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Aims, Description, and Goals

In a Chinese book on pharmacy, which dates to 2732B. C., references are found to the properties of MARIJUANA (a type of Old World HEMP, Cannabis sativa of the mulberry family). In an Egyptian papyrus from about 1550B. C., there is a description of the effects of OPIUM (a product of the opium poppy, Papaver somniferum). In almost every culture, the uses of ALCOHOL are documented in both oral and written tradition, often going back into antiquity—the Bible, for example, mentions both the use and abuse of wine. Although people have made observations on PSYCHOACTIVE substances for thousands of years, much remains to be learned about both alcohol and drugs of abuse; much research remains to be done before these substances and their effects can be fully understood.

WHAT WE NEED TO KNOW

Most substance-abuse research carried out today is a consequence of public health and social concerns. With millions of people using and abusing many different substances, and because of the close association between AIDS and drug abuse, it is imperative to know just how dangerous—or not dangerous—any given drug is to public health and safety. For economic as well as medical reasons, it is essential to find the most effective ways to use our health resources for preventing and treating substance abuse. So many questions still exist that no one scientific discipline can answer them all. The answers must be found through studies in basic chemistry, molecular biology, genetics, pharmacology, neuroscience, biomedicine, physiology, behavior, epidemiology, psychology, economics, social policy, and even international relations.

From a social standpoint, the first question for research must be: How extensive is the problem? Surveys and other indicators of drug and alcohol usage are the tools used by epidemiologists to determine the extent and nature of the problem, or to find out how many people are abusing exactly which drugs, how often, and where. As the dimensions of the problem are defined, basic scientists begin their work, trying to discover the causes and effects of substance abuse at every level, from the movement of molecules to the behavior of entire human cultures. Chemists determine the physical structure of abused substances, and then molecular biologists try to determine exactly how they interact with the subcellular structures of the human body. Geneticists try to determine what components, if any, of substance abuse are genetically linked. Pharmacologists determine how the body breaks down abused substances and sends them to different sites for storage or elimination. Neuroscientists examine the effects of drugs and alcohol on the cells and larger anatomical structures of the brain and other parts of the nervous system. Since these structures control our thoughts, emotions, learning, and perception, psychologists and behavioral pharmacologists study the drugs' effects on their functions. Cardiologists and liver and pulmonary specialists study the responses of heart, liver, and lungs to drugs and alcohol. Immunologists examine the consequences of substance abuse for the immune system, a study made critical by the AIDS epidemic. The conclusions reached through these basic scientific inquiries guide clinicians in developing effective treatment programs.

In considering drug abuse, people have long wondered why so many plants contain substances that have such profound effects on the human brain and mind. Surely people were not equipped by nature with special places on their nerve cells (called RECEPTORS) for substances of abuse—on the off chance that they would eventually smoke marijuana or take COCAINE or HEROIN. The discovery in the late 1960s that animals would work to obtain injections or drinks of the same drugs that people abuse was an important scientific observation; it contributed to the hypothesis that there must be a biological basis for substance abuse. These observations and this reasoning led scientists to look for substances produced by people's own bodies (endogenous substances) that behave chemically and physiologically like those people put into themselves from the outside (exogenous substances)—like alcohol, NICOTINE, marijuana, cocaine, and other drugs of abuse. When receptors for endogenous substances were discovered—first for the OPIATES in the 1970s and only recently for PCP, cocaine, marijuana, and LSD—their existence helped establish the biological basis for drug abuse. So did the discovery of a genetic component for certain types of ALCOHOLISM. These discoveries by no means negate the extensive behavioral and social components of substance abuse, but they do suggest a new weapon in dealing with the problem—that is, the possibility of using medication, or a biological therapy, as an adjunct to psychosocial therapies. Asserting a biological basis for substance abuse also removes some of the social stigma attached to drug and alcohol addiction. Since drug dependence is a disorder with strong biological components, society begins to understand that it is not merely the result of weak moral fiber.

Armed with information that was derived from basic research, clinical researchers in hospitals and clinics test and compare treatment modalities, looking for the best balance of pharmacological and psychosocial methods for reclaiming shattered lives. Finding the right approach for each type of patient is an important goal of treatment research, since patients frequently have a number of physical and mental problems besides substance abuse. The development of new medications to assist in the treatment process is an exciting and complex new frontier in substance-abuse research.

The best way to prevent the health and social problems that are associated with substance abuse has always been a significant research question. Insights gained from psychological and social research enable us to design effective prevention programs targeted toward specific populations that are particularly vulnerable to substance abuse for both biomedical and social reasons. Knowing the consequences of substance abuse often helps researchers to formulate prevention messages. For example, the identification of the FETAL ALCOHOL SYNDROME (FAS), a pattern of birth defects among children of mothers who drank heavily during pregnancy, was a major research contribution to the prevention of alcohol abuse. Drug-abuse-prevention research has assumed a new urgency with the realization, brought about by epidemiologists and others, that the AIDS virus is blood-borne—spread by sexual contact and by drug abusers who share contaminated syringes and needles. HIV-positive drug users then spread the disease through unprotected sexual intercourse. Public education about drug abuse and AIDS must use the most powerful and carefully targeted means of reaching the populations at greatest risk for either disease, and these means can be determined only by the most careful social research and evaluation methodologies.

Substance-abuse research is no different from any other sort of scientific endeavor: The process is not always orderly. Critical observations by clinicians frequently provide basic researchers with important insights, which guide the research into new channels. Observations in one science often lead to breakthroughs in other areas.

METHODS

The range of methods employed by scientists studying substance abuse is as wide as the range of methods in all the biological and social sciences. One important method is the use of animal models of behavior to answer many of the questions raised by drug and alcohol use. Animal models are used in biomedical research in virtually every field, but the discovery that animals will, for the most part, self-administer alcohol and the same drugs of abuse that humans do, meant that there was a great potential for behavioral research uncontaminated by many of the difficult-to-control social components of human research. The results of animal studies have been verified repeatedly in human research and in clinical observation, thus validating this animal model of human drug-seeking behavior.

Research Personnel.

Drug- and alcohol-abuse research is conducted by many different types of qualified professionals, but mostly by medical researchers (MDs) and people with advanced degrees (PhDs) in the previously mentioned sciences. They work with animals and with patients in university and federally funded laboratories, as well as in privately funded research facilities, in offices, and in clinical treatment centers. Other sites include hospitals, clinics, and sometimes schools, the streets, and even advertising agencies when prevention research is under way.

FUNDING

Who pays for substance-abuse research has always been an important issue. In the late 1980s and early 1990s, most of the drug- and alcohol-abuse research in the world was supported by the U.S. government. One of the federally funded National Institutes of Health—the NATIONAL INSTITUTE ON DRUG ABUSE (NIDA)—funds over 88 percent of drug-abuse research conducted in the United States and abroad. In 1992, this amounted to over 362 million dollars, which supported NIDA's own intramural research at the Addiction Research Center and the research done in universities under grants awarded by the institute. NIDA's sister institute, the NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM (NIAAA), plays a parallel role in funding alcohol-abuse research. In 1992, it funded 175 million dollars in alcohol-research grants. Many other U.S. government agencies also have important roles in sponsoring and conducting substance-abuse research. For the most part, state and local governments do not sponsor substance-abuse research, although they do much of the distribution of funds for treatment and prevention programs.

Other countries, most notably Canada, sponsor basic clinical and epidemiological substance-abuse research within their own universities and laboratories, but none does so on a scale that is comparable to that of the United States. Private foundations and research institutions like the Salk Institute for Biological Studies, Rockefeller University, and the Scripps Clinic and Research Foundation use their own funds, as well as federal grant support, to pay for their research endeavors. Pharmaceutical companies also support some substance-abuse research—mostly clinical work related to medications that might be used as part of treatment programs for drug and alcohol abuse. Again, much of this work is sponsored, in part, by the U.S. government.

(SEE ALSO: National Household Survey; ; Research, Animal Model; )

CHRISTINE R. HARTEL

Clinical Research

In the process of developing new drugs, pharmaceutical companies must perform rigorous studies in the laboratory, in animals, and then, if the drug looks promising, in humans. Carefully designed research into the safety and effectiveness of a drug in humans is called CLINICAL RESEARCH (or CLINICAL TRIALS). Research resulting from new surgical techniques, medical devices, and other medical treatments also fall under this heading.

To conduct research in humans, approval must be obtained from the Food and Drug Administration (FDA). The research sponsors (usually the pharmaceutical company) submit a detailed application termed an Investigational New Drug Application that summarizes the drug characteristics, manufacturing process, and results of any laboratory and animal studies. In addition, this application provides detailed information regarding proposed studies in humans, including the research protocol, data collection documents, and informed consent form. If the drug is proven to be safe and effective, the sponsors can submit a voluminous application called a New Drug Application to the Food and Drug Administration. This application contains the material in the Investigational New Drug Application as well as the data, analyses, and conclusions of all of the clinical trials conducted.

Clinical trials of drugs or medical devices progress through four phases. Phase I studies are conducted on healthy volunteers to assess the safety of the drug or device. Phase II studies are conducted on a relatively small group of patients with the target disease to assess effectiveness as well as safety. Phase III studies are conducted on a large group of patients with the target disease to confirm effectiveness, observe side effects, and to compare the test treatment to the standard treatment. Phase IV studies are performed for a variety of reasons after the drug or device has been on the market. Reasons for conducting phase IV studies include: to test the treatment in different populations (e.g., in children or the elderly), to assess the effects of long-term use of the treatment, or to use the treatment on a different target disease.

STUDY DESIGN

Study design is a crucial determinant of the strength, validity, and subsequent usefulness of clinical research results. Study design is the methodology used to conduct the clinical research. Many different types of clinical research studies exist. The strength of the data depends upon the conditions used during the conduct of the trial. Also, these conditions help to eliminate bias by the investigator, patient, or others who are involved in the collection and analysis of the data. The most important conditions are blinding, randomization, and controlling. The randomized, controlled, double blind study is considered to be the clinical research ideal.

Blinding refers to the process in which the patient does not know whether he or she is receiving the test treatment or a placebo treatment. In the single blind design, the patient does not know which treatment he or she is receiving. The investigator knows, however, and this may lead to bias. Ideally, studies should be double blind, a condition in which neither the patient nor any of the other people who are actively involved in the study have knowledge of the treatment.

Randomization refers to the process in which the patients are randomly assigned to the various treatments. This insures that the test treatment and controls are allocated to the patient by chance, and not the choice of the investigator. Randomization eliminates the possibility that an investigator could sway study results.

Clinical research studies can be either controlled or uncontrolled. Controls can be either the standard treatment for the target disease (active controlled) or a placebo (vehicle controlled). Many diseases have a natural tendency to wax and wane so study results can be misleading without a control group to serve as a comparator to the treatment group. Because controlled studies are a more reliable indicator of a treatment's effectiveness, uncontrolled studies are considered as preliminary or suggestive, or they may be disregarded altogether.

Another important component of study design is the determination of the sample size, or number of patients to include in the study. A sample size that is too small will yield a study in which the results are not strong enough (not statistically significant) to prove that the test treatment is effective. The sample size is based upon, among other things, the number of treatment and control groups in the study and an estimation of the expected differences between these groups.

The study design is contained within the study protocol, which is a detailed document that outlines every aspect of the study. The protocol is essentially a set of rules that the investigator (s) must follow. It covers such things as who may be entered into the study, how to collect and record data, and how to record and report adverse reactions. Violation of any of the rules set forth in the protocol can disqualify an investigator, a patient, or even the entire study.

Although the randomized, controlled, single and double blind studies are very common designs, there are other study designs which may be used. The sponsor may initially conduct dose-finding studies in order to find the optimal dose of a test drug to treat the target disease. In the cross-over design, patients receive both treatments being compared (or treatment and a placebo) which factors out inter-individual variability. Each patient would receive one treatment for a designated time period, their disease state would be evaluated, and then they would switch to the other treatment for a designated time period. Other, more complex study designs are also employed. However, with increasing complexity comes increasing difficulties in data analysis, interpretation, and validity.

ETHICAL CONSIDERATIONS

Federal regulations insure that the rights of subjects in a clinical trial are protected. Each clinical trial must be approved and monitored by a committee known as an Institutional Review Board, which has medical, scientific, and non-scientific members. Institutional Review Boards review and approve trial documents such as the protocol and informed consent form as well as the advertising materials needed to attract subjects. The purpose of the Institutional Review Board is to protect the rights, safety, and well-being of the study subjects.

The Food and Drug Administration requires that all participants in a clinical trial be informed of the details of the study. This process is called informed consent. Informed consent usually involves a lengthy document (informed consent form) that describes key facts about the study including: the purpose of the research, what the goals are, what procedures will be done, what the possible risks are, what the possible benefits are, and what other treatments are available for the target disease. In addition, the informed consent form stresses that the subject can leave the study at any time. An important component of the informed consent process is that the subject has the opportunity to ask questions regarding the study and/or the consent form.

CONCLUSION

Clinical research plays an invaluable role in the ongoing process of finding effective and safe treatments for diseases. The information obtained by clinical trials provides physicians with the necessary information to make informed choices in the treatment of their patients. Clinical studies are key in identifying the optimal doses of a new drug and also in providing information regarding the occurrence and incidence of adverse reactions. However, clinical research is limited by sample size. Even studies comprised of thousands of subjects will fail to pick up extremely rare, possibly serious adverse reactions that materialize during clinical use.

BELINDA ROWLAND

Developing Medications to Treat Substance Abuse and Dependence

Dependence on drugs, ALCOHOL, or TOBACCO is difficult to treat, and practitioners have tried many approaches in their attempts to arrive at successful treatments. One approach is to develop medications, or pharmacological treatments. This approach is most effective when the medication is given along with behavioral treatments. These behavioral treatments help the individual cope with the underlying etiology of his or her drug use and the problems associated with drug use; they may also help ensure compliance in taking the medication that is prescribed.

PERPETUATION OF DRUG ABUSE: EUPHORIA AND WITHDRAWAL

Many people who are drug- or alcohol-dependent want to stop their habit, but often they have a difficult time doing so. There are at least two reasons for this difficulty. First, the drugs produce pleasant or euphoric feelings that the user wants to experience again and again. Second, unpleasant effects can occur when the drug use is stopped. The latter effect, commonly known as WITHDRAWAL, has been shown after prolonged use of many drugs, including alcohol, OPIATES (such as HEROIN), SEDATIVE HYPNOTICS, and anxiety-reducing drugs. Other drugs, such as COCAINE and even CAFFEINE (COFFEE and COLA drinks) and NICOTINE (cigarettes), are also believed to be associated with withdrawal effects after prolonged use. These unpleasant withdrawal effects are alleviated by further drug use. Thus drugs are used and abused because they produce immediate pleasant effects and because the drug reduces the discomfort of withdrawal.

The symptoms of withdrawal are fairly specific for each drug and include physiological effects and psychological effects. For example, alcohol withdrawal can be associated with shaking or headaches, and opiate withdrawal with anxiety, sweating, and increases in blood pressure, among other effects. Withdrawal from cocaine may cause depression or sadness, withdrawal from caffeine is associated with headaches, and withdrawal from nicotine often produces irritability. All drug withdrawals are also associated with a strong craving to use more drugs. Much work has been done to document the withdrawal effects from alcohol, opiates, BENZODIAZEPINES, and tobacco; however, documentation of withdrawal from cocaine or other stimulant drugs has only recently begun to be examined.

NEURAL CHANGES WITH CHRONIC DRUG USE

Both withdrawal and the pleasant or euphoric effects from drug use occur, in part, as a result of the drug's action on the brain. The immediate or acute effects of most drugs of abuse affect areas of the brain that have been associated with "reward" or pleasure. These drugs stimulate areas normally aroused by natural pleasures such as eating or sexual activity. Long-term, or chronic, drug use alters these and other brain areas. Some brain areas will develop TOLERANCE to the drug effects, so that greater and greater amounts are needed to achieve the original effects of the drug. Some examples of drug effects that develop tolerance are the ANALGESIC or painkilling effect of opiates and the euphoria- or pleasure-producing effect of most drugs of abuse, which are probably related to their abuse potential.

Because some brain areas may also become sensitized, an original drug effect will either require a lesser amount of the drug to elicit the effect when the drug is used chronically or the effect becomes greater with chronic use. This phenomenon has been studied most extensively in cocaine use. Cocaine is associated with behavioral sensitization of motor activity in animals and paranoia (extreme delusional fear) in humans. There are physiological effects that develop tolerance or sensitization as well. For example, the chronic use of cocaine will sensitize some brain areas so that seizures are more easily induced. Other health risks of drug use will be addressed below.

In addition to these more direct acute and chronic drug effects, another phenomenon occurs with long-term drug use. This phenomenon is the conditioned drug effect, in which the environmental or internal (mood states) cues commonly presented with drug use become conditioned or psychologically associated with drug use. For example, when angry, a drug addict may buy or use drugs in a certain place with certain people. After frequently taking drugs under similar conditions, the individual can experience a strong craving or even withdrawal when in the environment in which he or she has taken drugs or feels angry. When the individual tries to stop using drugs, exposure to these conditioned cues can often lead to relapse because the craving and withdrawal effects are so powerful. Very little research has been done on the neural bases of these conditioned effects; thus it is not known whether these effects are mediated by similar or different neural mechanisms.

RESEARCH ON DRUG EFFECTS

Many of these acute and chronic effects of drugs on the brain have been investigated in animal research, which allows greater control over the research, including manipulations of drug exposure. A number of animal models are used to assess drug preferences, and, since most drugs that humans abuse are also preferred by animals, these models are useful for understanding human drug abuse. Moreover, animal research allows scientists to study directly the various areas of the brain that are involved in drug use. In addition, recent technological advancements on noninvasive IMAGING have allowed scientists to took at pictures of the brains of humans while they are being administered drugs or while they are withdrawing from drugs. This human work has also enhanced our knowledge of the drug effects on the brain as well as validated the information gained from animal research.

Another useful line of research in assessing the effects of drugs involves human laboratory studies. In one type of study, research volunteers who have had experience with the abused drugs are given a specific drug (e.g., morphine), and various psychological and physiological measurements are obtained. The psychological measurements can include reports from the subject on the effects of the drug as well as more sophisticated behavioral measures that tell the experimenter how much the drug is preferred. Another type of human laboratory study is to study the effects of drug withdrawal. For opiates, withdrawal can be precipitated by an opiate ANTAGONIST drug (NALTREXONE), and withdrawal signs and symptoms are measured. For other drugs (such as cocaine), withdrawal is more difficult to measure because little is known about their withdrawal syndromes.

Some of the information that scientists have learned from such studies includes delineating specific brain areas as well as the NEUROTRANSMITTERS (the chemicals released by the brain cells) involved in drug use and withdrawal. Thus, when specific neurotransmitters become identified as playing an important role in drug use or withdrawal, scientists can administer experimental drugs that act on these neurotransmitters to see if the animals will alter their drug preference or show less severe withdrawal signs. Researchers can also give these experimental drugs to the human research volunteers to see if the medication alters the subject's perception of or behavior toward the abused drug or if it alleviates withdrawal symptoms. If the results from these animal and human laboratory studies are promising, then these agents can be tested on treatment-seeking, drug-dependent individuals in clinical trials. This latter type of research is more time-consuming and expensive than the laboratory studies, but it helps provide an answer to the ultimate question: Does this medication help an individual stop abusing drugs?

APPROACHES TO DEVELOPING MEDICATIONS FOR DRUG ABUSE

Researchers can use the knowledge gained from animal and human studies of the effects of drugs on the brain as they develop medications for alcohol and drug dependence. Most likely, one medication will be needed to help detoxify the drug-dependent individual and a second medication to help sustain abstinence from drug use. This two-phase medication regimen is used for opiate and alcohol treatment, and it may ultimately be the approach used for countering dependency on other drugs, such as cocaine, sedatives, and nicotine. In theory, a pharmacological treatment agent or medication would block or reduce either the acute, rewarding effect of the drug or the discomfort of withdrawal. In practice, few treatment drugs have been found to be very effective in sustaining abstinence from drugs or alcohol.

Any pharmacological agent should be able to be given orally, as this is much easier than other routes of administration, such as injections. The agent itself must be medically safe and not enhance any of the health risks associated with illicit drug use, since the individual may illicitly use drugs while being maintained on the treatment agent. Finally, the pharmacological treatment agent must be acceptable to the patient. That is, if the agent causes undesirable side effects, individuals will likely not take it.

Current research with alcohol and drug effects on the brain and with treatment outcome hold great promise for effective pharmacological agents. This search process will necessarily include the animal and human laboratory studies mentioned as well as medicinal chemistry research. Medicinal chemistry research is used to develop new compounds that have similar but slightly altered chemical structures to the abused drugs or to the neurotransmitters that mediate the drug or alcohol effects. These new compounds are then tested in animals to see if they produce therapeutic effects. These effects include having a low potential for being another drug of abuse and attenuating the effects of the abused drug under study, preferably in a way that would lead to decreased drug abuse.

EXAMPLES OF MEDICATIONS USED TO TREAT DRUG ABUSE

Several types of medications have been developed for countering various kinds of dependencies.

Opioid Dependence.

Some of the best examples of pharmacotherapies for drug abuse were developed for opiate addicts. One of the first pharmacological agents used to treat opiate addicts is METHADONE. Methadone itself is an opiate drug and effectively reduces or blocks the withdrawal discomfort brought on by discontinuing use of heroin or other illegal opiate. Although methadone is itself addictive, it is delivered to the opiate-dependent patients in a facility with psychological and other medical and support treatments and services. Methadone is safer than opiates obtained illegally—in part because it is given orally. Because illegal opiates are often injected by addicts, they can lead to many diseases—including AIDS and hepatitis, if the needles are shared with an infected person. Illegal drug use is expensive, and many addicts steal to support their habit. Moreover, since drugs obtained illegally vary in their quality and purity, there is a greater chance of getting an overdose that produces severe medical problems and, perhaps, death. Thus methadone decreases the need to use illegal opiates, as a result of its ability to relieve withdrawal as well as to block the effects of other opiates by cross-tolerance. Moreover, it reduces the health risks and social problems associated with illegal opiate use.

Another treatment drug that was developed for opiate dependence and abuse is naltrexone. This agent blocks the ability of the opiate drug to act on the brain. Thus, if heroin addict maintained on naltrexone injects heroin, he or she will not feel the pleasant or other effects of the heroin. The principle behind this approach is based on research suggesting that drug use is continued, despite the dire consequences, because of the euphoria associated with its use. Once maintained on naltrexone, the addict may forget this association, because the drug can no longer produce these effects. Unfortunately, although naltrexone works well for some, others will simply discontinue using the naltrexone in order to get high from drugs again.

Before opiate abusers can be maintained on the medication naltrexone, they must be detoxified from the opiate drugs in their systems. Although abstaining ("cold turkey") from heroin use for several days will accomplish detoxification, the withdrawal process is difficult because of the physical distress it causes. Thus, another DETOXIFICATION method was developed in which the withdrawal is precipitated, or triggered, with naltrexone, while the symptoms are treated with another medication, CLONIDINE. When withdrawal is precipitated, the symptoms are worse than that seen with natural withdrawal, but the symptom course is much briefer. Moreover, clonidine helps alleviate the symptoms, to make this shorter-term withdrawal process less severe.

Alcohol Dependence.

An example of another type of medication is one used to treat alcoholism: DISULFIRAM. The basis for this agent's therapeutic effect is different from that of methadone or naltrexone. When someone is maintained on disulfiram, future alcohol ingestion will cause stomach distress and, possibly, vomiting, because the disulfiram prevents the breakdown of a noxious alcohol metabolite by the liver. Patients maintained on disulfiram should come to forget the pleasant effects of alcohol use, which is similar to the psychological basis of naltrexone maintenance. Moreover, they should begin to develop an aversion to alcohol use. Another similarity to the use of naltrexone is that disulfiram treatment of alcoholism has not been very successful, because the patient who wants to use alcohol again can simply stop using the disulfiram.

Some pharmacological agents have been tested to reduce craving for alcohol and thus help the alcoholic abstain from drinking. These drugs include naltrexone, which was developed for opiate addicts, and fluoxetine. The former medication is a potential treatment drug because most drugs of abuse are believed to be mediated, in part, through the brain's natural opiate system (ENDORPHINS, etc.). Based on research that implicates a specific neurotransmitter system (SEROTONIN) in alcohol craving, the latter medication and others of this type may be useful. However, as in the treatment of opiate abuse, alcoholics must be detoxified before any of these medications are used as maintenance agents.

Tobacco Dependence.

One commonly used pharmacological treatment for tobacco dependence is NICOTINE GUM (Nicorette). The main reason to quit smoking is that it is linked to lung cancer, emphysema, and other serious illnesses. Yet the active ingredient in cigarettes, NICOTINE, is associated with pleasant effects and with withdrawal discomfort, thereby making it an extremely addicting drug. Providing smokers with nicotine replacement in the form of a gum will help them avoid the health risks associated with cigarettes. One problem with nicotine gum is that it is difficult to chew correctly; people need to be shown how to chew it in order to get the therapeutic effect. A patch is also available that is placed on the arm and automatically releases nicotine. This method shows good treatment potential. Detoxification from nicotine may also be facilitated with the medication clonidine, the same agent used to help alleviate opiate withdrawal symptoms.

Stimulant Dependence.

Developing pharmacological treatment agents for stimulant (e.g., cocaine) dependence is a difficult task but has been the focus of a great deal of research. One of the difficulties for treating cocaine abuse is that cocaine affects many different neurotransmitter systems in various ways. Thus one approach may be to develop a treatment drug or regimen of drugs that affects a variety of neurotransmitter systems. However, the exact nature of the neural effects of cocaine are still not entirely understood.

Another difficulty is that it is not clear what approach to take in developing a treatment drug. One obvious technique in developing a medication for cocaine abuse is to use an agent that blocks the rewarding aspects of cocaine use. This type of drug would, presumably, decrease cocaine use because the rewarding effects are no longer experienced. However, this approach is similar to having opiate addicts use naltrexone, which has not been well accepted by heroin addicts. Clinical work with some treatment agents that were suggested to block the rewarding effects of cocaine did not prove to be useful in the treatment of abuse and dependence. Whether this lack of treatment effect resulted from a flaw in the method or from the limitations in our knowledge of cocaine's effects on neurotransmitter systems is not clear. One problem is that the potential blocking agents for cocaine may produce dysphoria, or an unpleasant feeling.

Another approach to treating cocaine abuse and dependence is based on a premise similar to that of methadone for opiate abuse. That is, a pharmacological agent similar in its effects to cocaine, but one that is not addicting, may be a useful anticraving agent. Just as methadone helps alleviate drug withdrawal, an agent of this type for cocaine abuse may alleviate the distress and craving associated with abstinence from cocaine. Several medications of this type have been tried, including bromocriptine and AMANTADINE. Thus far, these and other agents have shown some limited treatment promise.

Most of the approaches to developing pharmacological treatments for cocaine abuse have been based on research suggesting that one specific neurotransmitter (DOPAMINE) is important for cocaine's rewarding effects. Yet other neurotransmitters are activated during cocaine use and may be better targets for developing new treatment drugs. That is, although dopamine is critical for the rewarding aspects of cocaine use, other neurotransmitter systems may be more important in withdrawal distress. Although withdrawal distress from cocaine has been difficult to document, depression is thought to be one aspect of abstaining from chronic cocaine use. Antidepressant medications, such as desipramine and imipramine, have shown some, albeit limited, treatment potential.

Sedative Dependence.

Current treatments for sedative dependence include detoxification agents, not anticraving agents. Detoxification is accomplished by tapering the dosage of BENZODIAZEPINES over two to three weeks. More recently, carbamazepine, an antiseizure analgesic medication, has been shown to relieve alcohol and sedative withdrawal symptoms, including seizures and delirium tremens. Future work with agents that block the actions of benzodiazepines may hold promise as a maintenance or anticraving agent to help the sedative abuser abstain from drug abuse.

CONCLUSION

One of the greatest lessons learned from the practice of giving medications to drug-abusing individuals is that these medications must be accompanied by psychological and social treatments and support. Medications do not work on their own. Moreover, medications that are developed based on theoretical principles of altering or blocking the drug's effects in the brain may not be useful in the practice of treating drug abuse and dependence, because the premises of how to develop a pharmacological treatment agent may not be accurate. Yet the largest research challenge is to understand the etiology and mechanisms of drug abuse. Thus more research in many fields is needed to identify potential medications in order to develop more effective treatments for the difficult problem of drug abuse and dependence.

(SEE ALSO: Addiction: Concepts and Definitions; Imaging Techniques: Visualizing the Living Brain; )

THERESE A. KOSTEN

Drugs as Discriminative Stimuli

Human behavior is influenced by numerous stimuli in the environment. Those stimuli acquire behavioral control when certain behavioral consequences occur in their presence. As a result, a particular behavioral response becomes more or less likely to occur when those stimuli are present. For example, several laboratory experiments have demonstrated that it is possible to increase a particular response during a stimulus (such as a distinctively colored light) by arranging for reinforcement (such as a preferred food or drink) to be given following that> response when the stimulus is present; when that stimulus is absent, however, responses do not produce the reinforcer. Over a period of time, responding will then occur when the stimulus is present but not when it is absent. Stimuli that govern behavior in this manner are termed discriminative stimuli and have been widely used in behavioral and pharmacological research to better understand how behavior is controlled by various stimuli, and how those stimuli, in turn, might affect the activity of various drugs.

It is important to recognize that there are differences between discriminative stimuli that merely set the occasion for a response to be reinforced and other types of stimuli that directly produce or elicit responses. Discriminative stimuli do not coerce a response from the individual in the same way that a stimulus such as a sharp pierce evokes a reflexive withdrawal response. Instead, discriminative stimuli may be seen as providing guidance to behavior because of the unique history of reinforcement that has occurred in their presence.

DRUGS AS DISCRIMINATIVE STIMULI

Although the stimuli that typically govern behavior are external (i.e., located in the environment outside the skin), it is also possible for internal or subjective stimuli to influence behavior. One of the more popular methods to emerge in the field of behavioral pharmacology has been the use of drugs as discriminative stimuli. The procedure consists of establishing a drug as the stimulus, in the presence of which a particular response is reinforced. Typically, to establish a drug as a discriminative stimulus, a single dose of a drug is selected and, following its administration, one of two responses are reinforced; with rodents or nonhuman primates, this usually entails pressing one of two simultaneously available levers, with reinforcement being scheduled intermittently after a fixed number of correct responses. Alternatively, when saline or a placebo is administered, responses on the other device are reinforced. Over a number of experimental sessions, a discrimination develops between the administration of the drug and saline, with the interoceptive (subjective) stimuli produced by the drug seen as guiding or controlling behavior in much the same manner as any external stimulus, such as a visual or auditory stimulus. Once the discrimination has been established, as indicated by the selection of the appropriate response following either the training drug or the saline administration, it is possible to investigate aspects of the drug stimulus in the same way as one might investigate other physical stimuli. It is thus possible to determine gradients of intensity or dose-effect functions with the training drug as well as generalization functions aimed at determining how similar the training drug dose is to a different dose or to another drug substituted for the training stimulus.

BASIC EXPERIMENTAL RESULTS

One of the more striking aspects of the drug discrimination technique is the strong relationship that has been found between the stimulus-generalization profile and the receptor-binding characteristics of the training drug. For example, animals trained to discriminate between a BENZODIAZEPINE anxiolytic, such as CHLORDIAZEPOXIDE, and saline solution typically respond similarly to other drugs that also interact with the receptor sites for benzodiazepine ligands. Anxiolytic drugs that produce their effects through other brain mechanisms or receptors do not engender responses similar to those occasioned by benzodiazepines. This suggests that it is activity at a specific RECEPTOR that is established when this technique is used and not the action of the drug on a hypothetical psychological construct such as anxiety (Barrett & Gleeson, 1991).

Several studies have examined the effects of drugs of abuse by using the drug discrimination procedure, and they have established COCAINE and numerous other drugs—such as an OPIATE, PHENCYCLIDINE (PCP), or MARIJUANA—as a discriminative stimulus in an effort to help delineate the neuropharmacological or brain mechanisms that contribute to the subjective and abuse-liability effects of these drugs. As an example, Figure 1 shows the results obtained in pigeons trained to discriminate a 1.7 milligram per kilogram (mg/kg) dose of cocaine from saline. The dose-response function demonstrates that doses below the training dose of cocaine yielded a diminished percentage of responses on the key correlated with cocaine administration, which suggests that the lower doses of cocaine were less discernible than the training dose. In addition, other psychomotor stimulants such as AMPHETAMINE and METHAMPHETAMINE also produced cocaine-like responses, and this suggests that these drugs share some of the neurochemical properties of cocaine. In contrast, other drugs, such as the α₂-adrenoreceptor antagonist yohimbine, along with several other drugs such as morphine, PCP, or marijuana (that are not illustrated) do not produce responding on the key correlated with cocaine administration—thereby suggesting that the mechanisms of action underlying those drugs, as well as their subjective effects, are not similar to those of cocaine and the other psychomotor stimulants in this figure.

IMPLICATIONS

The use of drugs as discriminative stimuli has provided a wealth of information on the way drugs are similar to more conventional environmental stimuli in their ability to control and modify behavior. The procedure has also increased our understanding of the neuropharmacological mechanisms that operate to produce the constellation of effects associated with those drugs. The technique has wide generality and has been studied in several species, including humans—in whom the effects are quite similar to those of nonhumans.

Because it is believed that the subjective effects of a drug are critical to its abuse potential, the study of drugs of abuse as discriminative stimuli takes on added significance. A better understanding of the effects of drugs of abuse as pharmacologically subjective stimuli provides a means by which to evaluate possible pharmacological as well as behavioral approaches to the treatment of drug abuse. For example, a drug that prevents or antagonizes the discriminative-stimulus effects (and presumably the neuropharmacological actions) of an abused drug might be an effective medication to permit individuals to diminish their intake of abused drugs, because the stimuli usually associated with its effects will no longer occur. Similarly, although little work has been performed on the manipulation of environmental stimuli correlated with the drug stimulus, it might be possible to design innovative treatment strategies in which other stimuli compete with the subjective discriminative-stimulus effects of the abused drug. Thus, a basic experimental procedure such as drug discrimination has provided a useful experimental tool for understanding the behavioral and neuropharmacological effects of abused drugs.

Further work may help design and implement novel treatment approaches to modifying the behavioral and environmental conditions surrounding the effects of abused drugs and thus result in diminished behavioral control by substances of abuse.

(SEE ALSO: Abuse Liability of Drugs; Drug Types; Research, Animal Model)

JAMES E. BARRETT

JUNE STAPLETON

Measuring Effects of Drugs on Behavior

People throughout world take drugs such as HEROIN, COCAINE, and ALCOHOL because these drugs alter behavior. For example, cocaine alters general activity levels; it increases wakefulness and decreases the amount of food an individual eats. Heroin produces drowsiness, relief from pain, and a general feeling of pleasure. Alcohol's effects include relaxation, increased social interactions, marked sedation, and impaired motor function. For the most part, the scientific investigations of the ways drugs alter behavior began in the 1950s, when chlorpromazine was introduced as a treatment for SCHIZOPHRENIA. As a result of this discovery, scientists became interested in the development of new medications to treat behavioral disorders as well as in the development of procedures for studying behavior in the laboratory.

HOW IS BEHAVIOR STUDIED?

The simplest way to study the effects of drugs on behavior is to pick a behavior, give a drug, and observe what happens. Although this approach sounds very easy, the study of a drug's effect on behavior is not so simple. Like any other scientific inquiry, research in this area requires careful description of the behaviors being examined. If the behavior is not carefully described, it is difficult to determine whether a change in behavior following drug administration is actually due to the drug.

Behavior is best defined by describing how it is measured. By specifying how to measure a behavior, an operational definition of that behavior is developed. For example, to study the way in which a drug alters food intake, the following procedure might be used: First, select several people and present each with a box of cereal, a bowl, a spoon, and some milk after they wake up in the morning. Then measure how much cereal and milk they each consume within the next thirty minutes. To make sure the measurements are correct, repeat the observations several times under the same conditions (i.e., at the same time of day, with the same foods available). From these observations, determine the average amount of milk and cereal consumed by each person. This is the baseline level. Once the baseline level is known, give a small amount of drug and measure changes in the amount of milk and cereal consumed. Repeat the experiment, using increasing amounts of the drug. This concept of baseline level and change from baseline level is common to many scientific investigations.

In addition to defining behavior by describing how it is measured, a good behavioral procedure is also (1) sensitive to the ways in which drugs alter behavior and (2) is reliable. Sensitivity refers to whether a particular behavior is easily changed as the result of drug administration. For example, food consumption may be altered by using cocaine, but other behaviors may not be. Reliability refers to whether a drug produces the same effect each time it is taken. In order to say that cocaine reliably alters the amount of food consumed, it should decrease food consumption each time it is given, provided that the experimental conditions surrounding its administration are the same.

WHAT FACTORS INFLUENCE A DRUG'S EFFECTS ON BEHAVIOR?

Although good behavioral procedures are necessary for understanding a drug's effects on behavior, pharmacological factors are also important determinants of a drug's effect. Pharmacological factors include the amount of drug given (the dose), how quickly the drug produces its effects (its onset), the time it takes for its effects to disappear (its duration), and whether the drug's effects are reduced (tolerance) or increased (sensitivity) if it is taken several times. Although this point may seem obvious, it is often overlooked. It is impossible to describe the behavioral effects of a drug on the basis of just one dose of the drug, since drugs can have very different effects, depending on how much of the drug is taken. Moreover, the probability that a drug will produce an effect also depends on the amount taken. As an example, consider Figure 1, which shows the risk of being involved in a traffic accident as a function of the amount of alcohol in a person's blood.

The way in which a drug is taken is also important. Cocaine can be taken by injection into the veins, by smoking, or by sniffing through the nose. Each of these routes of administration can produce different effects. Environmental factors also influence a drug's effect. Cocaine might change the amount of cereal and milk consumed in the morning but it might not change the amount consumed at a different time of day or if other types of food are available. Finally, individual factors also influence the drug effect. These include such factors as how many times an individual has taken a particular drug; what happened the last time it was taken; or what one may have heard from friends about a drug's effects.

HOW IS BEHAVIOR STUDIED IN THE LABORATORY?

Human behavior is very complex, and it is often difficult to examine. Although scientists do conduct studies on people, many investigations of drug effects on behavior are carried out using animals. With animals, investigators have better control over the conditions in which the behavior occurs as well as better information about the organism's past experience with a particular drug. Although animal experiments provide a precise, controlled environment in which to investigate drug effects, they also have their limitations. Clearly, they cannot research all the factors that influence human behavior. Nevertheless, many of the effects that drugs produce on behavior in animals also occur in humans. Moreover, behavioral studies sometimes require a large number of subjects with the same genetic makeup or with no previous drug experience. It is easier to meet these requirements in animal studies than in studies with people.

Since animals are often used in research studies, it is important to remember that behavioral scientists are very concerned about the general welfare of their animals. The U.S. Animal Welfare Act set standards for handling, housing, transporting, feeding, and veterinary care of a wide variety of animals. In addition, all animal research in the United States is now reviewed by a committee that includes a veterinarian experienced in laboratory-animal care. This committee inspects animal-research areas and reviews the design of experiments to ensure that the animals are treated well.

WHAT APPROACHES ARE USED TO EXAMINE DRUG EFFECTS?

In general, there are two ways to examine drug effects on behavior in the laboratory. One approach relies on observation of behavior in an animal's home cage or in an open area in which the animal (or person) can move about freely. When observational approaches are used, special precautions are necessary. First of all, the observer's presence should not disrupt the experiment. Television-monitoring systems and videotaping make it possible for the observer to be completely removed from the experimental situation. Second, the observer should not be biased. The best way to insure that the observer is not biased is to make the observer "blind" to the experimental conditions; that is, the observer does not know what drug is given or which subject received the drug. If the study is done in human subjects, then they also should be blind to the experimental conditions. An additional way to make sure observations are reliable is to use more than one observer and compare observations. If these precautions are taken, observational approaches can produce interesting and reliable data. Indeed, much of what is known about drug effects on motor behavior, food or water intake, and some social behaviors comes from careful observational studies.

Another approach uses the procedures of classical and operant conditioning. This involves training animals to make specific responses under special conditions. For example, in a typical experiment of this sort, a rat is placed in an experimental chamber and trained to press a lever to receive food. The number and pattern of lever presses are measured with an automatic device, and changes in responding are examined following drug administration. These procedures have several advantages. First, they produce a very consistent measure of behavior. Second, they can be used with human subjects as well as with several different animal species. Third, the technology for recording behavior eliminates the need for a trained observer.

WHAT BEHAVIORS DO DRUGS ALTER?

Some of the behaviors that drugs alter are motor behavior, sensory behavior, food and water intake, social behavior, and behavior established with classical and operant conditioning procedures. By combining investigations of these behaviors, scientists classify drugs according to their prominent behavioral effects. For example, drugs such as AMPHETAMINE and cocaine are classified as PSYCHOMOTOR STIMULANTS because they increase alertness and general activity in a variety of different behavioral procedures. Drugs such as MORPHINE are classified as analgesics because they alter the perception of pain, without altering other sensations such as vision or audition (hearing).

Motor Behavior.

Most behaviorally active drugs alter motor behavior in some way. Morphine usually decreases motor activity, whereas with cocaine certain behaviors occur over and over again (that is, repetitively). Other drugs, such as alcohol, may alter the motor skills used in DRIVING a car or operating various types of machinery. Finally, some drugs alter exploratory behavior, as measured by a decrease in motor activity in an unfamiliar environment. Examination of the many ways in which drugs alter motor behavior requires different types of procedures. Some of these procedures examine fine motor control or repetitive behavior; others simply measure spontaneous motor activity.

Although changes in motor behavior can be observed directly, most studies of motor behavior use some sort of automatic device that does not depend on human observers. One of these devices is the running wheel. The type of running wheel used in scientific investigations is similar to the running wheel in pet cages. This includes a cylinder of some sort that moves around an axle when an animal walks or runs in it. The only difference between a running wheel in a pet cage and a running wheel in the laboratory is its size and the addition of a counter that records the number of times the wheel turns. Another device for measuring motor behavior uses an apparatus that is surrounded by photocells. If the animal moves past one of the photocells, a beam of light is broken and a count is produced. Yet another way to measure motor behavior is with video tracking systems. An animal is placed in an open area and a tracking system determines when movement stops and starts as well as its speed and location. This system provides a way to look at unique movement patterns such as repetitive behaviors. For example, small amounts of amphetamine increase forward locomotion, whereas larger amounts produce repetitive behaviors such as head bobbing, licking, and rearing. Until recently, this type of repetitive behavior was measured by direct observation and description.

Although technology for measuring motor behavior is very advanced, it is important to remember that how much drug is given, where it is given, and the type of subject to whom it is given will also influence a drug's effect on motor behavior. Whether a drug's effects are measured at night or during the day is an important factor. The age, sex, species, and strain of the animal is also important. Whether food and water are available is another consideration as well as the animal's previous experience with the drug or test situation. As an example, see Table 1, which shows how the effects of alcohol on motor behavior differ depending on the amount of alcohol in a person's blood.

Sensory Behavior.

The integration and execution of every behavior an organism engages in involves one or more of the primary senses, including hearing, vision, taste, smell, and touch. Obviously, a drug can affect sensory behavior and thereby alter a number of different behaviors. For example, drugs such as LYSERGIC ACID DIETHYLAMIDE (LSD) produce visual abnormalities and HALLUCINATIONS. PHENCYCLIDINE (PCP) produces a numbness in the hands and feet. Morphine alters sensitivity to painful stimuli.

It is difficult to investigate drug effects on sensory behavior, since changes in sensory behavior cannot be observed directly. In order to determine whether someone hears a sound, one must report having heard it. In animal studies, rats or monkeys are trained to press a lever when they hear or see a given stimulus. Then a drug is given and alterations in responding are observed. If the drug alters responding, it is possible that the drug did so by altering sensory behavior; however, care must be taken in coming to this conclusion since a drug might simply alter the motor response used to measure sensory behavior without changing sensory behavior at all.

One area of sensory behavior that has received considerable attention is pain perception. In most procedures for measuring pain perception, a potentially painful stimulus is presented to an organism and the time it takes the organism to respond to that stimulus is observed. Once baseline levels of responding are determined and considered reliable, a drug is given. If the time it takes the organism to respond to the stimulus is longer following drug administration and if this change is not because the animal is too sedated to make a response, then the drug probably has altered pain perception.

Among the most common procedures used to measure pain perception is the tail-flick procedure in which the time it takes an animal to remove its tail from a heat source is measured prior to and after administration of a drug such as morphine. Another commonly used procedure measures the time it takes an animal to lick its paws when placed on a warm plate or to remove its tail from a container of warm water. Thus, an alteration in pain perception is operationally defined as a change in responding in the presence of a painful stimulus. It is also important to note that the animal, not the experimenter, determines when to respond or remove its tail. Also, these procedures do not produce long-term damage or discomfort that extends beyond the brief experimental session.

Food and Water Intake.

The simplest way to measure food and water intake is to determine how much an organism eats or drinks within a given period of time. A more thorough analysis might also include counting the number of times an organism eats or drinks in a single day, or measuring the time between periods of eating and periods of drinking. Several factors are important in accurately measuring food and water intake. For example, how much food or water is available to the organism and when is it available? Is it a food the organism likes? When did the last meal occur?

In animals, food intake is often measured by placing several pieces of pelleted food of a known weight in their cages. The food that remains after a period of time is weighed and subtracted from the original amount to get an estimate of how much was actually eaten. Water intake is usually measured with calibrated drinking tubes clipped to the front of the animal's cage or with a device called a drinkometer, which counts the number of times an animal licks a drinking tube. An accurate measure of fluid intake also requires a careful description of the surrounding conditions. For example, was fluid intake measured during the day or during the night? Was food also available? What kind of fluid was available? Was there more than one kind of fluid available? These procedures are also used to examine drug intake. If rats are presented with two different drinking tubes, one with alcohol, another with water, they will generally drink more alcohol than water; however, the amount they drink is generally not sufficient to produce intoxication or physical dependence. Rats will drink a large amount of alcohol as well as other drugs of abuse such as morphine and cocaine when these drugs are the only liquid available. Indeed, most animals will consume sufficient quantities to become physically dependent on alcohol or morphine.

Social Behavior.

Behaviors such as aggression, social interaction, and sexual behavior are usually measured by direct experimenter observation. Aggressive behavior can be measured by observing the number of times an animal engages in attack behavior when another animal is placed into its cage. In some cases, isolation is used to produce aggressive behavior. Sexual behavior is also measured by direct observation. In the male rat or cat, the frequency of behaviors such as mounting, intromission, and ejaculation are observed. Another interesting procedure for measuring social behavior is the social interaction test. In this procedure, two rats are placed together and the time they spend in active social interaction (sniffing, following, grooming each other) is measured under different conditions. In one condition, the rats are placed in a familiar environment; in another condition, the environment is unfamiliar. Rats interact more when they are in a familiar environment than when they are in an unfamiliar environment. Moreover, antianxiety drugs increase social interaction in the unfamiliar area. These observational techniques can produce interesting data, provided that they are carried out under well-controlled conditions, the behavior is well-defined, and care is taken to make sure the observer neither disrupts the ongoing behavior nor is biased.

Classical Conditioning.

Classical conditioning was made famous by the work of the Russian scientist Ivan Pavlov in the 1920s. In those experiments, Pavlov used the following procedure. First, dogs were prepared with a tube to measure saliva, as shown in Figure 2. Then Pavlov measured the amount of saliva that was produced when food was given. The amount of saliva not only increased when food was presented but also when the caretaker arrived with the food. From these careful observations, Pavlov concluded that salivation in response to the food represented an inborn, innate response that did not require any learning. Because no learning was required, he called this an unlearned (unconditioned) response and the food itself an unlearned (unconditioned) stimulus. The dogs did not automatically salivate, however, when the caretaker entered the room; but after the caretaker and the food occurred together several times, the presence of the caretaker was paired with (or conditioned to) the food. Pavlov called the caretaker the conditioned stimulus and he called the salivation that occurred in the presence of the caretaker a conditioned response.

Events in the environment that are paired with or conditioned to drug delivery can also produce effects similar to the drug itself, much in the same way that Pavlov's caretaker was conditioned to food delivery. For example, when heroin-dependent individuals stop taking heroin, they experience a number of unpleasant effects, such as restlessness, irritability, tremors, nausea, and vomiting. These are called withdrawal or abstinence symptoms. If an individual experiences withdrawal several times in the same environment, then events or stimuli in that location became paired with (or conditioned to) the withdrawal syndrome. With time, the environmental events themselves can produce withdrawal-like responses, just as the caretaker produced salivation in Pavlov's dogs.

Operant Conditioning.

About a decade after Pavlov's discovery of classical conditioning, another psychologist, B. F. Skinner, was developing his own theory of learning. Skinner observed that certain behaviors occur again and again. He also observed that behaviors with a high probability of occurrence were behaviors that produced effects on the environment. According to Skinner, behavior "operates" on the environment to produce an effect. Skinner called this process operant conditioning. For example, people work at their jobs because working produces a paycheck. In this situation, working is the response and a paycheck is the effect. In other situations, a person does something to avoid a certain effect. For example, by driving a car within the appropriate speed limit, traffic tickets are avoided and the probability of having a traffic accident is reduced. In this case, the response is driving at a given speed and the effect is avoiding a ticket or an accident.

If the effect that follows a given behavior increases the likelihood that the behavior will occur again, then that event is called a reinforcer. Food, water, and heat are common reinforcers. Drug administration is also a reinforcer. It is well known that animals will respond on a lever to receive intravenous injections of morphine, cocaine, and amphetamine, as well as a number of other drugs. Not all drugs are self-administered, however. For example, animals will respond to avoid the presentation of certain nonabused drugs such as the ANTIPSYCHOTICS (medications used in the treatment of schizophrenia). Because there is a good correlation between drugs that are self-administered by animals and those that are abused by people, the self-administration procedure is often used to examine drug-taking behavior.

In most operant conditioning experiments, animals perform a simple response such as a lever press or a key peck to receive food. Usually the organism has to make a fixed number of responses or to space responses according to some temporal pattern. The various ways of delivering a reinforcer are called schedules of reinforcement. Schedules of reinforcement produce very consistent and reliable patterns of responding. Moreover, they maintain behavior for long periods of time, are easily adapted for a number of different animals, and provide a very accurate measure of behavior. Thus, they provide a well-defined, operational measure of behavior, which is used to examine the behavioral effects of drugs.

Motivation, Learning, Memory, and Emotion.

One of the biggest challenges for behavioral scientists is to develop procedures for measuring drug effects on processes such as motivation, emotion, learning, or memory since these behaviors are very difficult to observe directly. Drugs certainly alter processes such as these. For example, many drugs relieve anxiety. Other drugs produce feelings of pleasure and well-being; still others interfere with memory processes. Given the complexity of devised procedures, they are not described in detail here; however, it is important to emphasize that the approach for examining the effects of drugs on these complex behaviors is the same as it is for any behavior: First, carefully define the behavior and describe the conditions under which it occurs. Second, give a drug and observe changes in the behavior. Third, take special care to consider pharmacological factors, such as how much drug is given, when the drug is given, or the number of times the drug is given. Fourth, consider behavioral factors, such as the nature of the behavior examined, the conditions under which the behavior is examined, as well as the individual's past experience with the behavior.

SUMMARY

To find out how drugs alter behavior, several factors are considered. These include the PHARMACOLOGY of the drug itself as well as an understanding of the behavior being examined. Indeed, the behavioral state of an organism, as well as the organism's past behavior and experience with a drug contribute as much to the final drug effect as do factors such as the dose of the drug and how long it lasts. Thus, the examination of drug effects on behavior requires a careful description of behavior with special attention to the way in which the behavior is measured. Behavioral studies also require a number of experimental controls, which assure that changes in behavior following drug administration are actually due to the drug itself and not the result of behavioral variability.

(SEE ALSO: Addiction: Concepts and Definitions; Aggression and Drugs; ; Pharmacodynamics; Psychomotor Effects of Alcohol and Drugs; Reinforcement; Research, Animal Model; Sensation and Perception and Effects of Drugs; Tolerance and Physical Dependence)

LINDA A. DYKSTRA

Measuring Effects of Drugs on Mood

Subjective effects are feelings, perceptions, and moods that are the personal experiences of an individual. They are not accessible to other observers for public validation and, thus, can only be obtained through reports from the individual. Subjective-effect measures are used to determine whether the drug is perceived and to determine the quantitative and qualitative characterization of what is experienced. Although subjective effects can be collected in the form of narrative descriptions, standardized questionnaires have greater experimental utility. For example, they may be used to collect the reports of individuals in a fashion that is meaningful to outside observers, can be combined across subjects, and can provide data that are reliable and replicable. The measurement of subjective effects through the use of questionnaires is scientifically useful for determining the pharmacologic properties of drugs—including time course, potency, abuse liability, side effects, and therapeutic utility. Many of the current methods used to measure subjective effects resulted from research aimed at reducing drug abuse.

HISTORY

Drug abuse and drug addiction are problems that are not new to contemporary society; they have a long-recorded history, dating back to ancient times. For centuries, various drugs including ALCOHOL, TOBACCO, MARIJUANA, HALLUCINOGENS, OPIUM, and COCAINE, have been available and used widely across many cultures. Throughout these times, humans have been interested in describing and communicating the subjective experiences that arise from drug administration. Although scientists have been interested in the study of PHARMACOLOGY for many centuries, reliable procedures were not developed to measure the subjective effects of drugs until recently.

Throughout the twentieth century, the U.S. GOVERNMENT has become increasingly concerned with the growing problem of drug abuse. To decrease the availability of drugs with significant ABUSE LIABILITY, the government has passed increasingly restrictive laws concerning the possession and sale of existing drugs and the development and marketing of new drugs. The pressing need to regulate drugs that have potential for misuse prompted the government to sponsor research for the development of scientific methodologies that would be useful in assessing the abuse liability of drugs.

Two laboratories that made major contributions to the development of subjective-effect measures were Henry Beecher and his colleagues at Harvard University and the government-operated Addiction Research Center (ARC) in Lexington, Kentucky. Beecher and his colleagues at Harvard conducted a lengthy series of well-designed studies that compared the subjective effects of various drugs—opiates, sedatives, and stimulants—in a variety of subject populations that included patients, substance abusers, and normal volunteers and highlighted the importance of studying the appropriate patient population. Additionally, this group laid the foundation for conducting studies with solid experimental designs, which include double-blind and placebo controls, randomized dosing, and characterization of dose-response relationships. Investigators at the ARC conducted fundamental studies of both the acute (immediate) and chronic (long-term) effects of drugs, as well as physical dependence and withdrawal symptoms (e.g., Himmelsbach's opiate withdrawal scale). A number of questionnaires and procedures now in use to study the subjective effects of drugs were developed, including the Addiction Research Center Inventory and the Single Dose Questionnaire. Although many of the tools and methods developed at the ARC are still in use, other laboratories have since modified and expanded subjective-effect measures and their applications.

MEASURES

Question Format.

Subjective-effects measures are usually presented in the form of groups of questions (questionnaires). These questions can be presented in a number of formats, the most frequently used of which are ordinal scales and visual analog scales. The ordinal scale is a scale of ranked values in which the ranks are assigned based upon the amount of the measured effect that is experienced by each individual. Subjects are usually asked to rate their response to a question on a 4- or 5-point scale (e.g., to rate the strength of the drug effect from 0 to 4, with 0=not at all; 1=a little; 2=moderately; 3=quite a bit; and 4=extremely). A visual-analog scale is a continuous scale presented as a line without tick marks or sometimes with tick marks to give some indication of gradations. A subject indicates the response by placing a mark on that line, according to a particular reference point; for example, lines are usually anchored at the ends with labels such as "not at all" and "extremely." Visual-analog scales can be unipolar (example: "tired," rated from no effect to extremely), or they may be bipolar (example: "tired/alert," with "extremely tired" at one end, "extremely alert" at the other, and "no effect" in the center). Another frequently used format is the binomial scale, usually in the form of yes/no or true/false responses, such as the Addiction Research Center Inventory. A fourth format utilizes a nominal scale, in which the response choices are categorical in nature and mutually exclusive of each other (e.g., drug class questionnaire).

Questionnaires.

Frequently used subjective-effect measures include investigator-generated scales, such as adjective-rating scales, and standardized questionnaires, such as the Profile of Mood States and the Addiction Research Center Inventory. A description of a number of questionnaires follows; however, this list is illustrative only and is not meant to be exhaustive.

Adjective Rating Scales.

These are questionnaires on which subjects rate a list of symptoms, describing how they feel or effects associated with drug ingestion. The questionaires can be presented to subjects with either visual-analog or ordinal scales. Items can be used singly or grouped into scales. Some adjective-type scales are designed to measure global effects, such as the strength of drug effects or the subject's liking of a drug, while other adjective rating scales are designed to measure specific drug-induced symptoms. In the latter use, the adjectives used may depend on the class of drugs being studied and their expected effects. For example, studies of amphetamine include items such as "stimulated" and "anxious," while studies of opioids include symptoms such as "itching" and "talkative." To study physical dependence, symptoms associated with drug withdrawal are used; for example, in studies of opioid withdrawal, subjects might rate "watery eyes," "chills," and "gooseflesh." Most adjective-rating scales have not been formally validated; investigators rely on external validity.

Profile of Mood States (POMS).

This questionnaire was developed to measure mood effects in psychiatric populations and for use in testing treatments for psychiatric conditions such as depression and anxiety. It is a form of an adjective-rating scale. This scale was developed by Douglas McNair, Ph.D., and has been modified several times. It exists in two forms—one consisting of sixty-five and another of seventy-two adjectives describing mood states that are rated on a five-point scale from "not at all" (0) to "extremely" (4). The item scores are weighted and grouped by factor analysis into a number of subscales, including tension-anxiety, depression-dejection, anger-hostility, vigor, fatigue, confusion-bewilderment, friendliness, and elation. This questionnaire has been used to measure acute drug effects, usually by comparing measures collected before and after drug administration. Its use in drug studies has not been formally validated; however, it has been validated by replication studies in normal and psychiatric populations and in treatment studies.

Single Dose Questionnaire.

This was developed in the 1960s at the ARC to quantify the subjective effects of opioids. It has been used extensively and has been modified over time. This questionnaire consists of four parts; (1) a question in which subjects are asked whether they feel a drug effect (a binomial yes/no scale); (2) a question in which subjects are asked to indicate which among a list of drugs or drug classes is most similar to the test drug (a nominal scale); (3) a list of symptoms (checked yes or no); and (4) a question asking subjects to rate how much they like the drug (presented as an ordinal scale). The list of drugs used in the questionnaire includes placebo, opiate, stimulant, marijuana, sedative, and other. Examples of symptoms listed are turning of stomach, skin itchy, relaxed, sleepy, and drunken. While this questionnaire has not been formally validated, it has been used widely to study opioids, and the results have been remarkably consistent over three decades.

Addiction Research Center Inventory (ARCI).

This is a true/false questionnaire containing more than 550 items. The ARCI was developed by researchers at the ARC to measure a broad range of physical, emotive, and subjective drug effects from diverse pharmacological classes. Subscales within the ARCI were developed to be sensitive to the acute effects of specific drugs or pharmacological classes (e.g., morphine, amphetamine, barbiturates, marijuana); feeling states (e.g., tired, excitement, drunk); the effects of chronic drug administration (Chronic Opiate Scale); and drug withdrawal (e.g., the Weak Opiate Withdrawal and Alcohol Withdrawal Scale). The ARCI subscales most frequently used in acute drug-effect studies are the Morphine-Benzedrine Group (MBG) to measure euphoria; the Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) to measure apathetic sedation; and the Lysergic Acid Diethylamide Group (LSDG) to measure dysphoria or somatic discomfort. The use of the MBG, PCAG, and LSDG scales has remained standard in most studies of abuse liability. Subscales on this questionnaire were developed empirically, followed by extensive validation studies.

Observer-rated Measures.

These may frequently accompany the collection of subjective effects and are often based on the subjective-effect questionnaires. Ratings are made by an observer who is present with the subject during the study, and items are limited to those drug effects that are observable. Observer-rated measures may include drug-induced behaviors (e.g., talking, scratching, activity levels, and impairment of motor function), as well as other drug signs such as redness of the eyes, flushing, and sweating. Observer-rated measures can be designed using any of the formats used in subject-rated measures. Examples of observer-rated questionnaires that have been used extensively are the Single Dose Questionnaire, which exists in an observer-rated version, and the Opiate Withdrawal Scale developed by Himmelsbach and his colleagues at the ARC.

USES OF SUBJECTIVE-EFFECT MEASURES

The methodology for assessing the subjective effects of drugs was developed, in large part, to characterize the abuse liability, the pharmacological properties, and the therapeutic utility of drugs. Abuse liability is the term for the likelihood that a drug will be used illicitly for nonmedical purposes. The assessment of the abuse-liability profile of a new drug has historically been studied by comparing it with a known drug, whose effects have been previously characterized. Drugs that produce euphoria are considered more likely to be abused than drugs that do not produce euphoria.

Subjective-effects measures may also be used to characterize the time course of a drug's action (such as time to drug onset, time to maximal or peak effect, and the duration of the drug effect). These procedures can provide information about the pharmacological properties of a particular drug, such as its drug class, whether it has AGONIST or ANTAGONIST effects, and its similarity to prototypic drugs within a given drug class. Subjective-response reports are also useful in assessing the efficacy (the ability of a drug to produce its desired effects), potency (amount or dose of a drug needed to produce that effect), and therapeutic utility of a new drug. Subjective reports provide information regarding the potency and efficacy of a new drug in comparison to available treatment agents. Subjective-effect measures may be useful in determining whether a drug produces side effects that are dangerous or intolerable to the patient. Drugs that produce unpleasant or dysphoric mood-altering effects may have limited therapeutic usefulness.

DESCRIPTION OF MAJOR FINDINGS OBTAINED WITH DIFFERENT DRUG CLASSES

Drugs of different pharmacological classes generally produce profiles of subjective effects that are unique to that class of drugs and that are recognizable to individuals. The subjective effects of major pharmacological classes have been characterized using the questionnaires described above. Table 1 lists some major pharmacological classes and their typical effects on various instruments. While global measures provide quantitative information regarding drug effects, they tend not to differentiate among different types of drugs. Nevertheless, the more specific subjective-effect measures, such as the ARCI and the Adjective Rating Scales, yield qualitative information that can differentiate among drug classes.

CONCLUSION

Measures of the subjective effects of drugs have been extremely useful in the study of pharmacology. Questionnaires have been developed that are sensitive to both the global effects and the specific effects of drugs; however, research is still underway to develop even more sensitive subjective-effect measures and new applications for their use.

(SEE ALSO: Abuse Liability of Drugs; Addiction: Concepts and Definitions; Causes of Substance Abuse; Drug Types)

KENZIE L. PRESTON

SHARON L. WALSH

Motivation

Motivation is a theoretical construct that refers to the neurobiological processes responsible for the initiation and selection of such goal-directed patterns of behavior as are appropriate to the physiological needs or psychological desires of the individual. Effort or vigor are terms used to describe the intensity of a specific pattern of motivated behavior. Physiological "drive" states, caused by imbalances in the body's homeostatic regulatory systems, are postulated to be major determinants of different motivational states. Deprivation produced by withholding food or water is used routinely in studies with experimental animals to establish prerequisite conditions in which nutrients or fluids can serve as positive reinforcers in both operant and classical conditioning procedures. In more natural conditions, the processes by which animals seek, find, and ingest food or fluids are divided into appetitive and consummatory phases. Appetitive behavior refers to the various patterns of behavior that are used to locate and bring the individual into direct contact with a biologically relevant stimulus such as water. Consummatory behavior describes the termination of approach behavior leading subsequently to ingestion of food, drinking of fluid, or copulation with a mate.

Incentive motivation

is the term applied to the most influential psychological theory that explains how the stimulus properties of biologically relevant stimuli, and the environmental stimuli associated with them, control specific patterns of appetitive behavior (Bolles, 1972). According to this theory, the initiation and selection of specific behaviors are triggered by external (incentive) stimuli that also guide the individual toward a primary natural incentive, such as food, fluid, or a mate. Drugs of abuse and electrical brain-stimulation reward can serve as artificial incentives. In a further refinement of this theory, Berridge and Valenstein (1991) defined incentive motivation as the final stage in a three-part process. The first phase involves the activation of neural substrates for pleasure, which in the second phase are associated with the object giving rise to these positive sensations and the environmental stimuli identified with the object. The critical third stage involves processes by which salience is attributed to subsequent perceptions of the natural incentive stimulus and the associated environmental cues. It is postulated that this attribution of "incentive salience" depends upon activation of the mesotelencephalic dopamine systems. The sensation of pleasure and the classical associative learning processes that mediate stages one and two respectively are subserved by different neural substrates.

In the context of drive states as the physiological substrates of motivation, the level of motivation is manipulated by deprivation schedules in which the subject is denied access mainly to food or water for fixed periods of time (e.g., twenty-two hours of food deprivation). An animal's increased motivation can be inferred from measures such as its running speed in a runway to obtain food reward. Under these conditions, speed is correlated with level of deprivation. Another measure of the motivational state of an animal is the amount of work expended for a given unit of food, water, or drug. Work here is defined as the number of lever presses per reinforcer. If one systematically obtains an increase in the number of presses, one can identify a specific ratio of responses per reward beyond which the animal is unwilling to work. This final ratio is called the break point. In the context of drug reinforcement, the break point in responding for COCAINE can be increased or decreased in a dose-dependent manner by dopamine agonists and antagonists respectively.

Appetitive behavior also can be measured directly in animal behavior studies either by an animal's latency (the time it takes) in approaching a source of food or water during presentation of a conditioned stimulus predictive of food, or simply by measuring the animal's latency approaching a food dispenser when given access to it. The fact that these appetitive behaviors are disrupted by dopamine antagonists has been interpreted as evidence of the role of mesotelencephalic dopamine pathways in incentive motivation.

In extending these ideas to the neural bases of drug addiction, Robinson and Berridge (1993) emphasized the role of sensitization, or enhanced behavioral responses to fixed doses of addictive drugs, that occurs after repeated intermittent drug treatment. Neurobiological evidence indicates that sensitization is directly related to neuroadaptations in the mesotelencephalic dopamine systems. As a result of these neural changes, a given dose of amphetamine, for example, causes enhanced levels of extracellular dopamine and an increase in the behavioral effects of the drug. Given the role proposed for the mesotelencephalic DOPAMINE systems in incentive salience, it is further conjectured that craving, or exaggerated desire for a specific object or its mental representation, is a direct result of drug-induced sensitization. In this manner, repeated self-administration of drugs of abuse, such as AMPHETAMINE, produce neural effects that set the stage for subsequent craving for repeated access to the drug.

(SEE ALSO: Brain Structures and Drugs; Causes of Substance Abuse; Research, Animal Model)

ANTHONY G. PHILLIPS