Drug Testing in Animals: Studying Potential for Abuse

One of the questions that scientists must ask as they develop new drugs to treat various diseases is whether or not the new prescription drug is likely to be abused or used for the wrong reasons because of the effect it has on users. The likelihood that a drug will be abused by a patient must be carefully weighed against the benefit provided by the drug. Researchers must identify any and all reinforcing effects a drug may have that could lead to future abuse. In the past, researchers made predictions about the likelihood of abuse by observing humans who used the drugs, and sometimes by conducting experiments with these users. Increasingly, experiments with animals are replacing this method.

Research conducted since the early 1960s has shown that animals such as monkeys and rats will, with very few exceptions, repeatedly give themselves (self-administer) the same drugs that human beings are likely to abuse. Test animals do not self-administer drugs that human beings do not abuse.

Research based on animal testing is conducted in a slightly different manner and often requires laboratory procedures not needed for research using human test subjects. Test animals must be given a way to self-administer the drug. Since animals frequently are not physically able to give themselves a drug in the same way a human would, alternate methods must be used. Animals may be taught to push levers or do similar actions in order to get a dose of a drug. The results of these drug self-administration studies in animals play a critical role in predicting whether a new drug for humans is likely to be abused.

Substitution Procedure

The risk that a drug will be abused is often evaluated by what has been termed a "substitution procedure." Such research begins by giving an animal a known drug, which is then substituted with a new drug under investigation. The first phase in the substitution procedure is designed to establish a baseline or a measure of how much effort an animal is willing to make to obtain a dose of the drug. Each day an animal is allowed to give itself a drug of known potential for abuse. The researcher notes how frequently the animal takes a dose and how much effort the animal is willing to make to get a dose of the drug. The researcher can make a lever harder to push, make the animal push it repeatedly, or make the animal follow a complicated set of actions to get a dose. This provides a point of comparison against which the effects of the new drug that will be studied.

Step two in the substitution procedure begins once intake of the known drug, such as cocaine, is stable. In other words, the animal has taken about the same dosage of cocaine for several days. In step two, the liquid in which the known drug was dissolved is substituted for the baseline drug for several consecutive sessions. Since this liquid is usually neutral, with no positive or negative effects, the animal gives itself fewer and fewer injections until it hardly bothers pushing the lever at all. At the end of step two, the animal is briefly returned to baseline conditions.

At this point the animal is ready for step three: the substitution period. In this phase, a dose of the new test drug is made available. This continues for at least as many sessions as are required for the animal to stop pushing the lever to get the neutral liquid. This process is repeated with different concentrations of the new drug until the experimenter has tested a range of possible doses of the new medicine.

The rates at which the animal gives itself the test drug, neutral liquid, and known addictive drug are then compared. If the animal prefers the new drug to the neutral liquid, the new drug is said to have potential for "abuse liability." In other words, the new substance reinforces the desire for itself and will likely cause addiction .

Such substitution procedures provide information that indicates whether or not a drug is likely to be abused. The substitution procedure does not allow a comparative estimate as to whether or not a new drug is more addictive or less addictive than other known drugs. These procedures measure how frequently the animal gives itself a dose, a measure that reflects both the direct effects of the drug and the effects of the drug's reinforcement of the desire for itself.

Reinforcing Efficacy

Another method must be used to measure the reinforcing effect of a drug separately from its other effects. To compare drugs, it is useful to know how big the maximum reinforcing effect is—termed its "reinforcing efficacy." Several procedures have been developed to measure reinforcing efficacy. Most tests either allow an animal to choose between the new drug and another drug or nondrug reinforcer. This kind of test is known as a choice procedure. In addition, some tests, called progressive-ratio procedures, measure how hard an animal will work to obtain an injection.

In choice procedures, the measure of reinforcing efficacy is how often the new drug is chosen in preference to the other drug (or non- drug). In progressive-ratio procedures, the number of times the animal must push the lever in order to get a drug injection is increased until the animal no longer bothers to push the lever. At some point the animal determines that it is not worth the extra effort to get another dose. This point is called the "break point" and is a measure of the reinforcing efficacy of the drug.

The fact that animals choose a higher dose of a drug when given a choice between different strengths of the same drug is evidence that these procedures are a valid way to measure reinforcing efficacy. In addition, break points are higher in progressive-ratio experiments involving higher stable doses and lower for experiments involving lower doses. Results of both the choice and the progressive-ratio procedures in animal research are consistent with what is known about the abuse of drugs in human beings. Drugs such as cocaine, a highly preferred drug in choice studies, maintain higher break points in progressive-ratio studies than other drugs, and are frequently abused.

These experiments show how animals discriminate among drugs, and the extent to which they prefer certain drugs over others. The results may be used to predict potential subjective effects in human beings. Since subjective effects play a major role in drug abuse, such experiments are an important tool used to evaluate whether a new drug is likely to be abused. A new drug with subjective effects similar to those of a known, addictive, and often abused drug such as heroin is likely to be abused itself. Additionally, drug-discrimination experiments identify the potential for abuse, as well as provide important information that allows researchers to classify new drugs based on their predicted subjective effects. This cannot be done from drug self-administration experiments. Thus, drug discrimination provides additional information relevant to help compare a new drug to a known addictive drug. For example, a monkey shows a similar discrimination pattern using a new drug as it has shown previously using a known drug such as cocaine. This new drug is likely to be abused and to have subjective effects similar to those produced by cocaine.

If the researchers believe at this point there is a possible thera- peutic use of the drug for humans, they would have to test the drugs on humans. In other words, the above drug testing on animals represent only one part of a longer and more involved process for testing drugs.

Ethical Issues in Animal Testing

Some animal rights advocates object to the use of animals in drug testing and other scientific research. Most of those who oppose animal experimentation on ethical grounds believe that it is morally wrong to harm one species for the supposed benefit of another. However, most research scientists believe that the benefits of animal testing are too great to ignore. The American Psychological Association's Committee on Animal Research and Ethics (CARE) has developed and published a document, "Guidelines for Ethical Conduct in the Care and Use of Animals." The guidelines state that animal research should be adequately justified; personnel should be carefully trained to follow the guidelines; care and housing of animals should be reasonable and humane; animals should be acquired lawfully and as humanely as possible; experimental design should minimize animal discomfort whenever possible; and animals should be treated humanely after the research is concluded. Researchers who do not follow these guidelines will fail to get published in respected psychological or medical journals. This means that the data from the experiments will be essentially ignored and useless. For this reason almost all researchers follow these or similar guidelines.

Conclusion

Researchers have improved methods for predicting whether or not a new drug will be abused. Using animals in substitution, choice, and progressive-ratio procedures has greatly helped researchers understand the factors involved in determining the probability that a new drug or chemical compound will be abused. Current research techniques allow the evaluation of likely preference and the reinforcing efficacy of a new compound based on experiments with animals such as monkeys and rats. This information is then used to reliably predict whether a drug is likely to be abused and to which known drugs it is likely to be similar, both in terms of how addictive it is and what its subjective effects will be. Such information is clearly valuable in deciding how much to restrict a new drug and is a critical tool in the effort to reduce the abuse of therapeutic drugs.

see also Drug Testing in Humans: Studying Potential for Abuse; Research.