A complete understanding of brain–behavior relationships is limited in part by the voluntary ethical constraints investigators place upon experimentation on humans and nonhuman species. Most individual countries decide independently which experimental practices are acceptable for humans, for other vertebrates, and for invertebrate species. In general, the experimental methods acceptable for use on our species are fewer than those employed on our most closely related primate relatives. Thus, like most new treatments in medicine, a wide variety of nonhuman species have been used to develop and test treatments for human neurological or psychiatric disorders before they are tested on humans.

Although the human and the nonhuman brain have obvious differences with respect to language, the general brain organization across mammalian species is remarkably similar, and the functioning of basic neural circuits in nonhuman mammals appears to generalize to humans. Thus, neuroscientists use widely varying animal species to model human brain diseases as well as to infer typical human brain functioning.

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Two important issues surface in use of animal models to develop treatments for brain and behavioral disorders. The first is whether animals actually display neurological diseases in ways similar to humans. The second surrounds the ethics of using animals in research. We consider each separately.

Some disorders—stroke, for example—seem relatively easy to model in laboratory animals because it is possible to interrupt blood supply to a brain area and induce injury and consequent behavioral change. However, it is far more difficult to determine whether human behavioral disorders can actually be induced in laboratory animals. Consider attention-deficit/hyperactivity disorder (ADHD), a developmental disorder characterized by core behavioral symptoms: impulsivity, hyperactivity, and/or inattention. The most common issue for children with ADHD is problems at school. Lab animals such as rats and mice do not go to school, so how does one model ADHD in rodents?

ADHD has proved difficult to treat in children, and interest in developing an animal model is high. One way to proceed is to take advantage of the normal variance in the performance of rats on a variety of tests of working memory and cognitive functioning—tests that require attentional processes. The idea is that we can think of ADHD in people or in rats as one extreme on a spectrum of behaviors that are part of a normal distribution in the general population. Many studies show that treating rats with the dopaminergic agonist methylphenidate (Ritalin), a common treatment for children diagnosed with ADHD, actually improves the performance of rats that do poorly on tests requiring attentional processes.

One rat strain, the Kyoto SHR rat, has proved an especially good model for ADHD and is widely used in the lab. The strain presents known abnormalities in prefrontal dopaminergic innervation that correlate with behavioral abnormalities such as hyperactivity. Dopaminergic abnormalities are believed to be one underlying symptom of ADHD in children, as explained in Research Focus 7-4, Attention-Deficit/Hyperactivity Disorder. Methylphenidate can reverse behavioral abnormalities, both in children with ADHD and in the SHR rats.

Using nonhuman animals in scientific research has a long history, but only in the past half-century have ethical issues surrounding animal research gained considerable attention and laws been instituted. Just as the scientific community has established ethical standards for research on humans, it has also developed regulations governing experimentation on animals. The governments of most developed nations regulate the use of animals in research; most states and provinces have additional legislation. Universities and other organizations engaged in research have their own rules governing animal use, as do professional societies of scientists and the journals in which they publish.

Here are four principles, used as guidelines in Canada, for reviewing experimental and teaching protocols that will use animals:

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Legislation concerning the care and use of laboratory animals in the United States is set forth in the Animal Welfare Act, which includes laws passed by Congress in 1966, 1970, 1976, and 1985. Legislation in other countries is similar and in some European countries much stricter. The U.S. act covers mammals, including rats, mice, cats, dogs, primates, and birds, but it excludes farm animals that are not used in research. The U.S. Department of Agriculture (USDA) administers the Act through inspectors in the Animal Care section of the Animal and Plant Health Inspection Service.

In addition, the Office of Human Research Protections of the National Institutes of Health (NIH) administers the Health Research Extension Act (passed in 1986). The act covers all animal uses conducted or supported by the U.S. Public Health Service and applies to any live vertebrate animal used in research, training, or testing. The Act requires that each institution provide acceptable assurance that it meets all minimum regulations and conforms with The Guide for the Care and Use of Laboratory Animals (National Research Council, 2011) before conducting any activity that includes animals. The typical method for demonstrating conformance with the Guide is to seek voluntary accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care International.

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All accredited U.S. and Canadian universities that receive government grant support are required to provide adequate treatment for all vertebrate animals. Reviews and specific protocols for vertebrates, including fish, amphibians, reptiles, birds, and mammals, to be used in research, teaching, or testing are administered through the same process. Anyone using animals in a U.S. or Canadian university submits a protocol to the university’s institutional animal care and use committee, composed of researchers, veterinarians, people who have some knowledge of science, and laypeople from the university and the community.

Companies that use animals for research are not required to follow this process. In effect, however, if they do not, they will be unable to publish the results of their research, because journals require that research conform to national guidelines on animal care. In addition, discoveries made using animals are not recognized by government agencies that approve drugs for clinical trials with humans if they do not follow the prescribed process. Companies therefore use Good Laboratory Practice (GLP) standards, which are as rigorous as those used by government agencies.

Regulations specify that researchers consider alternatives to procedures that may cause more than momentary or slight pain or distress to animals. Most of the attention on alternatives has focused on the use of animals in testing and stems from high public awareness of some tests for pharmacological compounds, especially toxic compounds. In the United States, the National Institute of Environmental Health Sciences now regulates testing of such compounds.

In spite of the legislation related to animal use, considerable controversy remains over using animals in scientific research. At the extremes, people on one side approve any usage and people on the other side disapprove of using animals for any form of research. Most fall somewhere in between. The debate centers on issues of philosophy, law, morals, custom, and biology.

Because researchers in many branches of science experiment with animals to understand the functions of the human and nonhuman body, brain, and behavior, the issues in this debate are important to them. Because human and veterinary medicine benefit from this research, as well as do people and other animals with diseases or damage of the nervous system, this debate is important. Because many people are philosophically opposed to using animals for work or food, this debate is important to them. And because you, as a student, encounter many experiments on animals in this book, these issues are important to you as well.

Using Animals in Brain–Behavior Research

Before you continue, check your understanding.

Question 1

Question 2

Question 3

Question 4

Answers appear in the Self Test section of the book.