not help a student stay awake to study; a cupful will certainly help, and two might be better; five or six cups might lead to tremor and anxiety. These different responses to caffeine reflect the different concentrations of the drug in the blood. Technically, the lowest dose required to produce the desired effect (in 50% of the subjects) is termed the minimum effective dose (MED-50), and a dosage that is lethal to 50% of the subjects (the LD-50) is an index of the toxicity of the drug. The safety factor of a drug, the therapeutic index, is the ratio of LD-50/MED-50, which should be a large number (10 or more) to indicate that a lethal dose would be many times higher than the recommended dose.
Within the effective dose range, the responses may still be complicated. Typically, doubling the dosage does not double the effect, and many drugs show a bipolar dose-response curve. In the case of caffeine, for example, moderate doses can enhance typing skills but heavier doses begin to increase the number of errors. Furthermore, on tasks that are not well practiced, even low doses may impair performance; the dose-response relationship is determined as much by the details of the response as the details of the drug's biochemistry.
The effects of a particular drug dosage also depend on the condition of the subject when the drug is administered. The law of initial values is an old concept that was first formulated to describe the effects of drugs on the cardiovascular system. Some drugs, for example, may be very effective in lowering blood pressure, but only if the blood pressure is abnormally high to begin with. This concept applies equally well in psychopharmacology, and is frequently referred to as the rate-dependency effect. Individuals who are already highly aroused may respond adversely to even small doses of a stimulant drug because it effectively increases the arousal to a level that interferes with performance. Similarly, many drugs that have antidepressant or antianxiety effects may produce relatively little change in the mood of individuals who are not suffering from depression or anxiety.
A particularly interesting drug effect is one that can occur when the dosage is zero. The placebo effect (placebo means "I will please") occurs when an inactive substance such as saline or a sugar capsule is represented as a drug, and leads to the relief of symptoms. This does not necessarily mean that either the initial symptoms or the relief of symptoms were imaginary. In the case of pain relief, for example, it is now clear that placebo effects are the result of the body's release of endogenous opiates in response to the belief that a drug was given. This type of behavioural effect is almost certainly a regular occurrence that increases or decreases the impact of real drug effects.
Given the intricate nature of the dose-response relationship, it should come as no surprise that subject variables play an important role. From childhood through senescence, there occur systematic changes in metabolism, body weight, and neurochemistry which can alter the effects of drugs. Hormonal differences between males and females, systematic differences in certain enzymes, and even cultural and climatic differences can further alter the effects of drugs. Finally, the individual's history of drug use may also produce long-term changes in metabolism of certain drugs that can either reduce their effectiveness (tolerance) or, less commonly, increase their effectiveness (sensitization). These contributing factors rarely appear on the labels of either prescription or nonprescription drugs, but should always be considered for patients who do not represent a typical category.
Drugs are not magic bullets-- even under the most carefully controlled conditions, a particular drug can either influence multiple neurotransmitter systems or multiple systems that use the same neurotransmitter. The pattern of this combination of effects can change with drug dosage. As a result, drugs frequently have undesirable side effects, but these complications may diminish with time or be controlled by adjusting the drug dosage. In many cases, the side effects of the drug may mimic the symptoms of some other disorder, for example, a drug that successfully treats depression might cause anxiety. The existence of side effects simply means that the effects of the drug on the brain are influencing pathways that are not specifically a part of the problem that was diagnosed.
The utility of any particular drug or elixir can be determined empirically. The successful treatment of previous patients can provide information about the most appropriate route of administration and dosage to use and the types of side effects to watch for. For example, if it is observed that alcohol can reduce anxiety, the clinician might suggest that the anxious patient have a glass or two of wine with dinner. These types of observations and decisions have been useful in the development of folk medicines, but modern pharmacology relies more heavily on theory and mechanism. The development of a new and better drug treatment requires an understanding of both the disease process (i.e., the brain structures that are dysfunctional) and the way in which the drug alters this process (i.e., the neurochemical actions of the drug.) We turn now to a discussion of these mechanisms.
MECHANISMS OF DRUG ACTION IN THE BRAIN
One of the most elegant experiments in the history of pharmacology was performed in mid-1800's by a British physiologist named Claude Bernard. Explorers had brought back curare, a compound that native South Americans used as a poison on their blow gun darts to paralyse large mammals. Bernard was able to demonstrate that curare did not influence either the nerve fibers or the muscle fibers, but rather acted at the junction between these two structures.
Several decades later, Sir Charles Sherrington studied the special properties of the junction between one neuron and the next, and coined the term synapse to label this gap. He observed that the transmission of messages through the synapse differed in several ways from electric transmission through the nerve fiber: (a) messages passed in only one direction, (b) messages were changed as they travelled through the synapse, (c) messages were delayed at the synapse by 0.5 millisecond, and (d) some messages inhibited other messages. Knowledge of electricity was still in its infancy, but it was known that electric signals could not mimic these features of the synapse.
At the turn of the century, several researchers began to suspect that the transmission of messages across the synapse might involve chemicals. Many chemicals were known to influence the activity of the nervous system, and some of these (e.g., acetylcholine and noradrenaline) were present in the body. Although these chemicals could influence neuronal activity in laboratory preparations, there was no proof that they served as messengers under normal circumstances. The method of proof finally came to one of the researchers in a dream, and Otto Loewi went into his laboratory on Easter Sunday in 1921 to perform the critical experiment.
Loewi's experiment was elegant and simple. He dissected one frog's heart with a portion of the vagus nerve attached, a second heart without the vagus nerve, and placed them into separate containers of saline. Both hearts continued beating and, as expected from previous observations, electric stimulation of the vagus nerve caused the beating of the first heart to slow down. The clever part of the experiment was the pumping of the saline from the first beaker into the second. When this was done, the second heart also slowed down when the vagus nerve of the first heart was stimulated. There was no electric connection between the two hearts, and the only possible way that the message could be transmitted from one to the other was through the release of a chemical messenger into the surrounding fluid. Loewi dubbed the substance Vagusstoff (which turned out to be acetylcholine) and was later awarded the Nobel Prize for this first demonstration of the chemical transmission of neural messages.
Chemical messages could account for the special properties of the synapse observed by Sherrington. The release of a chemical messenger by one neuron onto the next would restrict the flow of information to one direction. Specific types of chemical messengers might be expected to inhibit rather than excite the next neuron. The chemical message would not be expected to maintain the specific temporal features of the volley of impulses that caused its release. Finally, the time required for the release and delivery of the chemical message could easily account for the 0.5-millisecond delay that Sherrington had observed. Despite all of these explanations, it still required a bold imagination in the 1920's to believe that tiny neurons could release several hundred chemical messages per second to conduct the complex functions of the nervous system.
Because of its accessibility and known functions, the peripheral autonomic nervous system became the natural choice as a test system for studying chemical transmission. Following Loewi's experiment, it soon became apparent that acetylcholine served as a chemical messenger in several locations. Not only was it released onto the heart muscle by the vagus nerve, but also onto the smooth muscles of all the organs and glands served by the parasympathetic system. Furthermore, acetylcholine was the messenger at the synapses in both the sympathetic and parasympathetic ganglia. It was also the messenger at the nerve-muscle junction for the striated muscles of voluntary movement (where the receptors can be blocked by curare, as in Bernard's experiment). But it became clear that acetylcholine was not the only neurotransmitter. Some other substance was being released onto the smooth muscles by the fibers of the sympathetic system, and that substance was determined to be noradrenaline, a substance very closely related to adrenaline, the hormone of the adrenal gland.
Now, the logic and the power of chemical transmission began to unfold. When different systems were anatomically separate as in the case of the separate locations of the sympathetic and parasympathetic ganglia, the same neurotransmitter could be used without confusion. But when two opposing systems projected to the same organ, for example the heart, then the release of different chemical messengers (e.g., acetylcholine to slow the heartbeat; noradrenaline to speed the heartbeat) could determine the different functions. But the autonomic nervous system was not going to yield all of the answers this simply:
A particular transmitter substance did not always produce the same effect. In the case of acetylcholine, there were two receptor types, muscarinic and nicotinic, which responded to different aspects of the molecule. Similarly, in the case of noradrenaline, there were also two receptor types, termed alpha and beta. The early researchers were eager to categorize these different receptor types into functional categories. The initial suspicions that acetylcholine was always inhibitory and noradrenaline was always excitatory had already been disconfirmed. The discovery of different receptor types for each compound held the possibility that these could be classified as excitatory or inhibitory. But it was not to be-- the specific receptor type is strictly for encoding the arrival of a message, and that message can be used as either a signal for excitation or inhibition.
While the details of chemical transmission were unfolding, other brain researchers had sought to relate anatomic structures of the brain to specific behavioural functions. Considerable progress was made in this effort, and research continues to sharpen the structure-function relationships. However, the discovery of chemical transmission required that yet another layer of organization be added--neurons within a particular anatomic structure could have different neurotransmitters.
One of the clearest examples of this was a set of experiments done by S. P. Grossman in 1961. Previous research had demonstrated that lesions of the lateral hypothalamus produced a dramatic reduction in both eating and drinking, whereas electric stimulation elicited both eating and drinking. Grossman was able to separate these functions by applying different chemicals directly into the lateral hypothalamus through a chronically implanted cannula. Drugs that mimic acetylcholine elicited drinking only, whereas drugs that mimic noradrenaline elicited eating only. Drugs that block acetylcholine receptors reduced drinking in thirsty rats, whereas drugs that block noradrenaline receptors reduced eating in hungry rats. These results provided a finer grained analysis than the experiments that were based strictly on anatomy. Within the anatomic boundaries of the lateral hypothalamus are chemically coded functions for eating (noradrenergic) and drinking (cholinergic).
Given the knowledge that chemical coding at synapses is superimposed on anatomic subdivisions, we can now begin to understand how drugs can produce their specific effects on behaviour. The third column of Table 1 describes the action of the drug at the level of the individual neuron or synapse. As more cells are filled in on this table, we gain a better understanding of the relationship between behaviour and its underlying pharmacologic bases. Drugs can be classified, for examples, as mimickers of acetylcholine, blockers of specific receptor types, presynaptic blockers of activity, inhibitors of specific enzymes, and so forth. The list of neurotransmitters grew slowly at first (acetylcholine, noradrenaline, dopamine), but in the last decade or so, the list has exploded to more than 100 different chemicals, some of which are listed below:
Acetylcholine Peptides (several dozen)
Serotonin Enkephalins (opiate-like)
Noradrenaline Miscellaneous Types
Amino Acids GABA
Glutamate Nitric oxide
Drugs that influence behaviour must do so by influencing the brain, and there are several features of the brain that have contributed to a widespread misunderstanding of its basic character. Neurons, unlike most other cells, do not undergo cell division, so the brain contains virtually all of its cells at the time of birth. These cells are already committed to the general structure-function relationships that are seen in the adult brain, thus encouraging the view of the brain as a stable, organized set of neural circuits with individual experiences simply selecting different combinations of existing pathways; not unlike the structure of a computer (the hardware) that can be used for a host of different functions (the software).
This view of the brain as a static set of complex circuits is wrong. Although the general features and structure-function relationships are fixed, the details of neuronal actions are dynamic and constantly changing. When certain activity in the brain acts repeatedly to produce some behaviour, the circuits that are active can undergo physical changes (e.g., increased production of neurotransmitter molecules, expansion of the branching terminals of the axons, increased complexity of the receiving dendritic tree, increased number of receptors, etc.) which result in the enhanced efficiency of the system. The behaviour that is produced can produce changes in the environment, and changes in the environment (whether mediated by behaviour or not) can, in turn, produce changes in the brain.
A good way to conceptualize this is to view the brain, behaviour, and the environment as an interacting triangle, with each dimension influencing the other two (cf., Hamilton & Timmons, 1990). These interpenetrating effects require a more complex view of the results of various experimental manipulations. Although a particular drug may produce a very specific change in behaviour, we must not fall into the trap of viewing this as a singular effect. The neuronal systems that were directly influenced by the drug will also undergo a longer term change as a result of the drug's presence (and absence). The resulting behaviour will change the environment and that change will change other aspects of behaviour, and so forth. An appreciation of this dynamic interaction helps to provide a more complete understanding of the effects of drugs on behaviour.
The discipline of psychopharmacology in its modern form arose from the convergence of two separate areas of study: (a) the growing information about neurotransmission and the drugs that influenced it, and (b) B. F. Skinner's development of operant conditioning techniques for the study of behaviour. Skinner's methodology (e.g., Reynolds, 1975; see also Chapters 5.1 & 5.2) provided powerful methods for analyzing behavioural change, and numerous animal models began to emerge for the screening of potentially useful drugs. The antipsychotic drugs rather specifically interfered with conditioned emotional responses, antianxiety drugs blocked the normal response to punishment, stimulant and depressant drugs changed general levels of activity, and so forth. The efficiency of these procedures greatly facilitated the accumulation of knowledge about the effects of drugs on behaviour, and became an indispensable link in the pathway of drugs from the chemist's bench to the pharmacist's shelf.
MECHANISMS OF DRUG ACTIONS ON BEHAVIOUR
Click here to see Table 1.
A. Drugs That Alter Moods and States of Consciousness
Central Nervous System Stimulants
Drugs can be classified as stimulants based on their ability to produce behavioural arousal, characteristic patterns of electroencephalographic (EEG) arousal, increases in motor activity, or some combination of these. These changes can be accomplished by several different mechanisms of action.
The so-called convulsant drugs such as strychnine, picrotoxin and pentylenetetrazol are representative of the different modes of action. Strychnine blocks the receptors for glycine, an inhibitory neurotransmitter. Picrotoxin reduces chloride permeability through its actions on the GABA receptor complex. (Gamma amino butyric acid, or GABA, is the most widespread neurotransmitter in the brain.) Pentylenetetrazol decreases the recovery time between action potentials by increasing potassium permeability of the axon. Drugs such as caffeine, theophylline and theobromine (present in coffee, tea, and chocolate) stimulate the activity of neurons by increasing the calcium permeability of membranes. Note that all of these drugs produce rather general effects that can influence neurons irrespective of the particular neurotransmitter system, and the state induced by these drugs is sometimes referred to as nonspecific arousal. In low to moderate dosages they can enhance learning and performance in a wide variety of situations, but with higher dosages, behaviour is impaired and dangerous seizures can be induced.
The amphetamines and cocaine may be the best known stimulant drugs, and both categories have rather specific effects on neurons that release dopamine or noradrenaline. Although the effects are not entirely specific, amphetamine stimulates these neurons by promoting the release of these neurotransmitters, while cocaine tends to block their reuptake. The restriction of the drug effects to a certain class of neurons is mirrored by a more specific change in behaviour. Some nonspecific arousal can be observed, but these two types of drugs have a profound effect in situations that involve specific behavioural responses that result in reward.
Central Nervous System Depressants
Drugs that are classified as central nervous system depressants appear to act on two major neurotransmitter systems. One of the neurotransmitters of sleep is serotonin, and certain drugs that enhance the activity of serotonin can induce drowsiness and sleep. The other important neurotransmitter is GABA, and the more common sedative and hypnotic drugs (e.g., the benzodiazepines, barbiturates, and alcohol) tend to produce their effects by acting on the GABA receptor complex. Acting on a special receptor site, they facilitate the action of GABA and inhibit neuronal activity by increasing the permeability of the neuronal membranes to chloride ions.
The narcotic drugs deserve special mention as CNS depressants. Extracts of the opium poppy have been used for thousands of years for both medicinal (pain relief) and recreational (general sense of well being) effects. Opium (a mixture of morphine and codeine) is naturally occurring, whereas heroin is a synthetic drug. The powerful effects of these drugs could not be explained by their actions on any of the known neurotransmitters. Finally, in the 1970's, it was determined that some neurons had specific receptors for these compounds, and that the body produced a variety of different substances (some chemical neurotransmitters and some hormones) that acted like the narcotic drugs. These endogenous morphine-like substances, termed endorphins, are released in response to various types of pain or stress.
Although drugs that stimulate or depress the general activity of the brain lead to changes in the interaction with the environment, these changes tend to be more quantitative than qualitative. Hallucinogens, on the other hand, produce fundamental changes in the sensorium. Visual and auditory distortions and imagery may be experienced. Tactile sensations may occur without stimulus. In some cases there may occur a conflation of experiences, called synesthesia, in which visual experiences may be "heard" or tactile experiences "seen" in ways that almost never occur in the absence of the drug. The drugs that produce these changes are derived from a variety of different plant sources as well as synthetic sources and tend to produce changes in many different neurotransmitter systems. The mechanism of action that causes the hallucinations remains clouded, but there is a growing consensus that these drugs act on serotonin receptors.
Some Observations on Abuse and Addiction
If a drug is administered repeatedly, there is frequently a reduction in the effectiveness of the drug, called tolerance. This can occur through several different mechanisms: (a) liver enzymes may be induced to speed up drug degradation; (b) presynaptic neurons may increase or decrease the production of neurotransmitters; (c) postsynaptic neurons may increase or decrease the number of receptors; and (d) opposing systems may increase or decrease their activity. Typically, more than one of these countermeasures is launched, and the brain's activity gradually becomes more normalized despite the presence of the drug.
Tolerance sets the stage for another phenomenon. If the drug administration is suddenly stopped, the mechanisms of tolerance are unmasked and withdrawal symptoms occur. As a result of the mechanisms of tolerance, the brain functions more normally in the presence of a drug than in its absence.
The types of tolerance described above are referred to as pharmacological tolerance. These mechanisms cannot always account for the observed decline in response to the drug. For example, amphetamine reduces the amount of milk that rats will drink during a daily session, but by the tenth day, drinking has returned to normal levels. However, if the drug is administered alone for 10 days, and milk is offered on the 11th day, the drug still suppresses drinking. The return to normal drinking requires learning to perform the behaviour in the presence of the drug. This type of effect is known as behavioural tolerance (Carlton & Wolgin, 1971).
The facts that many drugs have direct rewarding effects and that tolerance can develop to these rewarding effects can lead to motivation for self-administration of drugs. Drugs that have the capacity to produce such motivation typically share three characteristics: (a) they act on the central nervous system, (b) they act rapidly, and (c) the cessation of use produces withdrawal symptoms. These characteristics can produce an acquired motivational state (i.e., a desire or motivation for the effects of the drug) which can lead to addiction or abuse of the drug. The narcotic drugs are among the most potent in this regard.
Just as some individuals may be more sensitive to the effects of a drug because of differences in metabolism, specific neurotransmitter activity, or other subject variables, so might some individuals be more susceptible to acquiring the motivational states that we call addiction or substance abuse. There is growing evidence that this susceptibility may have a genetic basis. In the case of alcohol abuse, for example, there is a clear tendency for sons of alcoholics to be more likely to become alcoholics, and preliminary evidence points to a genetic defect that may alter the response to reward (e.g., Blum, 1991; see also Chapters 2.1 & 10.5). This and related evidence may soon provide a physiologic basis for the somewhat ill-chosen term, addictive personality.
B. Drugs Used to Treat Disorders of Behaviour
Click here to see Table 1.
The discovery of the drugs that are used to treat psychoses (primarily schizophrenia) followed a strange and fascinating pathway. A French surgeon, Henri Laborit, was convinced in the 1940's that many of the deaths associated with surgery could be attributed to the patients' own fears about the dangers of surgery. Attempts to reduce this distress with sedatives or by blocking the autonomic nervous system were only marginally effective. Laborit concluded that what was needed was a drug that could dissolve the fear response itself-- in his words, a Pavlovian deconditioner. His search led to one of the newly developed antihistamine compounds (promethazine), and a variant of this compound, chlorpromazine, proved to be dramatically effective. Patients who received this drug presurgically were calm, minimally sedated, and the incidence of deaths from surgical shock was greatly reduced.
Soon, of course, the use of chlorpromazine spread to the psychiatric clinic and was found to produce an equally dramatic reversal of the symptoms of schizophrenia. Chlorpromazine and related phenothiazine drugs were responsible for the release of hundreds of thousands of patients from institutions where they otherwise would have spent the remainder of their lives in heavy sedation, in straightjackets, or other restraints. The patients were not cured, but for many, they were able for the first time in years to engage in relatively normal day-to-day interactions.
Laborit's characterization of chlorpromazine as a Pavlovian deconditioner was upheld. In proper doses, the phenothiazines can specifically reduce signaled avoidance responding in animals while not influencing the direct response to an aversive stimulus. More recently, an even more specific animal (and human) model of this disorder has been developed by Jeffrey Gray and his colleagues at the University of London (see Baruch, Hemsley & Gray, 1988). They view much of the anxiety associated with schizophrenia as being the result of a discordance between current perceptions and perceived regularities of past events. For example, normal individuals who have heard 30 presentations of a bell do not readily acquire a conditioned response if this bell is now paired with electric shock-- a phenomenon known as latent inhibition. Patients suffering from schizophrenia are impaired in latent inhibition (i.e., do not learn that the bell was "safe"), and this deficit is normalized by chlorpromazine.
These antipsychotic drugs produce a variety of effects on neurons, but almost certainly produce their beneficial effects by blocking the D2 receptor for dopamine. When all of the drugs in common clinical use are rank ordered according to their potency, the rank ordering is identical to that achieved when they are rank ordered according to their ability to block the D2 receptor. A similar order is obtained when they are ranked according to their specific ability to inhibit avoidance responding, and given time, there will almost certainly be a similar concordance when rank ordered in terms of their effects on latent inhibition.
These close relationships between clinically useful drugs, animal models, affinity to specific receptors and theoretical models of neurotransmitters and behaviour have brought us to a point where it is not unrealistic to suppose that schizophrenia can be understood in the foreseeable future, perhaps even prevented or cured.
The success of chlorpromazine in dissolving the acute fears that surround surgery as well as the pervasive fears that torment the psychotic mind led to the search for milder drugs that could allay more commonplace anxieties. The barbiturate drugs (and alcohol) had been used with some success, but dosages that reduced anxiety also produced troublesome side effects of sedation. This situation led to the marketing of meprobamate, which was claimed to ease anxiety without sedation. This drug became very popular, even though it was in fact just a mild barbiturate that had as many sedative effects as the other drugs in this class.
Although meprobamate did not live up to its initial promise, the claims of specificity did promote the search for other drugs that could have these effects. By the early 1960's, two such drugs (chlordiazepoxide and diazepam) had been discovered. Marketed under the trade names of Librium and Valium, these drugs quickly became the most widely prescribed drugs of their time.
Chlordiazepoxide and related benzodiazepine compounds were initially termed minor tranquilizers (as contrasted with the antipsychotics that were known as major tranquilizers), but this terminology fell into disfavor and they are now known simply as antianxiety compounds. Nearly all of the compounds in this class act by facilitating the activity of the neurotransmitter GABA. The so-called GABA receptor complex is a complicated structure that has (a) a GABA site, (b) a sedative/convulsant site, and (c) a benzodiazepine site. There is now growing evidence that the brain manufactures its own antianxiety compounds as neurotransmitters that are released during periods of stress.
Antidepressants are drugs that help to reverse mood states which are characterized by sadness, lack of self esteem, and general depression. A variety of animal models of this disorder has linked depression to the monoamines, especially noradrenaline and serotonin.
The first drugs to be used in the treatment of depression were discovered by accident. Tuberculosis patients who were being treated with a new drug called iproniazid seemed to be enjoying a remarkable recovery, but it was soon learned that while their tuberculosis remained unaffected, their understandable mood of depression was being elevated by the drug. It was later learned that iproniazid and related drugs inhibit the activity of an enzyme known as monoamine oxidase (MAO), and tend to gradually elevate the level of activity of neurons that utilize dopamine or noradrenaline as neurotransmitters.
The search for better and safer drugs to treat depression led to the discovery of a class of compounds called the tricyclic antidepressants, so named because their basic chemical structure includes three carbon rings. Most of these compounds appear to act by blocking the reuptake of dopamine and noradrenaline, but some of them also block the reuptake of serotonin, some block serotonin alone, and some have no known effect on any of these systems.
Some patients who suffer from depression also have recurrent episodes of manic behaviour. This disorder, known as bipolar disorder, is treated most successfully by the administration of lithium salts. Lithium tends to stabilize the neurons, preventing the development of mania that is usually followed by a period of deep depression. The neuronal mechanism remains somewhat mysterious, although recent evidence suggests that lithium blocks the synthesis of a second messenger, a neuronal compound that promotes long-term changes in the general capacity for synaptic activity.
The future of psychopharmacology contains many challenges. Certainly one of the major challenges is to understand the biological bases of substance abuse in sufficient detail to allow the prevention and treatment of these devastating disorders. The foundations for this are already in place: The neurotransmitters and anatomic circuitry of the reward system are known in some detail; the psychology of reward and motivational systems has unravelled many of the behavioural contributions to substance abuse; and genetic studies have begun to demonstrate the possibility of predicting and understanding individual differences in the vulnerability of these systems.
A second set of challenges involves the development of more specific drugs ("magic bullets") which can restore the victims of depression, schizophrenia, anxiety, and other disorders to normalcy. Again, the development of these drugs will require a detailed understanding of the neurotransmitters, specific receptor types, and sophisticated understanding of the behavioural contributions to the disorders.
A third, related set of challenges will be to provide drugs that treat and otherwise modify behaviours that are of day-to-day concern for many people. Drugs that can facilitate memory, counteract the effects of aging on cognitive abilities, normalize food intake, and so forth. Some might claim that the availability of more drugs will only serve to exacerbate the problems that we already face with drug abuse. However, drug use and abuse are as old as humankind, and we can only benefit from a better understanding of the effects of drugs on the brain's control of behaviour.
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Acquired motivational state
GABA receptor complex
Law of initial values
minimum effective dose
Monoamine oxidase (MAO)
Route of administration
States of consciousness
LEONARD W. HAMILTON received his doctorate in Biopsychology from the University of Chicago and is now Professor of Psychology at Rutgers University in New Brunswick, NJ, USA. He has published articles on the limbic system and behavioral inhibition and is co-author (with C. R. Timmons) of a textbook entitled Principles of Behavioral Pharmacology: A Biopsychological Approach.
C. ROBIN TIMMONS received her Masters Degree in Biopsychology and her doctorate in Developmental Psychology from Rutgers University, New Brunswick, NJ, USA. She is now Assistant Professor of Psychology at Drew University, Madison, NJ, USA. She has published articles on development of behavioral inhibition, memory in infants, and is co-author (with L. W. Hamilton) of a textbook entitled Principles of Behavioral Pharmacology: A Biopsychological Approach.